Category Archives: Immune Therapies Old & New

What the heck is PD-1 anyway? Immune therapy?

Probably the most talked about studies at the June 2013 ASCO in Chicago swirled around the newly released trials about PD-1 (Programmed Death-1) and similar.  “What the heck is this  all about, and why should I care?”, you may be asking.  This is important as it shifts attention back to the original immune therapies that kept me alive (and many others) when there was nothing else to offer any hope in the olden days of the 1990s.

Though a number of targeted therapies have since emerged, and  you have been hearing about them, there is new interest in the earlier and modestly successful immune therapies.  I  confess a fondness for anything described as an immune therapy, as I am alive–which I would NOT have been–without the first FDA approved agent against kidney cancer, high dose interleukin 2, brand name Proleukin.

The first new agents in the 2005+, the anti-angiogenesis drugs (not easy to pronounce,much less to understand) brought new hope to metastatic RCC patients.  With the late diagnoses of many kidney cancer patients, we desperately needed hope.  For about 14 years, HD Il2 (high dose interleukin 2) was the only game in town.  Nothing else existed,  so any patient lucky enough to hear about it, and not actively discouraged by the very “realistic” doctors, probably considered it.  This is a hospital-based agent which revs up the immune system, so the immune system would go after the metastatic disease, at least for some number of months or years.  That is why I am alive.  Nothing else was offered and nothing else was available.  Nine years!

Since that time the anti-angiogenesis drugs–translation: those that fight against (anti..) the creation (genesis) of angio (think blood vessels) drugs were approved. Think Sutent (sunitinib) and Avastin (bevacizumab) and others,. They have been the weapon of choice for oncologists and patients.  Why is that?  Though these drugs rarely offer more than some pushing back of the drug, decidedly welcome, they have rarely given more than some slowing or relief from the metastases, and always with some side effects.

For us old-timers, who faced only death, whether by efficient means or by surgical cut-and-pastes as holding actions, this was a tremendous breakthrough.  For these options, even if only holding actions versus mop-up operations, we were grateful.  We who had nothing previously were slightly scornful of those who complained about the side effects, as we were grateful to be around to have such effects.  The Stage IV sufferer  in 2004 knew too well that Stage V was a damn unpleasant journey and without a return ticket.

Now we have become greedy again, wanting more than the “stability” or “some shrinkage”, which I applaud.  We want success and life, not holding actions.  High dose interleukin 2 continues to offer that success to patients, but no one can predict which patients and  which conditions that might be likely.

Bless those researchers who continued to wonder why kidney cancer and melanoma (and maybe non-small cell lung cancer) respond to some sorts of immune therapies, and what happens to make that happen and not happen.  Those fine people have come to understand that the immune response which is revved up by HD IL2 has a complex set of “calls and responses” which either let loose the dogs of war/and immune responses, or fail to do so.

Most people understand that the body tries to protect itself from assaults, whether by poison ivy, bronchitis or cancer.  The immune system responds, gives the body aches, pains, fevers, chills, etc.  Think of flu and how rotten you can feel.  Think also of old diseases like Black Death which stimulated the immune system so violently that it was the strong and healthy with good immune systems that succumbed to the immune response, dying with lungs filled with immune reactions and fluids.  Only those with weakened systems and slower responses managed to live through the symptoms.

Obviously the body’s immune response needs a moderation, and not one that saves the village by killing it.  All of this leads to an explanation of the newest immune therapies, now in clinical trials in RCC.  You may hear about PD-1 and CTLA-1 trials, and how they may be helpful in kidney cancer, melanoma, and now in non-small cell lung cancer.

To understand all of this, it is helpful to think of a system of checks and balances, perhaps in an electrical or computer communication system.  Just as every electrical impulse might be appropriate, it could also do damage by overwhelming the system, burning it out, or failing to meet the requirements to be able to answer a “send me” signal.  So it is with the latest research on immune therapies with the PD or Programmed Death agents.

Keep in mind that the immune response is typically used against infections, and not generally against cancer.  I assume that we cavemen needed more protection evolution-wise against infections and less so against the ravages of cancer, which seems to result from getting older and getting overwhelmed by changes/mutations in the body.  (Not always, I know, but that is a discussion for later.)

