Category Archives: Medications

by | August 1, 2012 · 3:43 am

Systemic Targeted Therapy for metastatic RCC in 2012

Dr. Eric Jonasch of MD Anderson Cancer Center gave the following talk at a KCA patient conference in April 2012.  “Systemic Targeted Therapies” include a group of drugs, all approved by the FDA in .  the last six years.  These drugs mark a critical breakthrough in providing more options for kidney cancer patients, and their use and complete integration into treatment is still ongoing.

(Where good slides were available, they were used; those which were hard to read have been recreated.)

I am going to talk as systemic targeted therapy for Metastatic Renal Cell Cancer, how we are using it, and the science about it, and how that leads us to new ideas, moving forward.  When we talk about kidney cancer, we cannot talk about just one disease type.  What I am going to talk about mainly is clear cell, and Dr. Tannir, my friend and colleague, is going to talk about the non-clear cell subtypes.

So what is ccRCC?  It is essentially a cancer that looks like this under a microscope, and it was called this, back in the day.  We more recently found that it has a mutation in the VHL gene (Von Hippel Lindau) in the vast majority of individuals with and I also run a clinic where I try to marry the information we have about hereditary kidney cancer with non-hereditary kidney cancer to improved therapies.

This is not to scale; it is 213 amino acids long and for the scientists in the audience, that is mercifully short, and it also has three exons in or three parts, or easier to study than most, but obviously still hard to study.

It essentially regulates how the cell reacts to oxygen.  Obviously, oxygen is our life’s blood, we need oxygen, we need water, we need glucose.  And our cells, if they feel like they need oxygen, they basically sit back and VHL will then take the transcription factor, which tells the cell which protein to generate, and then it breaks it down.  If you have low oxygen state, then the cell will say, “Help, I need oxygen” and the VHL will step back,  the transcription factors, HIF alpha and HIF beta are going to come together and you will get production of proteins, like VEGF which is a growth factor for blood vessels and some other things.  If you have a mutation or something how an inactivation of the VHL gene, you have essentially an ongoing process of these cells, now cancerous, saying—somewhat untruthfully—we need more oxygen, we need more blood, build me an infrastructure.

That infrastructure is as follows:  When we think of cancer we can’t think of cancer cells. The cancer cells are in black on slide and in blue are the stromal cells–the “glue” cells, and above those the endothelial cells or blood vessel cells.  This triumvirate plus other cells generate an organ—and it really is an organ—that we call cancer.  And when we use therapies, we are blocking specific areas there.

I’ll tell you a bit about the therapies we use now and that some of you are on, and what they are actually blocking.

Here is some terminology you are about to hear, some jargon, as we talk about trials.

Progression free survival (PFS)—time it takes for cancer to start growing again

Overall Survival (OS)—time it takes from start of treatment to passing of patients

So the “blood vessel starving” are the antiangiogentic therapies we currently have are listed here, and I am going to go through each of these in details.

Antiagiogentic Agents FDA Approved

1. Sunitinib  (Sutent)

2. Pazopanib (Votrient)

3.  Bevacizumab- IFN (Avastin + Interferon)

4.  Sorafenib (Nexavar)

5.  Axitinib (Inlyta)

mTOR Inhibitors   Mammalian Target of Rapamyin Inhibitors

6.  Temsirolimus (Torisel)

7.  Everolimus (Afinitor)

We also have some up and coming drugs.  And the way these drugs work with graphic shown again—is they block the blood vessels. They try to kill the blood vessels that feed the cancer.  They don’t seem to have much effect on the cancer itself.  That is why you have encountered resistance. That we can shrink this down, this cancer, but we can’t make it go away.  And what we need, and on our wish list, are kidney cancer cell-killing therapies for the future.

mTOR Inhibitors

The mTOR inhibitors, of which there are two, Torisel and Afinitor ( Temsirolimus and Everolimus).  What they do; they are actually working inside the cell perhaps both in the cancer cell and the  blood vessel cell.  And they are blocking particular proteins that seem to be up regulated, overexcited, that give them a selective growth advantage.

There we have on the bottom, kind of a brown color, mTOR, which if up regulated, results in production of and more survival advantage… for the cancer cells—which is shouldn’t have.  What Torisel and Afinitor is block that signal.

So let’s talk about the drugs that in 2012 were currently using.  The one that is probably most commonly used is Sutent or Sunitinib.  It this is a pill and what is does the block those blood vessel cells.  It doesn’t seem to block the cancer cells that much.  It’s given officially 4 weeks on, 2 weeks off, although I don’t remember the last time I prescribed that way for anyone.  I tend to start 2 weeks on, 1 week off as I find people tolerate it better that way, and its FDA-approved now since January of 2006, amazingly, a long time ago.  But it is pretty amazing that we have some people who are still on it, starting in January of 2006. 

The reason this drug was approved, it was compared to the old standard of Interferon. What we found saw was a prolongation of Progression Free survival, the time it took for the cancer to progress.  And this was doubled to 11 months from five months, with Interferon, which some of you might remember as shot you give under the skin, three times a week.  And the top line is where the individual were progressing, where they were on Sutent, and the lower line is where people were progressing on Interferon.

This is what is now call the Overall Survival curves, so essentially what we have here on the bottom is TIME, and the top lines the individuals that are still alive, and what we see on the top line are those on Sutent, and the lower line those on Interferon.  It may not look like a huge gap, but what has happened on these research studies, when we do them, is what we call “cross-over”.  When you progress on one of the drugs, you get to another and another and another.  And the good news about this, it that it raises up the survival expectations to some degree, but it makes it hard to say, “That one drug is the one that is really making the difference.”  Until we actually get therapies that consistently and reliably cure kidney cancer, we will still  have this dilemma of having incremental benefits, but, “Hey, we’ll take them!”

Another drug which has come out and has been used since 2009 is Pazopanib or Votrient.  It’s an oral drug, given daily, once a day.  Same sort of thing, a blood vessel blocking agent.

This was tested in a slightly interesting as you have study where you had no therapy before, or you had immune therapy, and they were randomized, randomly allocated between the Votrient (Pazopanib) or placebo.  I have to say that most of the people were enrolled in non-US sites because it is a little bit of a hard-sell for people, if you have not had any therapy before to be told we’re going to put you on placebo, maybe.

Nevertheless, the trial was accrued to and it demonstrated a very significant progression free survival, the time to progression of the disease for the individuals on the Votrient compared to those on the placebo.  And what we see on the left hand side here, we see one of these showing the charts, with the orange line on top is the group (with Votrient, )people who remained free of progression over time, and the lower line, the people on placebo. And the progression free survival data for the people who had not been on prior therapy was as good as we had seen with Sutent.

We had a trial that is currently completed and is being analyzed to see if Sutent is better than Votrient, and we still don’t know which is “better”, but Votrient is certainly gaining traction because of the fact that it looks kind of promising.

Now its interesting when they did Overall Survival analysis, they did not succeed in showing a big difference, because as lot of people had gotten onto Votrient when they were on placebo at the beginning, and they got onto all sorts of other drugs.

So the next drug we are going to talk about is a little different (Avastin).  What Avastin is –it’s an injectible antibody against the thing the cancer produces, the VEGF circulating in the circulation.  It tries to take it out of circulation, so the blood vessel cells can’t see  it.  It’s given every two weeks, by injection, and officially given with interferon three times a week, so a little less attractive for some people.

This is a bit messy to read; the progression free survival in combination with interferon is substantially better than interferon alone, and this was done to two different studies and the data were true in both these big studies.

Thus we’re pretty confident, that along with Sutent, and Votrient, this prolongs progression free survival.

In terms of overall survival, 21 month for the interferon group, and next to it the interferon and Bevacizumab, 23 months.  Again, in the same ball park as we were seeing with Votrient and Sutent, and not a statistically different figure.  That statisticians take these numbers and crunch them and take p values and such, but still there was a lot of cross over data, and clearly, we are moving up the bar here.

One of my favorite data pieces is from the Sutent study. The patients on that Sutent study who had received Sutent or interferon were treated in countries where there was no opportunity for second line therapies or 3rd.  All they got was Sutent or interferon.  And the people who were on the sutent arm only, and nothing else, had a 28 month survival, and the people who received interferon only, had a 14 month survival.  So that’s an untarnished bit of data, showing the magnitude of benefit that they were receiving.  That is more reflective of what we are seeing in our clinics today.

I wont’ go into this in detail, but bottom line is that. There’s a lot of number and you are probably getting numbered out.  Bottom line we look at historical data compared to these people who are on these drugs and then get subsequent drugs, and we are seeing survival in the two to three to four years.Also known as Nexavar

The next drug we are going to discuss is Nexavar, which was approved in 2005, the first of these drugs to be approved.  Same deal, the blood vessel starving drug, given twice a day, orally.

It was given initially to people who had not been given any targeted therapies before, but had progressed on immunotherapy  and it demonstrated that there was an improvement in progression free survival again. 

If you looked at Overall Survival there was improvement if you took out those people who crossed over.  So again, modest improvements and definitely doing something for patients.

Now when this drug was compared directly to the untreated patient group to interferon, what was happening, was that it did not look like it was better than interferon alone. I just finished telling you that Sutent, Avastin, Votrient all beat interferon, and here we have a drug, that seemingly, didn’t.  Subsequent studies were done which shows that PFS is somewhat better than this trial, but in reality in 2012, this drug is not much used in front-line therapy, for better or worse.  It’s not that commonly used, and personally don’t use it much, based on these data.

What I have been talking about now, has been about individuals who have clear cell RCC, good risk features, and these are features looking at “are you anemic?, is your calcium elevated?, are you feeling and so on.”  These are risk features to decide if a patient is in a good or intermediate risk category versus a not so good category.

 

And Torisel, an mTor inhibitor, which I talked about before, and was tested in this poorer risk population of patients, and was approved in 2007.  Essentially, they took patients who had not had any prior therapies, and they checked off boxes. Do you have a low performance status?, your “good feelingness”, have you had your kidney removed before or not?, have you had anemia?, have you had high calcium?, have you had high LDH?, six categories in all.  If you had at least three of those negative categories, they said, “OK, we’re going to put you on Torisel, and compare you with interferon and with Torisel and interferon in combinations.” And because they know this group of individuals tends to have a lower overall survival, they did an overall survival study.

 

It is a bit difficult to see in the background, but bottom line, that this was the first drug that showed in poor risk patients, that it improved overall survival, compared to interferon.  Does that mean Torisel is good for people who  have good risk features? Those who don’t have overall poor risk factors?  Unfortunately, we don’t have an answer to that since that study has not been done.  But this drug was approved, and we know that Torisel seems to provide benefit for patients with the poorest features.

SLIDE MAY BE MISSING

Does that mean that Torisel shouldn’t be used in a second line treatment where people have clear cell?  No, it doesn’t.  It simply means that those are the data that we have, and in the second, and third and fourth line setting—except for the data I am now going to present—we just have to figure out. “You’ve been on this, we’ve tried that, now let’s try this.”  There’s a certain amount of art to it, as well as science.Also known as Afinitor

Afinitor was approved in 2009 for individual who had received either sutent, sorafenbit or both.  This was a study that asked, “Have you progressed on Sutent or Nexavar?”

If yes, you were entered into the trial, randomized,ie the computer flipped a coin so that you went into the Afinitor or placebo, and we asked, “What was the progression free survival?”

This was clearly better in terms of progression free survival. And that’s why the drug was approved, and it is one of the most commonly used drugs in the second or third line for patients with metastatic kidney cancer.

The new kid on the block is Axitinib or Inlyta, in the second line setting.  Dr. Brian Rini presented these data last year, looking at this, another blood-vessel starving drug.  It’s the next generation, it’s more highly engineered to block more of the VEGF pathways, and it does less of the other stuff, which in some ways might be better, but you might want to have some “playing the field” in terms of stopping things in comparison of blocking one thing.  So what did this data show?

This is the study.  People had previously received one of these prior drugs, Sunitinib, Bevacizumab, interferon, Temsirolimus or Cytokine, and then they looked at the progression free survival.

The progression free survival was longer in the Inlyta(Axitinib) group compared to the Nexavar (Sorafenib), about 6.7 months versus 4.7 months. 

What was interesting, was this was a group of individual who had receive either these targeted drugs before or immune therapy, and it shows it nicely in table form, but what it shows is that if you had received prior immune therapy, the Axitinib or Inlyta was way better than the Nexavar.  If you had received prior targeted therapy, in the same class as Inlyta, then the differences were not that great.  Then it’s better, the Nexavar is better in people previously treated with Sutent, for example, but its not incredibly better, but it’s a clean drug, and it’s very welcome addition to the drugs we have available.  So we are using it and getting good results.

Up and comers.  For the last few minutes we will show Tivozanib, another one of these blood vessel starving drugs.  So we have 1,2,3,4,5, and now six of the same class, and like other classes of drugs, it is always good to have gradual improvement.  It is in a pill form, same sort of thing, blocking VEGF pathways.  There were some combinations, a phase III trial, showing that it does actually do better than Nexavar it was compared to, and is coming down the pipeline, probably an approved drug in the next year.

It is interesting that with all of these drugs, that the newer the drug, the lower the side effect profile as they are getting better and better at engineering these drugs, so at least we are getting a better drug in this class arena.  But it is not dramatically better, and we need something better.

Combinations and Sequences

 So what about combinations?  In oncology, we like to do this, combine drugs.  If you have drug A and that works and you have drug B and that works, then let’s combine it and hope we get a duplicative effect, and additive effect.  Hasn’t really happened unfortunately.

Bottom line.  Combinations at that time have not really consistently been shown to be superior to single agents. You get more side effects and you don’t get more bang for the buck in terms of survival or progression.  Sequencing is really what we do, meaning you start with drug A and move to drug B, you move on to drug C.  That’s what we do in the clinic.  One of the trials that Dr. Tannir has championed is the START trial and we have 80-90 patients on this.

We re looking at, if you start with Nexavar or Votrient or Avastin,  and you get randomized to one of the remaining drugs, does that provide you better benefit?