T cells are supposed to react to a number of infections and such, and trigger an immune response to fight back against the “aliens”, such as cancer and ragweed. Just right amount of fight, and the body recovers.  Too little, and you have the devastation of the Black Death, an over-the-top immune response.

The  immune system is supposed to respond to handle the natural threats to the body, but not over react and set the system on fire metaphorically.   It had built in checks in balances, as do normal cells.  We see this everyday when our normal growing hair cells decide to stop growing and the hair fall out.  Chemo patients struggle with the balance of killing all cells, with the faster-growing cancer cells being killed off first.

New agents have been developed that interfere with a signaling system that puts the T cells, the protective/fighter cells into action against cancer cell.  This naturally happens, but the nasty cancer cells try to evade that process by interfering with that process.  Not letting the body protect itself, by disguising itself as the evil twin, equally eager to live, as the good twin, the healthy cell, cancer interferes with Programmed Death.  More next time…

And as Mae West said, “I like a man who takes his time.”…
















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PD-1 Programmed Death for Cancer Cells “More, Please!” Dr. Wolchok

If anyone can find a cancer event exciting, it is the ASCO annual meeting, at which thousands of oncologists present their studies and learn from one another.  In the kidney cancer world, the “buzz” has been about “programmed death”–for the cancer cells, which we all prefer over that of our healthy cells.


This is a transcribed lecture, fairly short, to explain the immune therapies that may add to those weapons against RCC.  Dr. Wolchok clarifies how this happens, with the agents interfering with the “Shields Up!” commands that protect the cell from what should be their programmed deaths.  With appreciation to all researchers.

Peggy–Nine years of life free of cancer, thanks to the original immune therapy, HD IL2



ASCO Daily News June 6, 2013

Dr. Jedd D. Wolchok, MD PhD of Sloan Kettering Memorial Cancer Center

PD1 Pathway and Activity of Nivolumab  (Transibed interview with above link.  Easier to read and review, fans say!)

 We now recognize that there are several pathways that constrain T Cells and the immune system from achieving a state of full and persistent activation.

One of those pathways is called the CTLA4 pathway and there was a medicine approved call Ipilumimab last year, that blocks CTLA4 for treatment of melanoma. There is another pathway, the PD 1 pathway which usually constrains the immune system in a different way.  And PD 1 is also present on T cells in the immune system and it binds to a family of ligands, one of which is known as PD-L1 or PDL ligand 1.

In the ever-expanding a list of ways in which cancers try to evade the immune system, cancers have learned to express this PDL-1 ligand on their surface.  By doing so, they actually cause the death of T cells that come close enough to them or PDL-1 to bind to PD-1 on the T cell surface. This ability of cancer cells to express PD L1 on their surface allows them to defend themselves against T cells that the body is trying to educate to see the cancer and to defend itself.

So the PD-1 pathway is active across multiple disease sites. Some of the earliest work done with anti-bodies that block the PD -1 pathway used an anti-body called Nivolumab. Nivolumab was used in a phase 1 clinical trial that was presented at ASCO last year, and additional data will be presented this year.

The data last year showed that the antibody Nivolumab blocks PD -1, and that it can cause regressions in melanoma, in kidney cancer and importantly, really, non-small cell lung cancer. It is not traditionally recognized that as a cancer amenable to immune intervention. But when you people talk about cancers that responsive to immunotherapy, melanoma and renal cell carcinoma come to mind.

Now I think with the data generated first with Nivolumab and now with another PD-1 blocking antibody called Lambrolizumab(MK-3475), these anti-bodies which block the PD -1 pathway are demonstrating activity outside the “usual suspects”, melanoma and kidney cancer.

This ability to affect multiple different cancer types is important, as it shows that immunotherapy is not a treatment for one particular kind of cancer,.  It is a treatment that primarily targets the patient, Then it is the patient’s immune system that goes out and treats the cancer.

One of the most important characteristics of immunotherapy is its ability to induce durable and certainly there are many different types of anticancer medications which can cause a tumor to reduce in size, but the challenge has been and continues to be, how to get disease to regress and stay regressed.  Tumors, because of their genetic instability, can find pathways to become resistant to these interventions such as chemotherapy or targeted pathway inhibitions.

Immunotherapy really falls into a different category. Again, it is not targeting the tumor itself. It is targeting the patient’s immune system. It is causing the patient’s immune system to respond to certain parts of the tumor cells that the immune system finds interesting and then to control.

We know that the immune system has the ability to remember, through to a population of cells called memory cells.  Because the immune system is really a dynamic organ that cannot only sculpt itself around changes in the cancer, but also can remember what it has been exposed to in the past, we believe that durability is in fact a hallmark of response to immunotherapy. The first medicine to show us this in a meaningful way was a drug called interleukin two which was really actually developed now over 25 years ago and has led to the cure of some patients with melanoma and kidney cancer. That medicine is a hormone that causes the growth and differentiation of T-cells and patients who have a complete response to IL-2 and remain in complete response for at least two years don’t ever seem to recur with 10 or more years of follow-up.

We definitely need to learn more about the PD-1 pathway we specifically need to know whether it’s absolutely required for a tumor cell to express PDL-1 that on that surface to benefit from PD-1 or PD L-1blockade. It would be ideal, in fact, if a predictive biomarker that could identify the precise patient population who would benefit from that intervention. However, I think that is not going to be a simple as predictive biomarkers been for some of the targeted therapies, where it is mutation-present or –absent.  Here PDL-1 is not just important when it was expressed on the tumors, but PDL-1 plays a role by its presence on antigen-presenting cells. So, in its normal physiologic role, the PD -1 pathway actually involves interactions between T cells and antigen presenting cells and by blocking cells–even if the cells doesn’t express PDL-1–one could imagine that a patient could benefit, perhaps not as likely as if the tumor expressed PD L1.

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It’s Spread! Is It Too Late to Do Anything?

I love this study, as it really symbolizes the tremendous change that has occurred in kidney cancer treatment these last 6 years. It is remarkable that the 124 patients are described as having already received first- line treatment, and were now in their second-line. These same metastatic patients might have received neither just six years ago.

The study was really not to compare the response to the treatments received, whether Sutent (sunitinib),  Nexavar (sorafanib), or placebo.  (Why any party chose or was chosen to receive a placebo is another, darker question.)  That the median follow-up was 80 months is a triumph by itself.  This is in contrast to the clinical trials that often show just a few months extra time which we and politicians can focus on, when the reality of much longer responses is clearly shown here.  Of course, these longer survival times came from those trials which showed those few months–and this shows the reality of many more months and years of life!

Metastatic tumor burden(TB) was measured, based on the size of the sum of the longest unidimensional diameter of each targeted lesion.  The additional increase of 1 cm (about 3/8”) was significant in predicting response to the medications. Siimply, adding the one-direction measure of the lesions and comparing them showed that more tumor was a bigger problem.

One can also assume that to remove as much tumor as possible may be helpful in maximizing the benefit of the meds given, although this study does not address the actual types and locations of the mets, nor indicate why no other therapies, surgery or ablation, were used.  With 124 patients this would represent a mix of individual experiences, more like the typical patient group.

What does “median follow up of 80 months” really mean?  A median is not an average, but a measure of the time point at which ½ of the population studied had follow up less than 80 months and ½ had follow up for more than 80 months.  Since this is considered a long time in clinical trials and becomes more of a longitudinal study, we may never know the average length of time that these patients had either PFS (Progression Free Survival—time until the mets began to grow again) or OS (Overall Survival).  In any case, we are aware that following this second-line of treatment, there are still more therapies and interventions which may be available.  And even more options are up for FDA approval as I write.

All these options and the greater success of each muddies the study waters, but clarifies the hopes of those with metastatic RCC, or are at risk. This study proves that tumor burden (TB) is a disadvantage. Most patients have naturally assume that more cancer is worse for you than less cancer—who knew? But this gives weight to the notion that the removal of some tumors, if not all, can be beneficial used with targeted therapies. In the past, some oncologists have discouraged additional surgery in the light of metastases, with the implicit message, “It’s too late, and won’t help you anyway.”  Not the doctor for me.

The story is quite different right now, but patients may need to tell this to their doctors–in the language that the doctor speaks. Certainly, there was a time at which doing more surgery for mRCC patients added little, if anything, to survival and probably even less to the quality of life. That no longer is the case, and those older studies no longer have meaning.  While each patient must be treated as an individual, in light of all the variables that impact his health, there is increased optimism for the metastatic patient. Aggressive and early treatment can no doubt extend life and make it worth living.  