And there are other trials ongoing like that, the SWITCH trial, for example, going on in Europe, starting with Nexavar, then going to Sutent, or starting with Sutent and going on to Nexavar.

Or the RECORD 3 trial, with Afinitor followed by Sutent, or Sutent followed by Afinitor. We’re trying to figure out whether that works better for some patients than others.

This is a big table put up my former mentor Dr. Michael Atkins, a form thereof in 2006, and its been a gradually refined over the years.  Bottom line is we have favorite drugs for untreated patients in the first line setting.  We talked about immunotherapy before lunch, with Dr. McDermott talked about interleukin 2 and others, we have our blood vessel-starving drugs for that category as well.  People with poor risk features, we have Torisel.

In the second line setting we now have good data from these trials that show that Afinitor and Axitinib probably provide benefit after failing these other drugs, and we have ongoing studies to try to determine whether or not one sequence is better than another. All this is nice, and we’re making real strides, but what do we really need to do?

Coming back to the picture of the cancer, we are good at hitting the red part, (the blood vessel structure), but why, when they get used, are we getting resistance after 10-12 months or so.  Why can’t we kill the cancer cells?

We need new drugs that can block other receptors in those blood vessels cells.  We need agents that can actually fix, look under the hood of the cancer cell, see what is misbehaving there, fiddle with it, and make it act more like a normal cell.  If we can’t do that, kill the cancer cell.  Agents that can actually block novel targets in the blood vessels, so we are looking at new receptors on there, and seeing if those drugs, in combinations with other drugs, can starve the blood vessels, are useful.

I am part of a nano-medicine grant, where the hypothesis is that, the big idea, is that a lot of the VHL proteins are mutated, are kind of wounded, but not dead.  If we can revive them, maybe they can make the cancer cell behave more normally.  One of the ways to do that, to raise the level of VHL, is with a drug called Carfilzomib to validate that.

MET Inhibitors

The last thing is those agents that can actually kill the cancer.  This is amazingly, in 2012, still in the experimental stages. We have a colleague in Stanford, Imato Jatia(?) who has done some of these screens, some people at Harvard, all around the country, and we as well, looking at this strategy, where the cell kills itself.  We have go to perhaps stop focusing as much as getting as yet another blood vessel-starving pill.  An example of one of these drugs that might do this, is a MET inhibitor.  So, a MET is another protein that is found on the surface of the Cancer cell.  There were some reports at ASCO that this might a promising avenue.

So in summary, we are getting really good at blocking VEGF pathway, we’ve made real inroad in Overall Survival.  MTOR inhibitors are doing a good job; we kind of know where to use these, but we are getting better at it.  We have got to figure out why resistance occurs, and do something about it.  Participation in clinical trials is key.  We need to find drugs that kill the cancer cell directly.

QED

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Filed under RCC Basics, Targeted Therapies, Your Role

by | July 29, 2012 · 8:12 pm

T’was Beauty (or at least vanity) Killed the Beast

Being vain, and getting ever aware of the famous ravages of time around my eyes, I was thrilled to talk to a cosmetic surgeon about an eye lift.  The magazine ads tout the life-changing benefits of an eyelift, but I never envisioned the tumor in my kidney as a bonus.

Most people get a blood test, and read the reports with a frown, as the abbreviations and terms are pretty arcane.  An asterisk or two alerts the reader–rarely the patient–to values that are out of normal range.  Oddly, my hemoglobin, the red blood cell count was about half of normal, a 6.8 with a normal range for women about 12-14.  “Had to be a false reading,” said the doctor, and I agreed. I was always healthy, so one more lab test is in order.  Anxious to be beautiful and on the way to a concert, I was thrilled when the doctor phoned with the new results–until I heard them.  The hemoglobin was 6.6, and the doctor told me to go to the hospital.

“When? Right now? Why should I do that?” I questioned the doctor.

“Well, if you get into an accident, you’ll bleed out.”  Pretty compelling reason,  so I drove very carefully to my nice suburban Emergency Room, basically annoyed and bewildered.

I was admitted, had my poop checked for internal blood loss, and was given three units of blood.  Somehow this became more serious, when they pump blood into your arm, and come back and do it again.  All for a little eyelid surgery that I could certainly put off!

Halfway through the first pint of blood, I trailed my IV of blood into the bathroom and looked in the mirror.  So odd that my lipstick was still on after all those hours, when it never lasted that long…and then I realized that my lips were reddish again, not really needing lipstick, now that I had a bit of blood in me.  And still I did not realize how serious this was.

A colonoscopy and an endoscopy (an “upper and a downer” ) checked out my innards, with the finding of a “tiny, scabbed-over ulcer”.  Aha! Nothing to worry about after all.  I was sent home with iron pills, a promise to eat lots of red meat and dark green vegetables, and to come back in three months to show off.  But still no eye surgery.  Despite the blood, I was still officially seriously anemic.  But I suddenly had no periods, so that was good; world’s most efficient menopause.  Who could complain?

For nearly eight months I had blood tests, iron pills, more endoscopies but no more ulcer, more iron pills, and finally iron shots–black bruises of noteworthy sizes–don’t ask where.  Then a test of my entire gut, weight loss despite the good diet, incredible night sweats but no periods, and an increasingly haggard look.  Finally the doctor (number two in his class!) quietly decided that I must be a drinker, and sent  me to get an ultra sound of my liver for a biopsy. This was to “confirm the diagnosis of cirrhosis”, a condition never discussed with me, and despite my once a week wine-with-dinner history.

A cheerful ultrasound technician chatted with me as she swept the wand to the left for my liver and to the right for…sudden silence and a frown.  Instantly I knew something was wrong.

“What do you see? Is it my kidney?”  No answer.  “What have you found?” No answer, but a murmured, “One minute”, and she left the room.

This was the “Oh, s..t” moment.  It’s obvious that there is a tumor somewhere, but being the patient, I get no information.  My first reminder of my place in the food chain.

“You are going to get a CT scan; we’ll fit you in today. Leave your gown on.”

“What have you found?”  Silence.

Back to the cold waiting room in my “gown”.  Thought gowns were to be reserved for galas and balls, but this wasn’t it.  Within four hours I was in a CT machine and behind glass walls, two men (doctors?) were pointing at a screen out of my view, gesturing and nodding.

“What have you found?  Its pretty obvious there is something.  Is it on my kidney?”

“Your doctor will talk to you when he can.”  Translation: you have cancer, and we’re not going to tell you anything.

Hours later, and after many phone calls to the doctor, he finally called back.  “You have a mass on your kidney; it will probably have to come out.  I’ll find someone to refer you to in the area.”  Translation:  Welcome to cancer.  Guess it’s not a tiny, scabbed-over ulcer.  Now find somebody else.

On to the internet, reading about kidney cancer.  Stats; 38,000 new cases a year in the US, and 13,000 a year die of it.  Decent odds if they can find it early and take it out. Glad mine was found so soon.  Really pretty grim odds if it is large and has metastasized.  Efficient thing, kidney cancer.

With urgency, I check out the website of new doctor. No mention of kidney cancer at all, and he’s my new expert?  This is the recommendation from a guy who treated me for eight months for an ulcer.

Dr. Newdoctor’s receptionist won’t tell me if “doctor” treats kidney cancer.  I can ask “doctor” about it three weeks or so.  Translation:  We don’t care that you might have cancer.

But I am from North Dakota and grew up in a town without a doctor.  If you really got sick, you went to Bismarck, and if you were really, really sick, you went to Mayo.  I went to Mayo.

Five days after my ultrasound, I sat with Dr. Brad Leibovich, a doctor recommended for his surgical expertise and kidney cancer research.  Over the weekend, I had read about laporascopic surgery, where the surgeon makes little holes in my belly, his tiny scissors nip out the neat little ball, which he puts in a clever baggie (no ziplock?), and drags out into the light.  I plan to stomp on it. That’s the kind of surgery I want, simple, clean and efficient, so I can go back to normal.

But Dr. Formerdoctor (his name upon quiet request) failed to tell me that my tumor was the size of a decent orange. No nip and bag operation for me!  He failed to tell me that the CT scan showed the lower lobes of my lungs full of tiny dots of cancer.  A more complete scan showed “too many mets to count, with several of measurable size”.  No longer one of 38,000 new kidney cancer patients, I was suddenly one of the 13,000.  Maybe I would last until next year.  Maybe not.

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Filed under About Peggy, Biological Systemic, Immune Therapies Old & New

by | July 25, 2012 · 7:26 pm

Programmed Death-1–My Death Wish for Cancer–and Clinical Trials

PD-1—Programmed Death and Clinical Trials

 Even doctors need to study this stuff! Doctors are offered online study modules, and recently the topic of “immunotherapies” was offered.  This module explains the PD-1 antibodies and related BMS-936558 clinical trials, which is of interest to kidney cancer patients.  Since I am not trained medically, so this is my perspective as a patient only. Perhaps this  will start a discussion with you and your doctor, andupdate you about immune therapies and PD-1 studies.  Your corrections and comments are requested.

May I remind readers that the body’s immune response is a series of signals and responses, organized so that normal cells can grow and infections can be controlled without an overreaction of the immune system. But the immune system is not perfectly equipped to handle the mutations that characterize cancer, so when these signals get interrupted, or are not received properly, cell development goes wrong.

The FDA recently approved ipilumumab, an anti-body which has benefit in fighting prostate cancer, as it blocks a molecule called CTLA-4.  That is one of severalimmune checkpoints, and is one of the “call and response” pairs that is active in cancer and chronic infectious diseases.  Another of these immune checkpoints is PD-1 (programmed death-1), which arises early in the process of T-cell (fighter cell) exhaustion.  It binds with a molecule called ligand (think ligature as to meaning), PD-L1.  This will appear on the surface of a tumor cell, and may be a measurable signal that the interaction of the PD-1 and its ligand, PD-L1 are suppressing the natural anti-tumor immune response.  This interference with the natural immune response permits the cancer cells to grow more easily. Thus the goal of the research will be to interrupt this binding.  Theoretically, that will make the ongoing immune response more effective.

This theory is being tested and contested, as there seems to be another response in melanoma. Since both kidney cancer and melanoma have some immunogenic qualities in common, what happens in melanoma research is of interest to RCC researchers.

Researchers have developed molecules that block the PD-1/PD-L1 interaction; one of these molecules is the BMS-936558 from Bristol Meyers Squibb which is also referred to as MDX-1106.  A phase I trial which tests safety and with increasing doses, showed benign toxicity. That led to an expansion of the trial of 300 patients, and still showed minimal toxicity.

There were objective tumor responses in patients with advanced melanoma (28%), non-small cell lung cancer (18%), and kidney cancer (27%).  Some patients had response of stable disease for six months, and others up to one year.

Of the RCC patients as a group were “heavily pretreated.”  Patients had previously received one or more treatments, with 47% having had three or more treatments.  Other trials corroborated this type of result, and act as proof of concept that blocking PD-1 can give clinical results without undue toxicity.

Another phase II trial of BMS-936558 is now complete and should be published soon.  It used the agent in second- and third-lines of treatment, after other treatments have failed.

With that and other data, a phase I trial combining the PD-1 blockade action with TKIs, such as Sutent (Sunitinib) and Votrient (Pazopanib) is underway.  There is also a bio-marker trial with the patients who responded to treatment, which includes both pretreatment and on-treatment biopsies for histologic and molecular analysis.

Reading that there would be analysis of markers in those responding patients compelled me to write this.  We are long overdue for research on the responding patients, which may determine who is likely to respond, and to prevent those non-responders from using ineffective drugs.  Apparently preliminary data from the large 300 patient group has shown that there were tumor responses ONLY in the patients who expressed PD-L1, and no responses in patients without this PD-L1.  Since this can be measured, this might prevent patients from taking treatment likely not to be beneficial, and to determine the optimum doses.

Another trial with a very similar name—different number—uses the antibody BMS-936559—note the NINE—and attempts to block PD-L1 directly.  While many cancer types were included in this study, it is noted again that patients with melanoma (17%), non-small cell lung cancer (NSCLC) (10%), renal cell (12%) and ovarian cancer (6%) had objective tumor response, as well as a range of stable responses at six months.

Most combination trials of have been with two TKIs, like Sutent and Pazopanib, which seems to offer little benefit, but with greater toxicity.  This new combination offers two different mechanisms of action, this may give greater results without the additional severe side effects.  We may also learn who is more likely to respond to any one of these drugs, which would be invaluable to the patient.

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Filed under About Peggy, Biological Systemic, Immune Therapies Old & New

by | July 8, 2012 · 12:13 am

Clinical Trials for Renal Cell Carcinoma; Dr. David McDermott; Dana Farber Harvard Cancer Center

I am presenting for Dr. Bukowksi (of Cleveland Clinic Taussig Cancer Institute) and this is his outline.   It is not so much about novel therapies, but about clinical trials, why they are important.

Clinical trials, what’s in it for you?  We talked about it for the field, but what is in it for the patients who might want to consider a trial?  What is a clinical trial?

“A study conducted to allow safety and efficacy data to be collected for a health intervention such as a drug, device, or treatment protocol”, as per the slide.

They are designed on a certain ethical code of conduct which we follow very closely.  They are monitored very closely, followed by people, both internally and externally, the FDA and IRB, the Institutional Review Boards at our institutions.

This  list– I thought this was pretty funny– that Dr. Bukowski came up with is from a Persian physician, on the ways to conduct a clinical trial, from 1025 AD, a thousand years ago.  I don’t know how many clinical trials were done a thousand years ago, but I thought the last one was pretty good, “The experimentation must be done on a human body, for testing on a lion or a horse may not prove anything about its effect on man.”  We talk a lot about morbidities or complications on people on clinical trials; I can’t imagine being the investigator on any lion trial! Probably higher risk for the investigators than the lions.  I’m glad we made advances in the last thousand years.

This is one of the more famous clinical trials, given by James Lind in 1747.  He was given the task, and first to show that citrus fruits could cure scurvy.  He did what was like a randomized trial, comparing the effects of various acidic substances, citrus fruits or cider– gave them to sailors with scurvy, essentially proving that giving oranges and lemons can give quick recovery in patients with vitamin C deficiency.  He is one of the founding fathers of our field of clinical investigations. We’ve come a long way since then.