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Immunotherapy Part 3: Am I Cured? And How Big is 9mm?

Halfway through my high dose interleukin 2 (Proleukin) treatments, having completed weeks 1 and 2 and into the second rest period, I got the second most important scan of my life.  The most important CT scan changed my life, with its image of a tumor larger than a baseball, and countless tiny specs of white death in my lungs.
This new scan in August of 2004 would let me return to the hospital for more of the immune stimulant, Proleukin, which revved up my internal immune system to the max. My system was then to recognize and fight off the residual kidney cancer that had settled visibly in my lungs and any other new sites, as yet unseen.  The new vocabulary of cancer forces me to say that while hundreds of tiny lung mets/lesions/nodules–no wonder we patients get confused–were not just there, but ” visible”.  Implicit was the message that many hundreds more were  invisible, certainly  alive and thriving, just not yet “imaged”.
The tools of imaging cancer are varied and unequal, some more effective for some cancers, and yet inadequate for others.  First of all, the tumors are measured in centimeters and millimeters, and that language shift alone makes them even more inaccessible to Americans.  Just how big is 9 millimeters anyway?  And a centimeter seems a pretty vague measurement after years of holding thumb and forefinger together to how 1/2 inch with decent precision. Is a change from7mm to 9mm cause for alarm?
Plus the panic of hearing “cancer” drives any math computation out of one’s head.  The only math question that can be asked and then not understood is, “How long have I got, doctor?”.  And then there is the matter of what can be seen with which instrument.  When doctors tell smokers that their  x rays are clear,  naive civilians translate that to mean their lungs are free of cancer. A rough interpretation might be more like, “Your tumors–if you have them–aren’t big enough to be captured by this 100 year old device.  Come back when we can see something/you are pretty much past help.”  Notice that I provide the translation here.
The x ray is more like using a child’s microscope to look at something; great for noticing crud on your pet’s hair, but not quite like those grownup electron microscopes which can see cells.  Note to kidney cancer patients–don’t even bother.
Another imaging device is a PET scan, which measures the activity of cells, and which I understand a quick snap shot of liveliness of the cell, and it manifestation, the tumor.  Is it chowing down on the body’s nutrients faster than the orderly cells?  That activity will “light up” in a PET scan, so the lazier cancer cells might be overlooked.  Not to effective in kidney cancer, whose tumors are often slow-growing.  That is also possibly why kidney cancer can establish itself so thoroughly in so many patients, not noticed until a broken rib or vague back ache or a non-existent ulcer finally results in a CT scan. Note to lots of kidney cancer patients–don’t even bother with a PET scan.
So a CT scan, with contrast to enhance the vague and ghosty images is the way to go for most RCC patients.  A blood test to see if the single kidney can handle the assault of the imaging fluid precedes the test, and then the patient settles onto a big padded tray which is drawn slowly into a large doughnut-shape machine that somehow can see into the patients insides.  I’m not even trying to explain that.
That exam is not painful, not pleasant, and not anything you can study for; you simply submit, as patients are supposed to do, and then the impatience begins.  Most patients must wait to get their results from the doctor, and this is the longest wait of one’s life.  Am I dying more efficiently than before?  Are the cells multiplying more quickly?  How long have I got, doctor?
But I had learned the secret, which I now announce to all.  You are ENTITLED to your own reports, and with a bit of research as to when they get read, you can go get them.  Apparently for many imaging centers, this comes as a surprise, but we are all grownups and can explain that.  Sometimes your doctor will need to hear that too.  I have always just called ahead to the “Medical Records” department and asked for the report to be ready, as I have no patience…again.
But in August 2004, I had to be outside before I could read it.  To read a report of impending death inside a hospital with its metal window frames and linoleum floors and sad, bent people waiting their turns is too harsh a setting.  Immediately stepping outside, I could rip open the envelope, and read that my lung tumors were shrinking, even those big ones.  The 13mm lesion was now 8x9mm, the 8x7mm lesion was just 4x4mm.  And the countless other unmeasured one?  They were likely shrinking, too.  And 9mm is .354 inches, which I still can’t measure between my thumb and forefinger, but the CT scan could, and that was good enough for me.
Back to the hospital, a much easier trip than before, to get two more week-long sessions of HD IL2. The mets were shrinking and I was getting more ammo against them.  The cloak of invisibility was pierced and my immune system was working again.