As far as types of clinical trial, some are conducted in different ways. Some are what we call observational, meaning we collect data that other researcher use to study patterns, to study outcomes over the long period time, things like risks for heart disease.  For this group, we often do something for patients, usually with a device or a therapy, and this usually compared to a group receiving no therapy, no treatment, or commonly, the old standard of treatment of care.

There can be many different purposes for trials.  Some can be for screening, some are preventative, which we haven’t talked about much yet, but can improve the way we diagnose kidney cancer. So there are many different types of trials.

You want to ask, “What phase is this?”  The reason that is important is that each phase of testing has a different goal.  I will focus on the middle ones here; Phase I often focuses on the drug safety. It has  traditionally been about, “What’s the right dose of the drug?  What’s the right schedule for the drug?”  Traditionally, Phase I trials have not always been great for the patients, as the main focus is “What’s the safest way to give the drug?”, not whether the drug is effective. They were often left for patients with fewer or other options, when everything else had run out, you would consider a Phase I trial.

But nowadays, Phase I trials are changing somewhat.  They are often not open for patients with just any kind of cancer.  They are open for patients with specific kinds of cancer, because there is already some sense that this drug looked interesting in the laboratory, that it might be effective for a specific type of cancer.  W aremore focused in that regard.  We are also testing patients for certain tumor characteristics, so getting a sense, not of what kind of cancer they have, but what kind of tumor do they have, what kind of genetic changes are going on in that tumor.  Most importantly, some phase I trials—once they get the safe dose—are doing what is called “dose expansion”, where they take patients with specific tumor types and treat them all with the same dose. This is essentially doing a Phase II trial within a Phase I trial, though a smaller Phase II trial.  In many ways, there is an advantage on the being on that kind of trial, in my admittedly biased opinion, because you know you are getting a drug that has shown in many cases some sense of safety and activity. It is certainly something you should consider, not necessarily right off, just because your doctor wants to consider you for a Phase I  trial.

Phase II trials’ main focus there is the effectiveness; how effective is the treatment?  They usual focus on some single cancer type.

Phase III trials are a more comparative trial.  It’s comparing something that is new to an older or the standard treatment.  For many years, the “new” was really no better than the old, but one of the things that more recently, is that a lot of the new has been better and we often have had a sense that it was better, before we got to confirm it in trials.

One of the uncomfortable things about a Phase III trial, from a patient’s point of view is the randomization.  It makes them very anxious.  You lose a certain amount of control, both the physician and the patient, about what you are going to receive.  So a lot of people choose not to go on a Phase III trial because they are uncomfortable with that process.  The way I like to look at, not as a patient’s perspective, even in a randomized trial is that you get a 50% chance at trying a new agent earlier.  That may not be worth it to you, but it’s worth a discussion, a consideration as you go through treatment.  There often are also trials that come after the drugs has been approved, like expanded access trials, where they offer it to patients just to test further questions, safety, for example.

We talked a little bit about clinical trials, and some of the caveats, about randomized trials and how that can throw people off.  Like randomization: It turns out that this is the only way we know if a new treatment is effected. As many flaws as there might be from a patient’s perspective, it is here to stay. At least for the time being, we are going to have randomized trials.

One other concept that often also throws people off is whether the trial is blinded, that is, where the researcher and the patient may not what the patient is getting.  Why is that?  The reason is that because if you know what someone is receiving, you might make judgments that bias the outcome, both on the patient’s side and the physician’s side.  A lot of people don’t like not knowing what they are getting.

PLACEBOS

The one thing that throws the most wrenches into this is the whole concept of a placebo as a control arm, and unnerves a lot of people for good reason.  You are going to  to be told if a placebo is involved, number one, for sure, up front. Now that we have effective drugs, placebo-controls are less likely to be acceptable options.  Meaning, they are only acceptable if there is no standard treatment, so 5-6 years ago, when there was no or very few standard treatments for kidney cancer, we relied on placebos.

Now these are being compared to active treatments.  So you are either getting active treatment A or active treatment B, comparing it to a new treatment.  Going forward in kidney cancer, there will probably be fewer and fewer placebo-controlled trials.

Here’s a list; you’ve seen this before; all the important trials that they have done in the last ten years. The important thing about this is that is patient involvement that has made this progress possible.  This is a look at 8-9 trials that have enrolled 4000-5000 patients.  It is quite a long list of progress, made only by patients with a willingness to so, so it is important to encourage people that you may communicate with online or in your email to consider participation. It is only through that participation do we make this kind of progress.  Clearly we have more progress to go.

So summarizing our recent advances, to show that we can shrink tumor in 10% up to 50% of patients in these newly targeted agents.  As Dr. Jonasch was talking about, we can surely slow tumor growth which leads to lengthening of survival.  Patients are living longer, Hutson says 3-5 times longer.  My patients are living years longer than they used to in the past, but we are still not receiving enough remissions.  We need to work on getting remissions, once the treatments have stopped.

We talked about participation, we need to do that to improve outcomes.  We need to better understand the biology of kidney cancer, as Dr. Jonasch was talking about, to identify patients before they get treatment, and to assign them to treatment that is likely to help them. It is only through that–not just clinical research, but also laboratory research– that we will be able to do that in combination.  We need to increase the funding for those endeavors, as it is rather expensive, at a time when the NCI’s budget is fairly tight.

You hear a lot about personalized medicine in the treatment of cancer, but we are not yet in the era of personalized medicine for kidney cancer.  We are making certain decisions, but they are based on fairly rough guidelines, but we are making decisions based on whether a patient has been treated or untreated.  We are trying to assign to patients to certain risk categories based on certain features of that suggest a good or a poor prognosis.  We are making decisions, as we talked about earlier, on whether a patient has clear cell or non-clear cells, but these are very rough sort of guidelines.  We need better ones, obviously and we are hoping to come up with better ones, based on the patients’ own genetic profile and the profile of the genetics of the tumor.  There is a lot of work going on in that as we speak.

Recently reported trials; these are trials reported in the last year.

Not all trials are positive.  The first is called the Renal Effect Trial, randomizing patients to either prescribing the intermittent dosing of Sunitinib versus the continuous dosing of Sutent.  The hope was that giving the drug at a lower dose continuously that the treatment would be more tolerable or more effective.  It turns out that there was no difference, so they could be used interchangeably.

There was a second trial with Sorafenib, where they added on another anti-angiogenesis inhibitor, in hope of improvement with the standard drug, Sorafenib.  It’s the trial in the middle there, and unfortunately, the additional drug did not improve outcomes to the Sorafenib.

The last trial on the bottom, that both Dr. Hutson and Dr. Jonasch mentioned was a Phase III trial, once again a randomized trial that comparing—not a placebo—but a standard of care, Sorafenib to a new therapy, axitinib, which proved clearly that axitinib was a step forward.  It may be a small step forward, but it is important for our patients.  That led the FDA to approving this new, hopefully, second generation anti-angiogenesis drug for our patients earlier this year.

So what’s coming?  Hopefully, drugs that are less toxic and more effective.  There are a series of Phase II and III trials that are coming close to reporting their results you will be hearing about them in the next year.

Their names you see here:  COMPARZ, RECORD 3, TIVO1, you’ve heard a bit about, TORISEL 404.  We talk a little bit about these, what we can expect from these trials.  We can also talk a little bit about targeted immunotherapies, vaccines and ultimately, combinations that might make sense.  All these are being tested and in the next year, we’ll know a lot more.

There are several trials, trying to improve upon Sunitinib, which is the most prescribed treatment for patients with metastatic kidney cancer in 2012.  The COMPARZ trial is comparing Sunitinib with Pazopanib, which is Votrient.  The makers of Votrient would hope show that it is as effective as Sutent, and perhaps less toxic.  We’ll see that result later this year.  Obviously, drugs that are less toxic are worth developing.

The other trial looks at the proper sequencing of the RECORD trial.  Should you start with Sutent and move to Afinitor, or start with Afinitor and then move to Sutent? We should get some information on the proper use of Sutent, hopefully, with the RECORD 3 result

We mentioned the AXIS trial which compared axitinib to Sorafenib and led to Axitinib’s approval. That was a step forward.

Hopefully there will be another step forward in the second line setting, which is this new -1, a second generation of anti-angiogenesis inhibitors. This TIVO-1 trial which Eric (Jonasch) mentioned  targets a new, more specific antiangiogenesis inhibitor , comparing Pazopanib to Sorafenib, showing it was more effective, so once again, we are coming with better agents than five year ago.

Another important trial will compare an mTOR inhibitor to Sorafenib again, Torisel to Sorafenib standard and to answer the question, when you fail a prior treatment like Sutent, what is better—to give you a another drug like Sutent, or to give you a completely different approach—which is the Torisel drug.  We’ll be learning a little bit more about the proper sequencing of these agents.  All of this information should be available coming soon.

The Tivozonib data will be presented at ASCO in June and hopefully the Torisel data will be presented later this year.

Combinations of drugs; most oncologists think that if one drug is good, two have got to be better.  There have been a lot of combination trials done this far.  Most have been, I must say, somewhat disappointing, and we will talk about why that is.  Hopefully, as we get less toxic agents, we will bet smarter about putting these things together, and we will make some progress.  These are some of the drugs that have been used in combination.

Laboratory trials have suggested these: we don’t just do these willy-nilly. Laboratory studies have often shown that two drugs are better than one, but there are several important issues.  One of these is cost.  You all know that these are not cheap.  The other is toxicity, and so far, most of these combinations have proved pretty toxic when given together.  Here are two trials that are looking at a blood vessel strategy with mTOR inhibitors.  The RECORD 2 trial looks at Bevacizumab and Everolimus together versus the standard of Bevacizumab and interferon; the INTORACT trial looks at Bevacizumab and Temsirolimus together.  These are both large trials that will give us the answer to whether two approaches to attacking the cancer  better than just one at a time.  We’ll see that going forward.

As you know, as we talked about things today, that none of/very few of these drugs produce complete remissions, and we obviously need second- and third-line treatments.

 

There are a couple of trials accruing that will give us some answers to that.  There is another antiangiogenesis inhibitors, the TKI-258 (references  on left), and it is in phase III trials, once again comparing to Sorafenib, so that might be a step forward as well.  Looking at this Phase 3, looking at this Cooperative Group Trial, looking at combinations, adding Bevacizumab, hoping that will aid in outcomes with what Everolimus does. We’ll see.

We’ve talked about vaccine treatments, and I alluded to one trial, the ARGOS III trial, looking at combinations of vaccine and Sutent.  It is more than one trial, it is the IMMATICS trial on the right,; it looks at another peptide vaccine, also in combination with Sunitinib.  Hopefully it will lead to more durable benefit with this drug.  It is great that we are in large Phase III trials, as this will give us answers, but the answers are still a long way away, as these trials are still enrolling patients.

We mentioned the PD Antibody earlier.  This is one of the more exciting ones of the targeted therapies being developed.  Two things I did not mention this morning that I want to make now, is that this drug will soon be entering Phase III trials.  It’s moving pretty quickly, and hopefully Phase III trials will open later this year, and if positive, might lead to the drug’s approval.

But just as important, there is more than just one PD or PD L drug in development.  These are five separate companies, all of whom have decided it is important to find different way to block the “barbed wire” that I talked about, that protect cells from the attack by the immune system.  You will hear more about these agents, not just in kidney cancer, but in other tumor types as the year goes on.Chris Wood covered this very well earlier, so I won’t address that, but we are also doing clinical trials with drugs that have been used with Stage IV patients, we are now using those with Stage II and III patients.  And as he (Wood) said, it will take several years before we know if it will delay cancer from coming back after surgery, or will prevent cancer from coming back after surgery—there’s a big difference with those two.  We are several years away from knowing those results.  But the great news about these trials is that they are accruing well.  Patients have gone on them very quickly, much more quickly that we expected, though the drugs may have issues for the patients, side effects…..we will have to see about the effectiveness.  The patient community if very motivated to go on trials like this, so hopefully as we get better drugs, we can test them in patients in the early stages of kidney cancer and prevent recurrences.  That’s where we can have a huge impact, preventing the need for treatment for Stage IV cancer.

So, in closing this is obviously one fundamental question for folks who have not considered a clinical trial.  Obviously I am biased, incredibly biased, as it is what I do.  I think it gives you access to cutting edge approaches.  Obviously the newest thing isn’t always better, and sometimes it is harmful and we’ve seen multiple cases of that.  But I do think you get access to things sooner if you consider trials.

And I do think we are getting better, as I mentioned, picking treatments than we were ten years ago, and also picking patients for those treatments.  We are a little bit smarter.  We are having more positive trials.

But all that being said, the participation of patients in the US in clinical trials is still less than 3% of patients.  So when you think about it, I can sit up here all day and talk about all the things I want to do, and Eric (Jonasch) has great ideas, and Tom (Hutson) has great ideas, and Chris Wood’s ideas are OK (smiling), but we can’t do it without participation and convincing people to come and sacrifice, as there are costs to travel and risks .  It takes a lot and really requires a mobilization of the whole kidney cancer community.  I hope that this will increase the willingness to participate in clinical trials to get the message out about why it is important.  There a lot of reasons why you might want to consider it, but people ask, What else is in it for me?”  I know what is in it for me, and for the field, but what else is in it for me personally?”

There are some people who think that the care on clinical trials is better.  You can argue that back and forth, but you are certainly followed much more closely on a clinical trial that you wouldn’t be if you were not on a trial.  You are not only being watched more closely for side effects, you are watched very carefully to see if the treatment is working.  There are a lot of rules set up to protect you, not only from the side effects, but from ineffective treatment.  There are rules by which we have to remove you from your trial if it is not in your interest.  Most importantly, you can always stop at any time, once you join a clinical trial.

The other question which is a little bit harder to address is whether patients on clinical trials do better, and he has some interesting data

data that was presented last year.  This is looking at 238 phase III clinical trials of all cancers done in recent years.  When you look at this slide, and it’s a little bit complicated, I didn’t want to get too much data in it, but it is kind of important..

For the 158 trials that reached their goal, where they reached the sufficient number of patients, Sufficient Accrual, that was 2/3 of phase III trials. So not all phase III trials reached their goals of accrual of patients, which is a problem.  But of those that did, most of those trials showed positive results, in fact, 143 of 158 had positive results.  There were some that had negative results, closed early, or had side effect of toxicity.  But it was a relatively small number, only 15% on this slide.  The highest reason for trials not succeeding was that they did not get enough patients on them.

This makes a couple points.  One, we’ve got to get more patients on trials, so we can answer these questions.  Second, a lot of the trials that we are doing help advance the field, but we think help the patients who go on them.  That would be hard to prove, but it is certainly worth considering. There may be some advantages for you as an individual when you are considering going on a clinical trial.

 

So in conclusion, clinical trials advance our knowledge and  have improved outcomes in kidney cancer.  It has been a great effort by many patients.  Six thousand patients have gone on these trials that we have talked about over the day, not only improving outcomes for themselves, but also for future ways we treat patients.  Coming up with better way to treat patients is only going to happen with research.  We need to keep working on it, to define new approaches, we need to extend treatment earlier in disease, and we need to focus on patients who are unable, or don’t qualify for trials.  We need to do a lot more work in that area, but hopefully, in partnership we can make advances, like we have in this last ten years.

End of Lecture; Questions from patients and caregivers follow.

Questions;

ACOR list member has asked about XL 184.  How optimistic are you about XL 184 having activity in bone lesions, as well as soft tissue lesions; also, as far as imaging, she would be concerned about masking of bony lesions on imaging.  On recent studies, ie, questions whether bone scans are the best measure of activity of XL 184.

That is a pretty sophisticated question, and in my earlier talk, I got a questions about XL 184 and I think this.  In kidney cancer, it has only been through Phase I testing, so I think it is a little early to know how active it is.  But there are really people in our community that really want to study it.  The focus is not only the VEGF but the protein that Dr. Jonasch mentioned, that MET protein which is thought to be an important driver in all cancers, and kidney cancer.  Certainly we want to study it.  It’s been tested mostly in prostate cancer, and they’ve seen some impressive results. We’ve seen that in prostate cancer, but whether we will see that in kidney cancer, that remains to be proven.  That would be an advance, something that would control bone metastases. That would be exciting, since a lot of our drugs fail in bone. But it would need to be tested.  I couldn’t agree with that more.  How well it will be tested, that remains to be seen.  Dr. Tannir may be talking of this class of drugs in his talk.

 Soft tissue metastases, any activity in that?  I know we’ve seen activity with the bone mets, but soft tissues?

Answer: It is to early to say that we have seen that, but that is certainly the story in prostate but we don’t know yet in kidney cancer.  But you will see a presentation at ASCO, where you will get a sense of how well it’s working in kidney cancer, but it’s going to be a very small trial.  We need a much bigger trial.

  This is a more general question, and I never hear anything about it.  Is anyone collecting data on your outliers, those people who survived the interleukin 2, IL, or data, anything to see if there is something homogeneous about them or any attributes?  I just never hear anything about this.

DO you mean people who can’t go on trials, or people who do really great?

 Those who do really great, those with long PFS or OS, people

There are people who are thinking about those questions and there are more often cases, where when people present, their tissues or blood and tumor stored for analysis so we may be able to do that kind of study in the future.  There are people who are looking at genetic predictor of response to treatment but right now there are no great predictors of response to these agents.  We need to do a lot more work on that.  We don’t understand why there are great responders—yet.  We have the capability of learning about that now we are collecting information.

 I just wonder if it is lack of patients or lack of money, if there is no big drug involved.

Any research will say there is lack of money, we could also do with more money.  There is also a lack of insight.  If we have the information, can we tease out what it is important.  I think Dr. Jonasch is going to save me with an intelligent answer.

Jonasch:  I don’t know if it will be intelligent, but it is an answer!  Anderson has an unusual responders program, and what is to be done, and Dr. Tannir and I are both participating in that.  We are taking those with outstandingly good and outstandingly bad responses, and we are performing sequencing analysis to get clue to determine what exactly makes those people different.  Hopefully I am getting my data back in the the next month or so, with individual are treated with Sunitinib.  So it will give us some ideas , to understand those differences.  So, no answer yet, but work underway.

 I don’t want to be morbid, but want to understand.  You have just said about sending tissue, is that at the end of your life or?

It’s usually at the time of diagnosis, so Anderson is great example of this.  They will ask you after the tumor is removed, after Dr. Wood removes it, can we  have a piece for our tissue bank?  They will save it, save it in an impersonal way, and they will use samples from your body, not just the tumor, your urine or your blood, things like that and track your outcomes, along with a large number of people.  By donating that tissue upfront, it is a lot more useful and we can get a lot more information about your tumor if we can get a fresh piece of tumor.  We like fresh tumor.  We’ll take anything, but fresh is better.

 I am asking a question which may have explained a bit earlier,how the patient is handling side effects and how that puts a greater responsibility on the patient.  How is a patient who is not able to come to a place like MD Anderson or these other center.  How is a patient able to help guide or cooperate with his local oncologist and handle this massive amount of information and differentiate whether he is getting the best treatment possible.

OK, that is a complicated question,  For the most part, now that we are 5-6 years into these new agents, most oncologists are making good treatment decisions.  In the case where you are not sure, you’re unsure, you can always ask, “Can I get another opinion?”  I think most oncologists don’t feel awkward about that.  “Is there someone you can call to ask about my side effects?  Is there someone you might send me to for this next treatment decision? These days, the good news is that you can end up receiving a lot of your treatment close to home, since these drugs are approved, but getting a confirmation is sometimes helpful, just for piece of mind.  Most oncologists that I work with are pretty comfortable making that referral.  Going through your doctor is a lot more productive than going around.  That’s my personal experience.  They get experience, they work in tandem, which is better than losing track of the local person.

QED

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Filed under Immune Therapies Old & New, KCA Conferences

by | July 6, 2012 · 11:18 pm

Systemic Targeted Therapy for metastatic RCC in 2012

Kidney Cancer Association National Patient Conference

Dr. Eric Jonasch; MD Anderson Cancer Center

April 14, 2012

Systemic Targeted Therapy for Metastatic Renal Cell Cancer in 2012

I am going to talk as systemic targeted therapy for Metastatic Renal Cell Cancer, what we are currently using and how we are using it, and the science about it, and how that leads us to new ideas, moving forward. Although I can see people here benefiting from what we do it is not enough.

When we talk about kidney cancer, we cannot talk about just one disease type.  What I am going to talk about mainly is clear cell, and Dr. Tannir, my friend and colleague, is going to talk about the non-clear cell subtypes.

So what is ccRCC?  It is essentially a cancer that looks like this under a microscope, and it was called this, back in the day.  We more recently found that it has a mutation in the VHL gene (Von Hippel Lindau) in the large majority of individuals with and I also run a clinic where I try to marry the information we have about hereditary kidney cancer with non-hereditary kidney cancer to improved therapies.

Slide 2: This is not to scale; it is 213 amino acids long and for the scientists in the audience, that is mercifully short, and it also has three exons in or three parts, or easier to study than most, but obviously still hard to study.

Slide 3:

What it does, it essentially regulates how the cell reacts to oxygen.  Obviously oxygen is our life’s blood, we need oxygen to, we need water, we need glucose.  And our cells, if they feel like they hve enough need oxygen, they basically sit back and VHL will then take the transcription factor, it breaks it down  If you have low oxygen state, then the cell will say, “Help, I need oxygen” and the VHL will step back,  the transcription factors, HIF alpha and HIF beta are going to come together and you will get production of proteins, like VEGF which is a growth factor for blood vessels and some other things.  If you have a mutation or something how an inactivation of the VHL gene, you have essentially this ongoing process of these cells, now cancerous, saying—somewhat untruthfully—we need more oxygen, we need more blood, build me an infrastructure.

Slide 4

That infrastructure is as follows:  When we think of cancer we can’t think of cancer cells The cancer cells are in black on slide and in blue above, the stromal cells–the “glue” cells, and above those the endothelial cells or blood vessel cells.  This triumvirate plus other cells generate an organ—and it really is an organ—that we call cancer.  And when we use therapies, we are blocking specific areas there.

I’ll tell you a bit about the therapies we use now and that some of you are on, and what they are actually blocking.

 Here is some terminology you are about to hear, some jargon, as we talk about trials and therapies. 1) Progression free survival (PFS)—time it takes for cancer to start growing again and 2) Overall Survival (OS)—time it takes from start of treatment to passing of patient

 So the “blood vessel starving” are the five antiangiogentic therapies we currently have are listed here, and I am going to go through each of these in details.

We also have some up and coming drugs.  And the way these drugs work  (Slide 4 again) is by blocking the blood vessels. They try to kill the blood vessels that feed the cancer.  They don’t seem to have much effect on the cancer itself.  That is why you have experienced that we can shrink this down, but we can’t make it go away.  And what we need, and on our wish list, are kidney cancer cell-killing therapies for the future.

mTOR FDA approved;

Temsirolimus (Torisel)

Everolimus (Afinitor)

The mTOR inhibitors, of which there are two, Torisel and Afinitor, Temsirolimus and Everolimus.

What they do; they are actually working inside the cell both perhaps in the  cancer and blood vessel  cell.  And they are blocking particular proteins that seem to be up regulated, overexcited, in the cancer cell that give them a selective growth advantage.

There we have on the bottom, kind of a brown color, mTOR, which if it is overactivated, results in production of and more survival … for the cancer cells—which is shouldn’t have.  What Torisel and Afinitor do is to block that signal.

 

 

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Filed under RCC Basics, Targeted Therapies, Your Role

by | July 2, 2012 · 12:06 am

Integration of Surgery (Cytoreductive Surgery) and Systemic Therapy in the Treatment of Kidney Cancer

 

So we could predict who was going to respond in the primary tumor, so the question was, “Can we use that as some sort of bio-marker?”

PART Two of Several Parts;

“Cytoreductive Surgery for Metastatic RCC: It’s Not for Everyone”

Dr. Christopher Wood

Integration of Surgery and Systemic Therapy in the Treatment of Kidney Cancer

Also referred to in the KCA program as “Role of Cytoreductive Surgery in the Treatment of Metastatic RCC

UT MD Anderson Cancer Center

April 14, 2012; KCA National Patient Conference

Cytoreductive Surgery for Metastatic RCC: It’s Not for Everyone

Identifying Patients Who Will Not Benefit from Cytoreductive Nephrectomy

Cytoreductive surgery is not for everyone. Certain patients will not benefit from surgery.  We (MD Anderson) did a study to see if we could accurately select those patients who would not benefit from such a surgery, to save them from a surgery likely to be highly morbid and not beneficial. We compared 566 patients undergoing surgery to a group of 110 patients were treated with their tumors in place and treated with medical therapy only.

We tried to predict for which (patient) factors predicted outcome.  We at MD Anderson can be very aggressive in our surgeries as we believe in cytoreductive surgery, so these patients who could not have surgery were probably the worst of the worst.  For these patients, treated with medical therapy only, the median survival was only 8.5 months.

With that in mind, we looked at those patients who underwent surgery.  If those patients did not live beyond 8.5 months after surgery, they probably did not benefit from that surgery.  What factors predicted for those patients to live longer than the 8.5 months than did the medical therapy alone group?

What factors would be predictive of how one would do? We identified the above factors; low serum albumin, an overall nutritional status lab value, elevated LDH, also a blood test, the presence of liver mets, presence of symptoms due to those metastases, retroperitoneal lymph node involvement, (discussed earlier as a bad sign),supra-diaphragmatic lymph nodes and locally advanced T state.  All of these features predicted for a worse outcome.

If a surgical patient had three or fewer of those features, he did significantly better than those who received medical therapy alone.  But if a surgical patient had more than three of these features, that outcome was the same or worse than those who received medical therapy alone.  So now we are using these features to prospectively select patients for surgery.

Can We Do Better?

Is the relevant question whether or not surgery should be incorporated into the management of metastatic kidney cancer?

I argue the more relevant question is whether there is a role for “pre-surgical therapy” for metastatic kidney cancer.

Pre-surgical therapy means to give some targeted therapy for some defined period of time, then go to surgery and resume targeted therapy after surgery. The potential benefit may be to use the pre-therapy as a selection process: patients who do well are those taken to surgery, and the ones not doing well are spared a surgery that not likely to give them benefit.  It allows us to harvest (surgical) tissue that has been treated with these agents.  With that available, we can study it to see how targeted therapy affects the tumor, what pathways are turned on and off, to help generate the next treatments.  It may shrink the primary tumor and make the surgery easier, most important this is that it allows us to spare patients from surgery that they are not likely to benefit from.

However, targeted therapies don’t just target the tumor. They also target wound healing, which is why many patients who get this therapy have wound complications. The tumor will not respond to the therapy and may grow; a patient who was a surgical candidate all of a sudden becomes not a candidate for surgery, because the tumor has grown. He may need a more extensive surgery. The more I take out, the more difficult it is for you.  And timing is everything. If you get targeted therapy and respond well, why stop that to send you to surgery?  And as a surgeon, if you are not responding to targeted therapy, why would I want to take you to surgery?

Potential benefits are that the primary tumor may shrink, may downstage or downsize, and make surgery easier. Maybe we could do partial nephrectomies on everybody, save some kidneys.  It may make the unresectable become resectable.  It may improve prognosis. In patients without metastatic disease, it may eliminate micro-metastatic disease. (Pre-surgical targeted) therapy might be used as a litmus test of response, but there are risks, including surgical morbidity and lack of response. Plus there is pre-clinical data which suggests that in some cases, targeted therapy, treated in this fashion, may make the biology of the disease worse.

This is the MD Anderson trial with Bevacizumab (Avastin), where patients were treated with Bevacizumab for two courses of treatment and then went on to surgery and back on Bevacizumab after surgery.