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Immunotherapy Part 2: Is There Any Hope?

My first week at home following the CT scan was to be a recovery week, following five days in the hospital. When I had anticipated that first weekend, post Proleukin/High Dose InterLeukin 2 treatment, my plan was to go to a local kidney cancer meeting.  I would be a bit soggy, post “flu”, but not contagious, just recovering from the immune stimulant.  I planned to sit around, smile bravely, and look like those heroines in the old days of consumption.

As a measure of my mental competence, it was several weeks later before I realized I had missed the meeting, and in fact, had missed most of the week, and a good portion of the recovery week as well.  My response to the Proleukin was such that I did not receive but 9 of maximum 14 doses and had to spend an extra day in the hospital to recover.  The last thing I do remember of that week at UCLA was a doctor walking me down the hall, and seeing a sign overhead.  At least I could read, and knew I was in the hospital, and then somehow I was home.

Flashes of memory come to me of those first few days, retching in the toilet, and then being sat in the shower on a tiny plastic stool, and being scrubbed by my daughter, a miracle of an experience. And more odd oblivion.  At this time, my mother-in-law was headed deeper into an oblivion of Alzheimer’s, and I joined her.  One WEDNESDAY morning, I was reading the paper  v e r y s l o w l y…not my usual style, and I noted that the LA Times used Tuesday’s date.  Obviously this was major mistake, which rather incensed me, and tried to interest my husband in this crisis.  “What day is it?”  He also thought it was Tuesday!  For that matter so did the local paper, and the Wall Street Journal!

Naturally, I had misread or misheard this, so checked again, and asked again, and asked again, and read again.  Even the damn computer was in on this mistake, but I waited patiently for corrections to occur, and still they–now the entire world–claimed it was Tuesday.  And the family was getting a little odd in their responses to me. “Still Tuesday, Mom…”.

Not once all that Wednesday nor the Wednesday that followed it did I ever think for a second that I might have been mistaken.  My testing, my logic, my checking and rechecking all these reliable resources did not change my mind, but it did cause me to wonder why everyone else was wrong.  I figured the nice thing to do was to wait until they got it right.

It took me several months and a number of similar events to realize that this was a tiny gift from HD IL2–and insight into craziness, or whatever word describes the inability to accept fact in the face of facts from trusted and even beloved sources.  No wonder poor Nana could get so angry at all of us, and no wonder that telling her something in a logical manner was futile.  Her brain had been compromised by Alzheimer’s and mine by the medication that was trying to save the rest of me.

So was it working?  Brain issues aside, I felt fine, or so I told my oddly polite and amused family.  Taking a plate to the sink proved to me that I was doing all my household duties.  Writing a 25 word email in 30 minutes proved my computer skills were intact.  But what about those precious lungs and the icy white granules of tumor dividing relentlessly?

Without proof that the IL2 treatment was slowing down the growth, I would not have been permitted back into UCLA.  To push the immune system into the kind of response that causes it to seek and destroy the cancer cells so well-settled into my lung, not only the visible ones, but their countless and invisible spores, is dangerous.  No doctor wants to make a patient sick without hope that this synthetically induced sickness would drive out the virulent and relentless cancer cells, so it had to be shown to be worth the risk.

As I really became aware that I had missed one week and more in my life due to the treatment, and that I had no control of memory over what had happened in the hospital, I realized how hard it would be to readmit myself to the hospital.  Excuse after excuse–all good ones, of course–delayed my walk into the lobby, accompanied for the first time by fear.

Years earlier, as my father lay dying in our family room, he told me that he was afraid to go to sleep, for feared he would wake up dead.  We grinned wryly, and promised not to let that happen, though it did–everything but the waking up.  I was raising my hand and volunteering to do  just that, walking back in through the gray and damp parking entrance to UCLA.

Coming out the second week with equal blank spaces and some low blood pressure “events”, I was still alive, and could plan for my CT scan.  Back to the same place where they had first found and failed to tell me of the lung mets, and let them try again to “image” them.  (Is image now officially a verb?) One thing remained in my brain, and that was the knowledge of how to get the report from the CT scan done two weeks plus into my rest period after week two.

My son drove me to the scan center, as I was oddly not thought to be capable of going there myself, such a smart family, and parked as I rushed to collect the report.  It was at the desk, as promised, and I tore open the envelope, and pulled up the last few sentences of the report into view.  “Significant decrease in size of multiple pulmonary nodules!”

And back for more Proleukin.  And a cake that I ordered for myself, which read (Charlotte’s Web alert) “Zuckerman’s Famous Peg…Amazing.”



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Immune therapy in a Clinical Trial of Anti-PD-1 It Can be Good to be Anti

Dr. Suzanne Topalian, professor of surgery and oncology at Johns Hopkins Sydney Kimmel Cancer Center presented a paper at a recent ASCO meeting which caused quite a stir in the kidney cancer community.  Her short talk is in the link below, with the transcription to follow.Topalian and Title

What’s the good news about being anti?  The complex interplay of our immune system and the manner by which cancer escapes its notice is a challenge to the researchers, but this trial shows that there are many ways to interrupt the growth of cancer cells.  This trial and another mentioned offer new hope to patients who have already exhausted earlier options.

Not only did this trial show that this drug could provide relief to some patients with kidney cancer, lung cancer and melanoma, the presence of this anti-body may serve as a biomarker, and may predict which patients might respond to the drug treatment.  Another step forward and more hope for all of us.

Anti PD-1 (BMS-936558, MDX-1106)

Today I would like to describe do the clinical activity the safety and potential biomarker of clinical response to the drug PD-1, which is an anti-body therapy. PD-1 or Programmed Death-1 is a molecule that is expressed on the surface of activated immune cells it plays a very important role in suppressing the tumor by suppressing antitumor immunity.

1 role of PD-1 in suppressing antitumor immunity

In order to understand how anti-PD one works you need to understand a little bit how the immune system works, and how it can fight cancer. T-cells are a central cell type in the immune system that fight cancer. T cell function is regulated by two different signals. Signal one is a specificity signal, whereby the T cell recognizes its target and here we are talking about the targets being components of tumor Cell., but then you need a second signal to tell, the T Cells what to do, a regulatory signals.  That signal can be either positive or negative.

If the signal is positive or stimulatory,  t he T-cells become activated. They secrete cytokines. They can kill tumor cells. They proliferate; they percolate throughout the body, seeking out and destroying tumor cells.  All of that is what we want to see.

But after activation, T-cells naturally begin to express the molecule PD-1 on their surface. This is will turn the T-cells off.  If they encounter the partner molecule PD-L1 or PD ligand 1, tumors cells can express PD-L1. So the interaction between these two molecules becomes a protective shield, that shields the molecule from immune attack. Even if the T-cell can recognize the tumor and they can get to the tumor, once they get there and they are expressing PD-1, if the tumor is expressing PD-L 1, the T-cells will be turned off. The anti-PD-1 antibody is a blocking antibody to PD-1. It interrupts this interaction and functions to rescue exhausted T-cells and to enhance anti- tumor immunity.

The phase 1 trial of anti-PD-1 that I’m describing today is a multi-dose regimen in which something is given the outpatient in the outpatient clinic once every two weeks. Patients were treated for a cycle of four treatments over eight weeks. At the end of which, they were restaged. Patients were eligible for these trials if they had advanced metastatic melanoma, kidney cancer, lung cancer, prostate cancer, colorectal cancer with progressive disease after having had at least one prior systemic therapy.

But they were allowed to have up to five of the therapies. Generally these patients who came on this trial had good performance tab status. But they were heavily pre-treated. Approximately half of them had at least three prior therapies be before they came onto the trial.

After the first cycle of treatment if patients had rapid continuation of disease or clinical deterioration, they went off study. If they had unacceptable side effects, the patient remained on study. They did not receive any more drug, but they continued under observation. If the patient demonstrated tumor regression or stable disease or even if they  had some progressive disease, but were clinically stable, we continued to treat those patients until we saw confirmed Complete response, worsening or progressive disease or unacceptable toxicity.  We could treat patients on this trial continuously for two years. After, they went into a follow up phase.