We recently completed this Sunitinib trial. Patients completed two courses of Sunitinib, followed by nephrectomy and went on to receive Sunitinib post operatively when they had a response.

 

This is my Axitinib trial, where patients with locally advanced disease would receive three months of Axitinib, and go on to get a curative nephrectomy

Dr. Kamar showed you earlier an evolution in surgery over time.  Ten years ago, everyone got an open nephrectomy; it was done open and very morbid.  Then people began to use a partial nephrectomy and then a laparoscopic nephrectomy.

 

Each advance had to prove it was equivalent to the existing technique doing then and each had to show oncologic equipoise, i.e., equivalent cancer control.  To give equivalent cancer control was the most important hurdle for each advance in order to be accepted.  It also had to spare nephrons, for me, that the least important thing was this it was minimally invasive.  Between a minimally invasive operation that doesn’t work, and a maximally invasive operation that does work, which one would you choose?

Similarly this neoadjuvant approach has hurdles. It must be safe and it must have improved outcomes.  The least important is that it downsize or downstage the tumor.  It is the rare patient who presents that you can’t resect.  It would be nice if the tumor shrank, but that is the least important, I think.

Is NeoAdjuvant Therapy Safe?

 

Is neoadjuvant therapy safe?  This patient (on the left) went on Sunitinib, had surgery and went on to get Sunitinib after surgery.  What I did not know as the surgeon, that the patient started Sunitinib two weeks after surgery. And he had complete abdominal wall dehiscence (opening of the wound).  That is his greater omentum sitting on his abdominal wall.  The patient did not even realize that he had a problem and went to the MRI for his repeat staging study. He had no idea that he had a problem, so went he came to clinic and we saw that we went, “Oh, my God!”

Referencing another slide not shown here: On the right is a patient on the bevacizumab trial who had abdominal wall dehiscence, four months out from surgery.  That is her small bowel (referencing upper portion of CT scan) and you can actually see it on the abdominal wall.

“Is this safe?”  We did a retrospective study on 70 patients using pre-surgical therapy and compared them to 103 patients who had upfront cytoreductive surgery, and we looked at complications over 12 months.

Patients who had pre-surgery treatment did not have more complications than those who had upfront surgery, nor were there more severe complications.  However, they were more likely to have late complications, and to have more than one complication if they had a complication. They were more likely to have wound complications, related to the targeted therapy and wound healing.

 

Looking at a multi-variate analysis, all the factors that predict for poor wound healing, the only factor that was significant was pre-surgical therapy.

 

Thus patients who get this therapy before surgery have a higher risk of wound complications—but not a higher risk of overall complications.  They have a higher risk of wound complications, but for overall complications, it is the exact same risk as patients who got upfront surgery.

Patients who had a decline in their serum albumin while they were being treated had greater problems with wound complications. Serum albumin is seen as a marker for nutritional status. Now we follow that variable and find that for patients who have serum albumin decline, we are more likely to reinforce their wounds with surgery.

Happily, patients who received pre-surgical therapy did not have a worse survival than those who had upfront surgery, followed by systemic therapy.  They may not do better, but they do not do worse, and that is an important feature and shown here graphically.

So What About Tumor Downstaging/Downsizing?

In the era of classical immunotherapy with interferon and IL2, with the primary tumor in place, the primary tumor never responded. That in part, was the impetus to take us to cytoreductive tumor, since the primary never responded.

These patients were treated here at MD Anderson.  This is a patient had a very locally advanced tumor, and very large lymph nodes. Had this been done as cytoreductive upfront surgery, it would be a huge operation. Treated with Sunitinib and he had dramatic regression in the primary tumor, the nodes all went away, and he was able to have a laparoscopic nephrectomy. Arguably, he benefited from this approach.

This patient was treated with Axitinib for a very large locally advanced primary tumor here, treated with Axitinib, (on right CT). On the right, there was dramatic regression of the tumor.

 

Here’s a look at the specimen we removed.  Here is the tumor sitting in the kidney right here, and arguably, this patient could have been treated with a partial nephrectomy.  We wanted to do that, but they were reluctant.

This is another patient treated with Axitinib, that received neoadjuvant therapy, and again you can see (on left) a very large locally advanced tumor sitting in the right kidney.  He received Axitinib and after three months, and you see a dramatic regression (right CT).  With this he would have had to receive an open nephrectomy and with this, this patient can undergo a laporascopic nephrectomy.  Much less morbid.

Here’s a picture of the specimen, dramatic improvement. All of this used to be viable tumor, nowhas been killed by the Axitinib and this rim is the tumor present.

Are These Just Anecdotes, or Can We Rely on These Agents to Downstage Tumors? 

I would argue that if it is true, as a surgeon, I would say, give it to everybody.  Maybe we can offer partial nephrectomies to all our patients.

S

So what is the data? This study looked at 17 patients treated with their primary tumor in place with Sunitinib.  Only 23% of the patients actually demonstrated had a response, but those that did had a response rate of 31%.

At the Cleveland Clinic, the patients were treated with Sunitinib, and the overwhelming majority had little or no response in their primary tumor.  In some patients, their tumor grew while on treatment.

Data from our Bevacizumab trial shows the recurrent theme; the overwhelming majority of patients had little or no response in their primary tumor to targeted therapy.

 

The University of North Carolina tested Sorafenib. Again, there were some dramatic regressions, there were some dramatic progressions, but the vast majority of patients had little or no response in their primary tumor.

Trying to determine once and for all, we want to ask whether there should be this treatment with the tumor in place.

In a larger study of 168 patients treated with tumor in place, we looked to see there would be tumor shrinkage.

Reasons for not removing the tumor is below, with the vast majority not considered good candidates for surgery, or were enrolled in a clinical trial.

 

These were the therapies they received.  The vast majority received Sunitinib, which is the frontline standard of care, with other therapies intermingled.

As to the response rates, we had some patients who had dramatic progression of their tumor, some patients who had dramatic regression of their tumor.  The vast majority of the patients had little or no response in their primary tumor.

One of the things that is common in the community is that patients with large venous tumor thrombi may hear their community oncologist say, “Here, take this medication, it will shrink your thrombus and it will make your surgery easier.” So is this data true?

A significant patients will present to me on Sunitinib.   In this series, 48 patients had different levels of tumor thrombi and were treated with these agents.

 

 

Unfortunately, a recurrent theme (references “Stable Disease in 75%), patients had little or no response in their tumor thrombus. In fact, 15% of patients progressed while in treatment.  Only 10% of patients demonstrated shrinkage in their venous thrombus in response to treatment.

Initial Body of Evidence Would Suggest that Significant Primary Tumor Downstaging Will NOT Be Realized with the Current Generation of Targeted Therapy Agents

 I would suggest that the initial body of evidence suggests that significant primary tumor downstaging will not be realized with the current generation of targeted therapy.  Nevertheless I must confess that I have been quite impressed with the responses that we have been seeing with Axitinib.  Every patient has had a response.

As to the report card on presurgical/neoadjuvant therapy.  I would argue that it is indeed safe.  We see more wound complications, but those are pretty easily dealt with. It does not seem to reliably downsize tumors. I would this does not. Is this worth doing?  Should we continue to do this clinical research at MD Anderson and around the world to determine if neoadjuvant therapy has a role in the treatment of patients?  I would argue that it does for the following reasons.

In our Bevacizumab trial, 50 patients were enrolled, but only 42 underwent nephrectomy. Six patients had disease progression and went on to salvage systemic therapy rather than nephrectomy.  These six patients were saved from a surgery that would not benefit them.

In our series, we asked, “Is there something about pre-surgical therapy that we can use to predict prognosis, and can we use the primary tumor as a bio-marker to predict outcome?”

 

This is a spidergram looking at primary response in the tumor. We noted is that patients, who did respond in their primary tumor, they responded early.  If you don’t see it early, you will not see it; there is no sense to continue treatment if you don’t see some shrinkage.

Those patients who had at least a 10% reduction (in the first 60 days) in their primary tumor size went on to have their tumor shrink almost 25%.  If patients did not have that 10% in the first 60 days, they were likely to have little, if any response.

So we could predict who was going to respond in the primary tumor, so the question was, “Can we use that as some sort of bio-marker?”

 

We treated 75 patients with Sunitinib with their primary tumor in place, and we found that those patients who had a greater than 10% response in their primary tumor had a significantly greater survival than those patients who did not have that early shrinkage of greater than 10%.  If they had a greater than 10% response within 60 days, their survival was even better.

And that was in univariable analysis, and it also held up in multivariable analysis.

 

 

 

For the first time, looking at the primary tumor’s response to targeted therapy could be used as a prognostic variable for outcome of patients.

In Europe, there was another study, looking at Sunitinib. They arrived independently at the same conclusion that we did, that those patients (treated with their primary tumor in place) with a greater than 10% response in their primary tumor, when treated with their primary in place, had a significantly better outcome than those treated patients who did not.

Cytoreductive Nephrectomy for Metastatic RCC in The Era of Targeted Therapy

Not a question of “IF” but “WHEN”?

I argue that cytoreductive nephrectomy is not a question of “if”, but really more a question of “When?”

58

This trial that is currently ongoing in Europe through the ERTC, the CERTIME trial. Patients are randomized to cytoreductive nephrectomy followed by Sunitinib versus two course of Sunitinib followed by nephrectomy.  This examines timing of the nephrectomy, not whether we should be doing a nephrectomy.  This is a much more relevant research question, and this trial is accruing quite nicely over there.

In conclusion, targeted therapy has dramatically improved the outcomes for patients with metastatic RCC.  Efficacy in the adjuvant and neoadjuvant setting still is under investigation.  Without complete responses from this targeted therapy, surgery will remain an integral part of a multi-disciplinary approach, both as to control of the primary tumor and as metastasectomy. Show me an agent that demonstrates reliable and complete response, I will be the first to argue that we need to reexamine the paradigm.

Do not think that pre-surgical therapy is the standard of care.  It is not.  It has merit, but it needs further study and validation.  It is not clear to me when it is appropriate to integrate surgery into the context of receiving systemic therapy.  Thank you very much for your attention.

END OF LECTURE>

Questions and responses from audience.

 

Audience. “My question is regard to your last comment, as to the immediate impact of say, Sutent, showing up prior to surgery with an early response, does that also mean that Sutent–having a response in metastatic disease–does that tell you than an early response also means a generally better outcome?

Dr. Wood: I’ve got to tell you we haven’t looked at that, but that is a very worthwhile study to do.  Intuitively, my answer would be yes, but I don’t think that we have anyone who has done a formal study on that. It is a very good question.

 

Audience: “How should ablation and the small tumors be monitored if you have those small tumors like less than 3 cm, like if you are a tumor producer, if you have “multi-foci” tumors?”

Dr. Kamar: Do you mean after or before the ablation?

Audience: “Before the ablation.”

Dr. Kamar: While you are on active surveillance?

Audience: “Yes, and if you have multiple primary tumors less than 3 cm.”

Dr. Kamar: This is more common in patients who have VHL syndrome, which is a syndrome where patients have a tendency to have more than one tumor in their kidneys.  The follow up is every six months or so, so we don’t really want to image too often for the radiation risks that are involved with doing too many CT scans.  Initially every 3-6 months and after the first year, move to every six months or one year.  It also depends on whether the patient is young and healthy and why would we want to observe.  In VHL patients that is done commonly, because we wait for the tumors to become 3 centimeters before we intervene.  We don’t want to do surgery when the tumors are only 1-2cm in that particular patient population.

Wood; The 3cm we are talking about comes from the NCI where they have a huge experience in treating genetic kidney cancer, and they noted that patients with tumors 3cm or less never metastasize.  So we use that 3cm size as a sort of trigger to tell us when we need to do surgery.  With multi-foci disease, once it hits that 3 cm size, we will go in and debulk the tumors from the kidney, take all the tumors we can take out, and then follow them over time.

 

Audience: “I have a question re ablation.  Is that an option if you have metastasized to your lungs?”

Dr. Kamar: You mean to use it on the lung tumor?  (Yes) Do you mean on the mets or do you mean on the tumor in the kidney.

Audience: “No, my kidney is gone, but I have metastasized to the lung, and I have had cyberknife, but is it an option to be used on the lungs.”

Dr. Kamar: I think it is an option, but typically, if it is doable by surgery, which is the preferred way.  The ablations that are done outside the kidney are mostly done for bone lesions, where cyroablation of RFA is done, because it is typically harder to remove a lesion from the bone than it is from the lung, for example.  It is more commonly done for liver metastases if anything

Wood:  It is more common to use it to treat symptomatic metastases, but there is some interesting work going on here at MD Anderson by one of our colleagues, where there may be some immunologic phenomena associated with ablation.  We have some case studies that have been done, where patients who have undergone ablation, particularly RFA, not so much Cryo and had a complete regression of their metastatic disease, almost like a vaccine had been put on the met, and actually Seren is studying that with alone and with some of the immunologic agents that you will hear about from Dr. McDermott to see if that may be a viable treatment option for patients with kidney cancer in the future.

 

Audience: “After ablation, do you usually see necrosis in the body of the tumor? Can you see that during imaging?”

Kamar: You can see that afterwards, and typically more common with cyro. You see necrosis, coagulative necrosis.  Typically it is coagulative to the tumor. You see that on the pathology, when you end up removing that tumor later on. So what we see is absence of contrast enhancement. The tumor before treatment was lighting up when you give contrast. After the procedure, it stays dark. That is our best indicator, other than biopsy, that the tumor is really treated by radio frequency.  We don’t see really necrosis on imaging quite like for larger tumors like Dr. Woods showed earlier.

Audience: “So during subsequent imaging, you might see necrosis?”

Kamar: You might but typically what we look for is absence of enhancement.  Necrosis is not something we reliably see or depend upon for follow up.

 

Audience: “For Dr. Wood, re venous thrombosis, do you insert an IVC filter prior to surgery, I’ve heard, or do you consult with cardiology to get that done.  Is that helpful?”