3 BMS-936558 related Adverse Events Here I’m showing you the drug-related adverse events are side effects that occurred in at least 5% of 296 patients which was the total patient population on this trial You can see that serious side effects were encountered in 14% of the patients. The most common side effects are listed here (fatigue, rash diarrhea, pruritis, etc.) There other side effects that are not listed here because they occurred less frequently. Many of the side effects were consisted with the side effects with over immune related causality as you might expected if you release the brakes on immune responses. As we are seeing anti tumor responses, you might also see immune-related sided effects.

We did see three treatment related deaths on this study. This was in 1% of the patient population due to pneumonitis, or lung inflammation which we’ve believe has an immune-related etiology. Over the course of time we developed better ways to identify people who are at risk for the side effect and also better ways to detect it early on and to treat it aggressively.

Also note that only 5% of all patients treated on this trial had to discontinue treatment, due to related side effects so in general the treatment was well tolerated in an outpatient setting, and in general the side effects were manageable.

4 Clinical Activity of BMS-9356558

This is showing the clinical activity of anti-PD-1 antibody in three different types of cancer across a wide range of doses. (Showing doses (mg/kg) of 0.1-10 for melanoma, 1-10 for lung cancer, and 1 or 10 in RCC). The largest number of patients in this treatment population of 236 patients who had at least six months of follow-up were 94 with melanoma.  We had 26 patients (28%) who had objective responses. An objective response means either a complete response or a significant partial regression of cancer.

We also saw stable disease that lasted at least six months in another 6% of patients. Among lung cancer patients we saw patients with squamous as well as non-squamous subtypes we saw a CR plus PR of 18%, and with a patient population of 76 and again 6% with stable disease, with another group of patients with stable disease (referencing 7% of lung cancer patients.)

Finally in kidney cancer (33 patients), 27% had a response rate and 27% who had prolonged stable disease.  There were 31 patients on this trial who had a response that occurred at least one year ago and among those 31 patients, two thirds of them had a response that persisted for more than one year. One of the remarkable features about this therapy is that it can induce very durable responses in otherwise treatment-refractory patients with advanced disease.  We did not reserve any objective responses in 19 colon cancer patients or 13 prostate cancer patients.

Finally I’d like to draw your attention to a possible molecular marker that would allow us to predict which patients are most likely to respond to therapy.

In a subset of 42 patients on this trial, we examined pre-treatment tumor biopsies for presence of PD-L1—and again this is the partner molecule to the PD-1 that is expressed on tumor cells. What we found was a correlation between the expression of PDL-1 on tumor cells and here I am showing you the pre-treatment staining biopsies.

I am showing you with its ringed expression an example of melanoma, kidney and cancer in a sample of lung cancer. When we saw this kind of expression in that group of patients we had a 36% objective response rate.  If we did not see that expression on the surface of tumor cells we did not had no responders. I would stress that these are very preliminary data but give us an important lead for further investigations and potential biomarker development.

In conclusion anti-PD-1 antibody–BMS 936558– can be administered safely in an outpatient setting for heavily pretreated patients with durable clinical benefit for patients with lung cancer, melanoma and kidney cancer.

6 Conclusions

These results will be released tomorrow, as you know in the New England Journal of Medicine, which is under embargo until early tomorrow morning. At the same time in the New England Journal, there’s a companion paper with the blocking antibody against PDL-1. The lead author of that paper here is Dr. Julie Braemar of Johns Hopkins and shall be available to answer questions at the end of session.

We found responses also in melanoma and lung cancer and kidney cancer with a blocking antibody against PD-L1, so we feel these two studies are in a sense bookends to point up the point the importance of the PD-1 pathway in cancer therapy across multiple histologies.

The preliminary data correlating PDL-1 expression in pretreatment tumor biopsies with outcomes needs to be further explored and that’s an area of active investigation.  Finally controlled clinical registration trials of this drug with patients with the three types of cancer that seem to respond are planned. Thank you for your attention.





Filed under Biological Systemic, Clinical Trials, Immune Therapies Old & New

Immunotherapy: A Trial by “Flu-Like Symptoms” and a Lot More

When I was diagnosed with Stage IV kidney cancer, I just assumed that the doctor would take some sort of medically-approved SMALL melon baller, scoop out the bad stuff, and send me on my way, never to sin/cancer again.  That was my first plan, and one which couldn’t be.