Wood: Definitely that is not helpful before surgery.  We have both had patients where some guy on the outside decided it would be helpful to put a filter in the vena cava, just in case a piece of the tumor thrombi broke off.  It made surgery extremely, much more difficult.  After the thrombus has been removed, in some patients we will leave a vena cava filter, which is like a screen put in the vena cave, so that blood clots below that screen blocks them from going to the lungs.  A large pulmonary embolism could be fatal.  So patients who do have evidence of a clot down in their legs, we will put a filter in, but if they don’t have any evidence of that, typically we don’t.

 

 

 

 

 

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by | July 1, 2012 · 10:07 pm

Integration of Surgery and Systemic Therapy/Cytoreductive Surgery in Treatment of mRCC

Dr. Christopher Wood

Integration of Surgery and Systemic Therapy in the Treatment of Kidney Cancer

Also referred to by the KCA as “Role of Cytoreductive Surgery in the Treatment of Metastatic RCC

UT MD Anderson Cancer Center

KCA National Patient Conference: April 14, 2012

The topic “Integration of Surgery and Systemic Therapy in the Treatment of Kidney Cancer” is near to my heart and in active research at MD A

nderson Cancer Center.  The vast majority of patients present to us with locally advanced disease, and the reality is that almost half of patients with kidney cancer will at some time develop metastatic disease, which we all know is currently not curable.

Again, as to stage, the vast majority of patients present to us with locally advanced disease, and the reality is that almost half of patients with kidney cancer will at some time develop metastatic disease, which we all know is currently not curable.  (Editor’s note: my stage IV RCC with innumerable lung mets in 2004 is now in remission or “cured”, or close enough to “cured”, that I must add this note.  It is still shocking to understand that Stage IV RCC is considered incurable. PZ)

Six years ago, we did not have much to talk about.  I could show this slide and sit down. For locally advanced disease, we took out the kidney; for stage IV disease, we took out the kidney and gave systemic treatment, usually cytokines.

Now we almost have too many therapies and don’t know how to use them all.  How do we integrate surgery into the context of these treatments that we offer patients with metastatic disease? The sad reailties of this are no home runs. These therapies control the disease for some time in these molecular pathways they target. But in most patients, resistance will develop and they have to move on to the next treatment.

I will talk about how we integrate surgery into systemic treatment in 2012, the role of cytoreductive surgery, and then introduce the idea of pre-surgical therapy, something that we have been studying here at MD Anderson that has shown some promise.

These are two randomized trials, one in the US, the other in Europe, which demonstrate the benefit of patients undergoing cytoreductive surgery. The first is the EORTC trial where patients were randomized to upfront surgery followed by interferon, or by interferon alone.

Next is the SWOG (South West Oncology Group) trial done in the US, again demonstrating the value of undergoing a nephrectomy prior to interferon, versus interferon alone?  Frankly, many surgeons referred to this trial as “Surgery followed by ineffective therapy is better than ineffective therapy alone.”  You can see by these that the response was only 3-4%.

Now that we have more effective therapy, what is the role of surgery in the context of patients with metastatic disease?  We don’t even know why cytoreductive surgery works.  Does it just reduce tumor burden?  Does it produce some sort of immunologic phenomenon where tumor antigens are exposed or is there an immunological “sink”.  Is it an alteration in the metabolic milieu where taking out someone’s kidney and altering the ph in the body somehow is anti-tumoral?  Or is taking out the “mother ship”, where some sort of endocrine or paracrine phenomenon that promotes metastases.  We have absolutely no idea how it works.

Why not take out everybody’s kidney in the setting of metastatic disease? 

The morbidity and side effects can be significant, and people can die from this operation.  Though it has been proven beneficial in the context of interferon, and it’s quite possible that patients will spend the majority of their time left on earth recovering from surgery.  We’ve seen metastatic disease explode post-operatively.  Those patients never even get to go on to targeted therapy after surgery.  Perhaps these new therapies will cause the primary tumor to shrink.  Maybe we don’t need to take out everyone’s kidneys in the face of metastatic disease.

The French are testing this in their Carmena trial. Patients are randomized to an upfront nephrectomy followed by Sunitinib versus Sunitinib alone.  It is a non inferiority study design, and the randomization is 576 patients.  There is a problem; the trial is not at all accruing very well. Patients don’t like to have surgery randomized, with a computer saying, “You’re going to have surgery, and you are not”.

With the slow accrual to this trial it will be many years  before we have an answer. Sunitinib may not even be relevant at that time.  And what are we doing for patients in the meantime? Should I take the kidney out or not?

There is evidence that removing the kidney in the presence of metastatic disease is beneficial, from retrospective data derived from the expanded access trial with Sunitinib.  These patients had their

kidney removed, not just cytoreductive surgery, but any time in their past.

They were compared to patients treated with their kidney in place.  Patients who had their tumor out had a much better response rate than those treated with their tumors in place. 

They also had a better progression free survival (PFS) and a better overall survival (OS) than patients treated with their primary tumors in place.  Now this is retrospective, it is biased as it is not clear why the kidney was left in place for any one patient. That might have been because the patient was on death’s door and could not have had the kidney removed.  But the data shows a benefit of being treated without having your kidney in place.

Newer data from Dr Toni Chouieri at Dana Farber compares are patients who presented with their primary tumors in place. Those who had the kidney removed prior to targeted therapy had a (overall) survival more than doubled compared to those treated with the primary tumor in place.

Those retrospective and (with patient selection) bias, it gives some guidance there may be some benefit to the removal of the kidney in the setting of targeted therapy.

Lecture continues as PART 2 with topic:

Cytoreductive Surgery for Metastatic RCC: It’s Not for Everyone

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by | June 26, 2012 · 8:09 pm

Immunotherapy for Metastatic Renal Cell Carcinoma; David McDermott, M.D.

 Status of Immunotherapy in Metastatic RCC in 2012

(The lecture is from a patient conference, and may be seen by clicking through to YouTube. My transcription may make it easier to STUDY the information from Dr. McDermott and to review the slides.)

Dr. David McDermott; Dana Farber Harvard Cancer Center; KCA Conference

April 14, 2012; MD Anderson Cancer Center; Houston, TX

“This is a great opportunity to talk about this new research. The last six years brought great advances to the treatment of metastatic kidney cancer with newly approved therapies. No other area of cancer that has had made more progress with new treatments in that time, and there is more good news to come.

In this era of targeted therapies, some have asked if immunotherapy–once the only option for kidney cancer–has any role.  In the next twenty minutes, I will show you that it probably still does–for the proper patient.

Dr. Wood talked about limitations with the targeted therapies, the anti-angiogenesis drugs.  They are excellent at pruning the tumor, much like I do with my weed whacker. Though they can delay progression, and improve survival, you need to be on treatment to have its effect and all these tumors come back. Once you are off treatment, the effect wears off. They can delay progression, extend life and patients are living longer.

There has been a greater understanding about how the immune system works over the last 20 years when this was introduced.

The Immune System
Adaptive defense system that protects an individual from invading microorganisms
The immune system is specific
Involves multiple large polypeptides that function in:
     Antigen presentation
     Antigen recognition
     Intercellular signaling
Involves multiple cell types                                                           Slide 2

These insights can improve outcome for our patients. The immune system is a defense system, which protects the person from invading bacteria and viruses.  This system contains multiple moving parts and multiple cell types.

Here is a cartoon example of all the different cells and antibodies, which can protect against bacteria, others that can target a microorganism, or more importantly, a tumor cell.  This system was not designed to fight cancer; it was designed to fight infection. That means it is designed to turn on when you have an infection like a virus, and when the virus is controlled, the same “turned on” cells of the immune system are then shut off. These shutoff mechanisms are in part responsible why cancer can evade the immune system, and why it has been so difficult to use the immune system to fight the cancer, as opposed to fight infections.

Different approaches are being used with the immune system to fight cancer, some we’ve used in the past and some exciting new approaches currently being tested. The first approach is much like pressing on the gas. This approach to immune therapy has mostly involved cytokines, with interleukin 2 and interferon, and was used for a long time.  They rev up the immune system and are growth factors that stimulate a lot of the parts of the immune system, such as T-cells.

Dr. Wood said there were no home runs for patients for Stage IV kidney cancer, but that is not exactly true. There are very few home runs, a few patients with stage IV disease who obtain a remission of their disease. Remission means treatment of Stage IV disease in which the cancer goes away, treatment stops, and cancer does not come back. To most patients, that is their goal. Very few patients meet that goal, but for some that remission has lasted decades.

Pressing on the Gas of the Immune System

 It is also true that this “pressing on the gas of the immune system” does not work for most patients.  It is hard to identify which patients it will work for and is associated with lots of side effects.  To be effective, as with interleukin 2, these treatments must be given in a hospital. They involve serious side effects, sometime life-threatening side effects, so the kind of patient who can receive this type of treatment is relatively limited.

At Beth Israel Deaconess in Boston we try to be selective choosing patients for this therapy. We try to identify the patients who may receive the home run, before we put them through the side effects, because so many patients go through the side effects without benefit.

 High-Dose Aldesleukin “Select” Trial in Patients with Metastatic RCC
D. McDermott, M Ghebremichael, S Signoretti, K Margolin, J Clark, JSosman, J Dutcher,M French, and M Aktins on behalf of the Cytokine Working Group

We had clues about things that might improve the selection, so created the IL2 SELECT trial, reported at ASCO two years ago. The activity of IL2 in this era of these new treatments is still relatively good, as good as it was 20 years ago.  The response rate in this trial with 120 patients was 25%, significantly greater than it was when the drug was introduced 20 years ago. The drug is not any better, or are we any better at giving it.  But we are better choosing our patients. Choosing who should get it, and who shouldn’t, and that improves the responses of our patients.

It has been known that patients with non-clear cell are less likely to respond to immunotherapy, so in this trial there were very few patients with non-clear cell cancer—and no responders in that group.  It is also known that patients who had their primary tumor removed when they presented at Stage IV disease are more likely to respond to immune therapy.  In this trial, 99% of patients had that surgery before they went into this trial.  It is almost certainly true, that with new therapies available, that the types of patients being referred to an IL2 centers like ours is probably different.  Changing the types of folks we are treat means our numbers are improving somewhat.

To improve the selection process and based on earlier research, we wanted to show that certain features of the patient’s pathology of the tumor might predict for response. We looked at what the tumor under the microscope and special proteins (CA IX or carbonic anhydrase IX) that the tumor might produce.  We thought those things might predict either high chance for response or low chance for responding to treatment.

Unfortunately for me as a researcher, although fortunately for the patients who went on this trial, the folks who were in the poor risk group–those we thought would not benefit from IL2–did just as well as those not in the poor risk group. It surprised us and showed the importance of testing theories in the proper trials. We clearly need to do more work in this direction to find something to explain why some people benefit and some do not. And it may turn out that response may have more to do with the patient’s immune system than the cancer as how they benefit from treatments that boost the immune response to cancer.

RCC IL-2 SELECT Trial; Conclusions
Tumor features did not predict for response.
Efforts to confirm other predictors are ongoing.
Lessons from this work may guide the development of targeted immunotherapies in mRCC(e.g. CTLA-4, PD-1 antibodies)         Slide 9a

So in conclusion for this trial, the tumor features did not predict for response, but we had a higher response than we expected higher than 20 years ago.  This work continues and some of this work will educate us as we go into this new world of targeted immune therapy for kidney cancer.

So as discussed, the immune system is not designed to fight cancer, but to fight infections.  This graphic shows where the immune system turns on in response, and at its greatest, starts to shut off, as it is designed to do. The shut-off valves of the immune system–the brakes–are in some ways stronger than the gas pedal.

Releasing the Brakes

In the laboratory over the past ten years we have been able to identify what are those brakes are.  Now we ask how to block those brakes. One of the most important brakes on the immune system is a protein called CTLA-4 (CytotoxicT-Lykmphoctye Antigen 4). We can block the action of this protein, to release one of the most important brakes to immune response to cancer.

On this slide you see the T-cell on the left, an activated T cell, as it activates a protein, turns itself on. The same T–cell that turns itself on, puts out a protein on its surface, called CTLA-4.  When that CTLA-4 protein comes in contact with another protein on that cell, an antigen-presenting cell, it actually shuts off the cell, a natural way of shutting off the immune response. That way these cells don’t overreact to an infection and attack healthy tissues,  Now we can interrupt that interaction by bringing in a monoclonal antibody, which interrupts the connection between CTLA-4 and important proteins of the immune system.  So we can block the natural shutoff that many patients experience.

Does that work to clinical effect with kidney cancer patients?  The short answer is it does.  Data presented in the New England Journal of Medicine two years ago. Blocking this protein in melanoma gave improved outcomes, and this was an out-patient treatment, intravenous, given every three weeks for four doses.  It’s actually been shown to improve survival for patients with metastatic melanoma.

Blocking CTLA-4

And it’s not treating the cancer; it’s treating the patient’s immune system. The immune system is going out and detecting the cancer in ways that it might not have before getting this antibody.  It is outpatient therapy, but it is still associated with significant side effects.  Most of those are auto-immune side effects, where the body is now being attacked by its own immune system.  Some of these are been quite serious and patients have died from this treatment.  We are getting smarter at managing the side effects so there are fewer major complications, but do not get the impression that it’s not serious treatment.  It’s less toxic than IL2, can be given to more patients, but still has side effects.

Ipilimumab in mRCC
                                                     Single institution (NCI), Phase II trial
Major response rate of 9%.
Max dose test 3/mg/kg.     (Dose response in melanoma)
Survival effect in melanoma despite low response rate.
Additional studies alone and in combination warranted.           Slide 14

This data led to FDA approval last year of Ipilumimab, now called Yervoy. It was approved in melanoma, but it has been tried in kidney cancer patients at the National Cancer Institute in a very small 36 patients, phase II trial.  The response rate, the chance that the tumor shrank by half, was only 9% in this trial. That may not sound great, it was tested at a dose which may not be the right dose; higher doses of treatment may be tested in the future. In melanoma we saw improvements in survival and saw lasting remissions for Stage IV patients. We saw those benefits even with a very small response rate. Go to the “Blocking CTLA-4” slide, and look way out on the survival curve towards the end. These are patients out 3 and 4 years, still in remission and off treatment. That happened even though the response rate to treatment wasn’t very high.  It is possible that we might see a long-term benefit for some patients with kidney cancer with an agent like this. Some others are being tested in the coming year, so I would be thinking that additional studies with this approach are certainly warranted.

 Steering the Body’s Immune System

We need not just the “accelerator” and the “brakes” to make these things work.  We also need improved steering. Investigators want to improve steering by giving patients vaccine approaches. This may get patients’ immune systems to recognize proteins found on the tumor, to wake up and to go and attack those proteins, and to try to control the cancer. These approaches are now in phase III trials that have shown some encouraging results, where we will get some answers.

The agent AGS-003 is being combined with the most commonly used drug for kidney cancer, Sutent. Patients are randomized to use either Sutent alone or Sutent with this drug.  Whether this will lead to more response rates and to more long term benefit than with Sutent alone remains to be seen. At least we will get an answer from a large Phase III trial.  One of the problems with immunotherapy trials over the years is that they haven’t been large enough to give us clear answers. But this trial is enrolling patients and there are others like it.

 Putting up the Barbed Wire Defense

Since we’re in Texas, so I thought I’d give you a barbed wire analogy. One way in which tumor cells evade detection by the immune system putting up this “barbed wire” on their surfaces. When a T-cell comes, tries to sniff out the cancer cell, it is shut down, as opposed to going on to kill the tumor cell.  We now know a little bit about that natural barbed wire which comes into play with this particularly important protein interaction, the programmed death pathway, and what that stands for is the inactivation, or the programmed death of the T-cell, which acts like barbed wire.

Why is this important?  In kidney cancer, many patients’ tumors are coated with this barbed wire. Patients who have this on their initial tumor specimen have been shown to be more likely to have more disease recurrence in the future.  Since we can identify the barbed wire, can we block its activity and lead to an improved effect? The question is, can we target this protein and can we improve outcomes?  There is early evidence that maybe we can.  This is a Phase I trial, admittedly very early.

Programmed Death (PD)-1/PD-L1 Pathway: The Basics
Several tumor types, including RCC, have been shown to over express inducible PD-L1
Over expression of PD-L1 by RCC tumors has been shown to be associated with adverse clinical/pathologic features, including the following:
            More aggressive disease
            Shorter survival
            Also report to impair tumor immunity
             Can PD-1 pathway blockage head to clinical benefit?                          Slide 18

 

 Phase I Study to Evaluate the Safety and Antitumor Activity of Biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in Patients with
Renal Cell Carcinoma and Other Advanced Refractory Malignancies. 

Patients received an outpatient treatment, intravenously, with a drug that doesn’t even have a name yet, BMS-936558, a PD-1 anti-body.  This is blocking the interaction between the barbed wire and T-cells.  In this trial it is given every two weeks; on other trials it’s been given every three weeks.  Patients were allowed to stay on this drug for up to two years as long as they were getting some clinical benefit.

SAFETY RESULTS; ALL PATIENTS
For the entire group, MTD (Maximum toxic dose) was not reached at doses of 1, 3, and 10 mg/kg
There was no apparent relationship between drug dose & AE (adverse effects) frequency
One treatment-related death 
Grade 4 drug-related pneumonitis                                                 Slide 20

The main reason to do a phase I trial is to test the safety of the drug. This drug was found to be relatively safe, and we got up to the highest dose without getting into serious side effects.  There didn’t seem to be a relationship between the dose and the side effects, which was good. There were still 10-15% patients who had serious side effects. In this group of kidney cancer patients and there was one treatment-related death, due to an inflammation in the lung that was probably contributed to by the drug.

  SAFETY RESULTS; ALL PATIENTS

Any grade, drug-related (investigator attributed*) serious AEs (SAEs) occurring at a frequency >1% in the entire study group (n=126)
            Total with an SAE=11%
            Investigations=3.2%
            Endocrine disorders=2.4%
            General disorders and administration site conditions=1.6%
            Hepatobiliary disorder=1.6%
            Neoplasms benign, malignant and unspecified=1.6%
            Respiratory, thoracic and mediastinal disorders=1.6%                         Slide 20a

 This trial of 126 patients was a much larger group and not just a kidney cancer trial with five cancer types in this trial. There are now 300 patients in this trial, and we’ll get more data in the next several months.  But in general the safety population is much larger than the efficacy population.  The main point here is that serious adverse events occur in about 11% of all patients, much less than in HD IL2 and CTLA-4.

What did we see in terms of effectiveness?  For the first 16 patients analyzed, we saw five partial responses (31.3%), and three patients (18.8%) with stability that lasted over six months. About 50 % of patients were getting some clinical benefit with this antibody. Once again, a small number of patients tested.

Here is an example of the patients we studied, a young man who was diagnosed in 2009, received IL2 and progressed, received Sutent and progressed, had disease in multiple places, including the kidney and the bones and lungs. You can see the before and after pictures after receiving two courses of treatment of ipilumimab with a significant response in the lungs, which is ongoing therapy after two years.

We’ve also seen responses in some unusual places.  One place that a lot of our VEGF targeted patients fail is in the bone. This is a patient, before and after, who had a response with a bone metastases you can see here (left scan), and actual healing bone (right scan), just a year later with treatment.  That’s certainly an encouraging result for us.

How long do these responses last?

For this admittedly small group, it looks like the major responses for a majority of these patients who had a response, that response lasted over a year.  Most who had a response still have that response at a year.  Whether that response will continue or stop, when the drug is stopped, remains to be seen. That will be a very important question. But the good news is the patients can tolerate this treatment for a year or more.

In summary, the PD-1 antibody concept is very early, but it has displayed reasonable side effects at all doses we’ve tested, and we seen some anti-tumor activity in some patients with kidney cancer.

PD-1 Antibody Summary
At this EARLY point, BMS 936558 has displayed manageable side effect at all dose levels tested
Anti-tumor activity observed in a small number of patients with RCC
            Responses may be durable?
16 patients added to this cohort-ASCO 2012
Responses in NSCLC
Trials launched in 2011 in RCC:
Dose finding Phase II study in patients with prior therapy
Biomarker Trial
Combination RX + VEGF TKI (Phase I)

Were these remissions, i.e., durable, or just responses?  Will the patients’ tumors grow after we stop the drug?  We don’t know that yet, but we’ve added 16 more patients to the study. We will present data at ASCO in two months (6/12), with more information on this anti-body soon.  It is important to note that with this drug and for the patients on it and for the field of immunotherapy for cancer that we are we seeing responses for kidney cancer and melanoma, where we’ve seen immune responses before. It is quite important also that we are also seeing responses in lung cancer. Should that be true, that will bring a lot of energy into the field going forward, as lung cancer is obviously a much more common illness, with very few options available.

There were a lot of new trials launched in 2011. We’ll have a Phase II trial in 2012, including multiple doses, to find the best dose in this treatment and also in combinations with other drugs like Sunitinib to find the best combinations.

So for those who say, “Is there a role for immunotherapy for RCC?” I would say there’s been a lot of progress over the last 30 years in the field of immunology, and we can now better target immunotherapy, and it’s worth preserving.

Is there a role for immunotherapy for mRCC?            There has been progress in the field of immunology in the last 30 years

            Immunotherapy can be “targeted”

            Immunotherapy is worth preserving                          Slide 25

There is a role for immunotherapies shown by survival curves like this; this is from the SELECT trial mentioned before.  These are patients who responded to treatment, now out three years, off treatment. The 13% percent of these patients, 16 patients have that benefit which really achieves the patient’s goal, which is worthwhile to try to get for more patients. It is proof of principal that we can do this, but we need to do it for lots more patients.  If we work on this, hopefully we can achieve Dr. Wood’s goal of more cures for kidney cancer, with targeted immunotherapy.

QED

Audience: Does the pathway of the targeted drug therapy have any impact on whether or not immunotherapy would have any effect on tumor growth or not? Different targeted therapies have different modes of blocking pathways.  Would that have impact, or has your research shown any impact on different pathways.

 Mc Dermott: “That is a very good question and not simple to answer.  Many of the treatments I talked about, like the cytokines, like IL2 or interferon or CTLA-4 work on the patient’s immune system-we think ONLY, only, meaning they are boosting the immune system to an established cancer.  For reasons we don’t completely understand, that is effective in some patients and not in others.  In the case of the PD-1 antibodies, they may be acting on the immune system, and may act on the tumor as well.  There is some evidence of that in the early research, as I mentioned with patients who have this barbed wire on the surface of their tumors, or have this pathway activated, or when this pathway is on, they may be more likely to respond to this approach.  Meaning, when the barbwire is up, and you can block its activity, maybe you can lead to an effective immune response.  And what that may say something important about the pathway, but it may also say something about the immune system’s response.  The barbed wire, we think, is up, as a reaction, a survival mechanism for some tumors. That is one of the reasons that cancer is so difficult to deal with, that there are so many different ways the tumor can evade the treatments. That barbed wire, that PD-1 may be one of those protection mechanisms.  So that means tumor turns on, the barbed wire is up when the immune system is there, you can’t kill it, but you can block the barbed wire, take these immune cells are right there and it can kill the cancer.  This may explain why some patients have a benefit and some don’t.  And we are now looking to see, if your tumor has barbed wire, whether you are more likely to respond to treatment.  There will be a lot more information about that in the future.  Good Question.”

 Question: I wonder if you knew if there was a clinical trial going on for prostate cancer, believe it is called XPl 4(sic), and its for bone mets, and if you knew anything about it’s work with RCC.

 McDermott:   “Re this med and RCC,I don’t treat prostate cancer, just melanoma and kidney cancer.  Is the drug you are talking about XL 184?  This is a drug that is in early trials, and maybe Dr. Jonasch will talk about it and similar drugs.  These drugs work in the blood vessels to attack the cancer.  They target two proteins, VEGF, which you’ll hear a lot about, and another protein which is important, C-MET, called MET inhibitors.  There has been interesting activity in prostate cancer with this drug in trial, and a very small trial we participated in Boston with this agent with kidney cancer patients.  You will see more info on this drug at the ASCO meeting in June and the info will be public on May 16.  ASCO publishes all its info, so you will be able to get your hands on the results from that very small trial in a very few weeks, which is good.  It’s a drug that has promise, but it has some side effects that need to be managed.  The fundamental question here is for the kidney cancer advocacy community, is it going to be tested in kidney cancer?  We are still not definite yet, but we are pushing to test this class of drugs in kidney cancer, this particular drug. We are pushing sponsors to do trials, but they are most interested in prostate cancer.  When those trials are to start and with kidney cancer, we are not entirely clear.  We need to push them to keep developing these interesting drugs for our patients.”  

 ME:  This is an extension of the question, as to how you choose the best patients who have the best chance of responding to IL2.  Does the histology or the pathology, and frankly I don’t know the difference between the two, have a major impact, and can you expand on that?

 McDermott:  “Yes, I may have gone too quickly on that.  We thought the answer was yes, and when it comes to big differences,  clear cell versus non=clear cell, it does, meaning when patients come to us, non-clear cell cancer for IL2, we will say to them, ‘It’s not going to help you, or the chances are so small, that the harm or potential harm outweighs the help.’  So to answer one of your questions, non-clear cell histology, which is simply a medical term for ‘What does this thing look like under the microscope?’.

 For non-clear cell histologies, we don’t offer IL2.  Whether one of these newer immune therapies work for that class of patients, should be tested because there is hope.  That is why I mention the lung cancer story, because if it can work in lung cancer, it might in one of these less common kidney cancer types.  It may work for many other forms of cancer.  So that is a hopeful thing and exciting.  But to take it a step further, while we thought clear cell cancer was more likely to benefit, we also thought it was that certain types of clear cell cancer were likely to benefit.  That is what we tried to prove in that trial, but we couldn’t prove it.  Doesn’t mean it wasn’t so, we just couldn’t prove it. We haven’t improved out selection ability based on looking under the microscope in ways that we had hoped.  We can do it a little bit, and that’s why the response rate went from 14% when the drug was approved to 25 % today, but it’s not enough, so patients don’t have to go through the side effects if they are not to benefit from the treatment.”

 Question; I don’t know if I know enough to ask a coherent question, but this is related.  Why would it be that certain tumor types or subtypes would respond to IL2 or not?  Is it because their profile of cell surface markers that let the immune system targets them better?

 McDermott:  “That’s actually a very sophisticated question, and one that does not have a clear answer.  It may be, one thing you mentioned, it may be that the immune system usually recognized proteins, usually proteins associated with infections like viruses or bacteria.  So it may be, as you point, that there are certain tumors that have show these proteins to the immune system better than others.  And then the immune system can detect these proteins and say, “This is something wrong here, let’s go kill it”.  That’s one possibility, and we tried to prove that in our trial, because one of the proteins we looked at was the protein called carbonic anhydrase IX.  We thought this protein was being recognized by the immune system and that might predict for benefit, but we couldn’t prove it.  So many people suggested your theory, which was that these proteins are important, but we could not prove it in this trial.  It doesn’t mean that there aren’t others that are important, we just couldn’t confirm it.  It may also mean that there are certain aspects of the tumor, that even though it is recognized by the tumor, something is preventing it from dying under the strain of an immune attack. That has to do with how well a cancer cell dies under stress. There may be some that don’t automatically shut down when they are being surrounded, that’s part of it.   There are also other important proteins that the tumor can make to avoid detection so the opposite of what you are talking about, that barbed wire analogy.  These are proteins that the tumor can turn on, and act like barbed wire, so that when the cells are coming it, they are turned off.  So there’s a variety of different theories and more than one aspect of that.  It’s a fairly complicated story.”

 Me; Back to CA IX, the fact that you expected that more of that would lead to greater response, you found the opposite to be true?