First of all, there is no medical melon baller, and certainly not for a tumor the size of a big orange.  No tiny key hole scar for me, but a large incision, and the removal of my tumor, my kidney, an adrenal gland, and  a few local lymph nodes for good measure. Though the scan seemed to indicate that the tumor was scrambling up my vena cava, a big vein heading toward the heart, the scan was more ambitious than the tumor.  The pathology confirmed that my cancer was “clear cell”, which was good, as it is the most common subtype of kidney cancer.

Bad news.  There were hundreds of tiny mets all over my lungs,  the CT scan showing tiny evil snowflakes throughout my lungs. “Too numerous to count”. Impossible to remove by surgery or radiation. Systemic metastatic disease–very bad stuff– and the reality that  visible mets were outnumbered by the tinier ones still unseen in a CT scan.  Only one medication was approved for advanced kidney cancer in 2004. It didn’t really work for many people, maybe just 7%, according to the clinical trials that had led to its approval 12 years earlier.

This treatment was High Dose InterLeukin 2, brand name Proleukin.  No one else seemed to have ever heard of it> When I asked if they had heard of  “interferon”, most people nodded politely.  That’s how much general awareness there is of the life-saving regimen recommended to me.  Most doctors and few oncologist have never seen a patient in treatment with it.  Not the popular choice–but none other treatments existed!

Statistically, the odds for a good response were pitiful, but so were the odds for my getting kidney cancer in the first place.  The “Why me?”s became “Why not me?  Someone has to be in the 7%!”.   I talked to a patient who had gone through the treatment. She described it as “Hell”. I winced visibly, and she nodded in sympathy.  Still she was alive and at a meeting. Given the chance, she said she would do it again!   Thank you, Paula, for your courage.

Proleukin is essentially a synthetic version of your body’s immune system reaction protein. Thus, the patient reacts with a wide range of immune responses–all in hopes of revving up the immune system so that it recognizes and fight off the cancer cells. Those cells have escaped detection by the immune system, disguised as “evil twins” of the healthy cells.  If the Proleukin could empower the immune system to be super sensitive and aggressive in finding the tumor cells, maybe the cancer would be destroyed.

This is not traditional chemotherapy, in which all the cells are targeted for destruction, with the fastest-growing ones–the cancer cells–being the most vulnerable.  Chemo patients are bombarded again and again, in a delicate balance between killing the cancer cells and keeping the others and the patient intact.  Many people stay on chemo for months and months. But no chemo ever worked for my cancer.

My treatment was to happen in five-day spurts, offset by days and home to recover and then to return.  Roughly, I was to be in the hospital one week, out a week, back in for a week, and then rest and await the verdict delivered by a CT scan.  Good news meant I could be permitted to return for another set of treatments.  Bad news–go home and look for another clinical trial and…no one wanted to speak of it.

My mets were shown to be fast-growing after a series of CTs , so even  stabilization of  growth would be considered ample reason to return to the hospital. ” Just slow them down”, I prayed, “Let me back in the hospital.” Determined that even if the doctor could not whole-heartedly recommend it, I would go back for more.  Of course, that was before I had the Proleukin and understood what would happen.

Had Proleukin not been effective for me, I would not be writing this. Still I have little independent knowledge of all that I endured during the treatment.  My family usually says that I am happier not knowing, that it was brutal, that it took me to the edge of life.  No wonder they don’t want to talk about it.  But I was in a excellent hospital, with experienced staff, having been considered to be healthy enough to get through the treatments, and determined to live, what ever it took.

This medication is delivered by IV, through a port which led a tube straight into my heart, a channel to get that and all other meds to me as quickly as necessary.  Doses are given every eight hours, unless the patient is unable to tolerate the next dose, needing to recover from the reactions to the previous.  Over the five day period, a patient might get 14 doses, though few ever do.  In my case, I received an average of nine doses per week, and my length of day was twice extendedby a day, so that I could recover before I was sent home to recover some more.

I remember arriving home, rather suddenly, it seemed. No memory of the drive, just a vague recollection of  walking down the hospital corridor with a doctor and trying to read a sign.  Apparently that was a bit of a test, which I passed, because I was home.  Home–to recover and praying do it all over again.


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

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.


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

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

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.


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.


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.


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