  “No, we didn’t find the opposite to be true, we found that the folks who had CA IX protein on their tumors did well, or better than the old numbers.  Those patients responded at about the 25%, but they did as good anyone.  What was different was that the patients who didn’t have CA IX on their tumor did just as well.   So that is why I said it was bad for the research, but good for those patients.  We would have assumed, if we hadn’t done the trial, that to those patients, we might have said, ‘You don’t have CA IX on your tumor, no IL2.’ We did the trial to show that, we couldn’t.  That means that going forward,, we should include those patients getting IL2.”

 Me:  I went on IL2, and I am a complete responder, and I had a relatively low level of CA IX, so I always watch that and wonder.

 McDermott:  “You are an example of why my research career is floundering,” laughing.

 Me; Sorry, but it works for me, works for me!

 McDermott:  “I am very happy for you and for those patients on the trial.  That is why you do the research.  The CA IX story, and this was scary when I saw it, actually made it into the medical training literature.  So if you were an oncology fellow, you learned that McDermott at Beth Israel and others said CA IX was important, and that high CA IX patients should IL2 .And then when I saw the results of the trial, I thought, O my gosh, this has become gospel, and is maybe not right. You are a perfect example of it, and it means we need to do more research into the area . You are an excellent plant could not have been better.”

 Audience: Did you say that you have some non-clear cell patients on the MDX trials? 

 “Not yet. Most of them whose tumor type we knew all have been clear cell.  But in some of the future trials there are small numbers of non-clear cell patients who will be enrolled.  If there is any sense of activity, it may encourage study sponsors/drug companies to develop it in non- clear cell patients.  They will not be excluded on trials going forward.”

 Audience: So you your knowledge there is not one which is limited (to non-clear cell) for MDX 186?

 “I haven’t seen a response in that category, since most of the patients are clear cell the assumption in the field is that clear cell benefits from immunotherapy, so when you try to prove a principal, they try to collect the patients most likely to benefit, so not to put people through treatment that will not benefit.  But now that we have this proven—really not proven—but a hint of effectiveness, different types of patients are being included in the trial.  For example, the trial which includes the addition of MDX agent with Sutent allows non-clear cell patients.  Hopefully there will be more of those in the future.  The good news is there is more than one drug company developing these antibodies, and I will include those in my talk this afternoon.

We don’t do all the work at our place, but I haven’t seen a non-clear cell responder at my place.  I have seen responses with very aggressive tumors, that had sarcomatoid features, for example, but I haven’t seen one with non-clear cell.  That does not mean that it has not occurred.”

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by | June 7, 2012 · 7:27 pm

Locally Advanced RCC/ Kidney Cancer; Dr. Chris Wood; TumorThrombi; Tumor in Vein; Part 2/4

Dr. Chris Wood; MD Anderson Cancer Center

KCA Patient Conference; April 14, 2010

Part 2 of 4

Surgical Management of Locally Advanced Renal Cell Carcinoma

Next is the management of more advanced disease, in patients who present with tumor thrombi, nodal metastases, adjacent organ invasion and renal fossa recurrence.

The first is venous tumor thrombi. This is one of the biggest operations that I do, as about 15% present with venous thrombi from their kidney cancer.  These can be huge.  This can be very complicated, as these thrombi can go up into the heart. We then have to put these patients on by-pass, open up their chests, stop their hearts and put them on a bypass, so we can take the thrombus out.  We use TransEsophagealEchocardiogophy to monitor of the thrombus, to make sure that the thrombus does not break off.

This is a series that we recently published at MD Anderson, 605 patients with venous involvement, median age of 60 years, follow up of 24 months.  45% had no evidence of metastatic disease; conversely 55% obviously had advanced disease.  The more advanced stage, the higher the risk of metastatic disease.

 

These are big operations; median blood loss is a liter and length of time is 3 hours, with complications in the first 30 days for 25% of patients. Patients stay in hospital about six days. But even with venous involvement up to the heart, in the absence of metastatic disease, there is a median survival of five years, so even these patients can be cured with surgery alone.  But once they demonstrate evidence metastatic disease, survival drops off dramatically.

Predictors of Overall Survival Slide

We looked at a variety of different parameters, won’t bore you with all the details. We looked to see what predictor survival for these patients and this is what we found.

Those patients who had clear cell histology actually had a more favorable outcome  than those with non-clear cell. Those who had advanced grade, sarcomatoid de-differentiation, those who had peri-nephrectic fat, nodal metastases, distant metastases, all were associated with a more adverse outcome than patients with venous thrombus involvement.

Interesting was in our studies, not shown elsewhere in the literature, is that the height of the thrombus in the vena cava did not seem to matter.  In other words if it was only in the renal vein, versus in the vena cava and that is at odds with the literature that is out there. It only seemed to matter when it went up into the heart, the red line at the bottom and with that, we saw a decrease in overall survival.

 Tumor Thrombus and Survival

Our series are in concert with others, in regards to survival in the absence of metastatic disease that patients can have a long term durable survival, with about 60% with five year disease-free survival

Microscopic Positive Vein Margins  Associated with Increased Local Recurrence & Metastatic Progression

One of the other things we noticed from our series that made me wake up was the concept of the vein margin.  Of 270 patients, who had no evidence of metastatic disease, almost 20% of patients had cancer present at the margin of resection.  When we resect the vena cava, we are obviously limited  in how much we can take, unless we are doing a reconstruction, which is really fraught with complication.

(associated with increased metastatic progression.

But those with a positive margins, meaning they had cancer sitting at the edge of resection, where we cut the vein, had a greater risk of local recurrence, a higher Fuhrman grade.  Those patients had a worse outcome, not surprisingly.

So now when we do these surgeries, we send the resection for a frozen section to be sure there is no cancer at the margin.  If there is cancer at the margins, then we will do a reconstruction to try to reconstruct the vena cava to try to eliminate all the cancer.

Also in the literature that is out there that is a bit at odd with our series; here they noted that patients who had only renal vein involvement had significantly better outcome than those who had IVC (Inferior Vena Cava) involvement. There is some data that suggests that the height of the tumor in the vein is somehow related to outcome but that is not what we are seeing in our patients.

In this series, IVC (inferior vena cava) wall invasion, tumor size, fat invasion, nodal metastases, and distant metastases all were associated with an adverse outcome in patients with venous tumor thrombi.”

Dr. Wood continues his discussion of surgical management of “Locally Advanced Renal Cell Carcinoma” with Budd-Chiari Syndrome in Part 3.

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Locally Advanced RCC/Kidney Cancer; Dr. Chris Wood; Options & Treatment 1/4 Parts

Dr. Christopher Wood, of MD Anderson Cancer Center lectured at an April 2012t KCA patient conference on this critical subject.  It is a technical discussion, highly important for the patient whose kidney cancer is not longer consider “small and curable” by surgery alone.  For greater ease in following this, I have posted this in four segments. My comments  will follow in a separate blogs.  My hope is that the information is meaningful, so that a patient can learn enough to have a discussion with his/her doctor.  Print out the information you have read and give it to the doctor to start that discussion.  Some slides were principally text, so I have recreated some to keep the file size down; anything which was not readily converted to text remains as the best available slide.

Consider saying to your doctor, “Here’s what I have been learning, doctor.  How does that fit into our plan for my treatment?” That tells your doctor know you are willing to learn and to listen, and to take an active role in your treatment decisions.  Unless your doctor deals daily with many kidney cancer patients, he is unlikely to be able to keep up with all the information, ever changing, and ever more complex, about your disease. If the doctor is not willing to listen and learn from the leaders in the field…find another doctor.

Peggy: RCC Patient, Stage IV mRCC 2004; healthy today, thanks to HD IL2

“Outcomes for Patients with Locally Advanced Renal Cell Carcinoma”

http://www.youtube.com/watch?v=Ns7qDbn_0_E&list=UUv0VRYOltlNQJLCyNMN61Nw&index=49&feature=plpp_video

Dr. Wood begins: “My first lecture is “The Management of Locally Advanced Renal Cell Carcinoma”. Slide 1

Stage is the most important predictor of outcome: the more advanced the stage, the greater risk that the tumor has spread, with distant metastases, making the disease incurable.

This is the staging system we use in 2012,  where we stage tumors,  assess regional lymph node involvement and look for evidence of metastatic disease.  People get hung up on their staging, but this allows doctors to communicate about patients in the same language about how advanced one tumor is.  With increasing stage, there is a more locally advanced tumor or metastatic disease.

Let us start with definitions. (Reads slides 2 & 3)

Adjuvant Therapy means some form of therapy– chemo, radiation, vaccine, whatever–after complete surgical tumor resection with the idea to decrease the risk of recurrence of disease.  The benefit is that the patient has already had surgery before getting additional therapy, but the downside is that many of those patients may have been cured by the surgery and they may get treatment they don’t really need.

Neoadjuvant therapy is taking some form of therapy, whether chemotherapy, radiation, vaccine, etc. prior to surgery to the primary tumor in hopes the tumor may decrease in size, and decrease the risk of recurrence.  The benefit is it may allow the tumor to shrink and make surgery easier.  The downside is that the therapy may not be effective and not inhibit metastases, and the primary tumor would not regress, but progress during therapy.

Slide 4

Effective adjuvant or neoadjuvant therapy does not exist for kidney cancer in 2012

Any therapy must be developed in the context of a clinical trial setting, and  including a placebo.  The only way we  make advances is to test what we do now with any advance in the future. And what we now know, as I said, is nothing.Patients have a hard time, with placebo trials. If you participate in such a trial, the treatment you are getting may not be good and the placebo arm, not so bad.

Slide 5  Who should get these therapies?  Why not give them to everyone?  Anyone taking the targeted therapies today knows the toxicity is significant, and you may treat a significant number of people who really don’t need the therapy.  Then if nothing works, why not give it to anyone? Well, we are never going to make advances that way, so it is important that we continue to do research and focus on those who are highest risk for relapse.  Should we give it only to those at a highest risk for recurrence?  The difficulty how do we define risk, how high is high?  So it’s not really clear.

Adjuvant Therapy: 2012

A variety of trials have been performed. Many  patients  have participated. They include radiation, embolization, energy ablation, a variety of different hormonal therapies, immunotherapies with interferon and interleukin 2, all having been used in an adjuvant setting.  There have been a variety of vaccines preparations and we did a Phase III trial of thalidomide trial here. To date, not one of these therapies has shown benefit in the adjuvant setting.  In fact, many of the patients on the treatment arms did worse than those who were not treated.

Slide 7 What about targeted therapies?  That is also the great unknown where  things stand with targeted therapies in the adjuvant setting.

Since 2006 there have been seven new agents against kidney cancer. It’s been a revolution. And to be honest, many  have benefited from that advance.   How do we use these agents in the context of adjuvant therapy?

Slide 8 There is a variety of trials recently completed or in accrual, ongoing. Tthe ARISER Trial used an antibody called G250 against Carbonic Anhydrase IX, and patients were randomized to get  either antibody or placebo. This trial completed accrual many years ago, in fact, and we are still awaiting results which leads me to believe that is probably going to be a negative trial.

But this same agent has recently shown promise for use in PET scans for kidney cancer.  You can use this as an imaging agent. The patient is infused with the antibody and linked to item 125, and it will show up on x ray, and may potentially detect micro metastases not visible on CT scans.  This is actually undergoing FDA approval.

­Slide 10

This is the ASSURE trial we conducted at MD Anderson.  It is a randomized, double-blind phase III trial of Sunitinib vs Sorafenib vs Placebo. Patients underwent surgery, then were treated with these agents for 1 year.  This trial was completed accrual last September (2011) and we are now waiting for the trial to mature to see whether these agents have any benefit in the adjuvant setting.

Slide 11

One thing that we did learn from this trial is that tolerance for the toxicity associated with targeted therapy in the adjuvant setting is not the same as in the metastatic setting. In this trial 41% of patients stopped therapy early, not because disease returned, or because they finished, but because of toxicity.   I think it comes down to an individual assessment of the risks.  If I told you that you have a 20% risk of your cancer coming back, versus your 70% chance of your cancer coming back and you are miserable on this therapy, all of a sudden 20% doesn’t look so bad.

My concern about this, because at the end of the day, if this trial matures and it is negative, will it be negative because the agents did not work, or because the patients could not tolerate the side effects. And too many patients stopped the trial early or had dose reductions.  I’m afraid it is not going to be interpretable.

Slide 12 This the S-TRAC trial, sponsored by Pfizer, recently completed accrual.  It’s randomized between Sunitinib with a placebo for one year. It is estimated results will come out in 2017. That’s the other problem with these trials. Are the agents we are testing now, will they even be relevant in 2017?  No one knows.

Slide 13/12

There has been a real problem in accruing to this trial. In fact, we can’t even keep patients on Sorafenib for three years in treatment, never mind adjuvant setting.


Slide 13

This is a trial going on in the US, sponsored by Glaxo-Smith-Kline. This is called the PROTECT trial.  Patients are randomized to Pazopanib (Votrient) or placebo for one year. This is primarily open to clear cell patients, here at MD Anderson.

SLIDE 15 A

This is the EVEREST trial, sponsored by the SWOG, going on around the US, with patients randomized to one year of Everolimus (Afinitor) or one year of placebo.

You can see that clinical research is actively ongoing to identify if these agents work in the adjuvant setting. But it is going to take more time to understand from these trials before we know if this is applicable in these setting or as with the other agents, if they remain ineffective.

Slide 16

One other concept we are testing at MD Anderson that I will talk about a bit more in the next talk is a neoadjuvant therapy, testing Axitinib in the neoadjuvant settings. Some in the audience have been on this trial, where patients receive Axitinib for three months and then undergo nephrectomy.

I would like to applaud the patients who participated in this trial.  Like to give you an idea how this went the first time we enrolled a patient.  Patient comes in with a tumor, curative with surgery, and we say, “We’d like to give you this agent, we don’t know if it will work.  In fact, your tumor may grow and metastasize while you are getting this agent.  If we took you to surgery tomorrow, we could probably cure you. What do you say?”  It was really amazing. The first patient who enrolled in this trial was very brave.  But since we have been able to show activity with this agent, enrollment has picked up significantly.”

Dr. Christopher Wood ends the first part of this lecture, with the next section about “The Surgical Management of Locally Advanced Renal Cell Carcinoma.”

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