Category Archives: Therapies

by | September 14, 2018 · 10:51 am

Is the Cheapest Medication the Best for YOU? Or is the Best Medication Cheaper in the Long Run?

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Started by Peggy Z less than a minute ago

Imagine hearing from your doctor that you must, “Fail first on this cheaper drug. Then I can prescribe a carefully chosen treatment.”

In January of 2019, new Medicare Advantage prescription rules change. Cleverly called “step therapy”, this is a step backwards for our RCC friends with MA plans, undermines the autonomy of doctors, limits timely access to approved medications and may shorten lives of patients given ineffective medication.

“Step therapy” takes treatment recommendations from the doctor and gives it to the bookkeepers looking for savings first. Benefit to patients is likely delayed, while the cancer grows.

With our multiple tumor types, not every medication is right for every patient, their side effects and stage. “Step therapy” is threat to basic and effective care and life-threatening for some.

Before getting the drug thought best for him, the patient must “fail first” before he can “step” to the next. What consitutes a failure?Lack of response, toxicity at a certain level, growth of more mets, and over what period of time? When can the patient go to the more effective drug?

In the long run, this may all Medicare patients, and all insured patients We cannot let this rule stand.

KCCure, on whose board I serve as a Patient Advisor  is one of 239 different organizations which is sending a letter to CMS–the Medicare agency–to protest the change and to explain its impact on us. ( Check www.kccure.org for lots of valuable information on kidney cancer issues.)

Do be aware that you can help by contacting your federal reps, to let them know how dangerous this change can be for all of us. Be prepared to explain that not every patient is the same, nor is every medication. Take a stand for yourself and your fellow patients.

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Filed under FDA Medications, FDA Meds & Trials, Guidelines, Patient Activism, Patient Engagement, Therapies

by | October 16, 2017 · 11:51 am

Clinical Trial for NEWLY DIAGNOSED–Surgery Now or Later with an Immune Therapy Option

Kidney cancer patients are stunned by their diagnosis, anxious to make a treatment decision, and  simply not know what to expect.  If you are struggling with the issue of surgery to remove the tumor/kidney or to start with a med, you need to read this.  Deb Maskens, Kidney Cancer Patient and Patient Advocate, our guest writer is a valued member of our disease community and currently serves on the Renal Task Force for the National Cancer Institute.  A series of links below will also be helpful.  (My extra comments will be in italics, like this. )Welcome aboard, Deb! 

Clinical Trial Opportunity for Newly Diagnosed (Non Metastatic) Kidney Cancer

As a community of kidney cancer patients, we  hear from newly diagnosed patients  looking for treatment options. This is written for those patients, and for patient advocates who help patients navigate through their treatment decisions.

The challenge: this clinical trial is available at many locations across the U.S. and Canada, but patients must ask about it BEFORE they have a nephrectomy. Their own doctors may be unaware of the trial and how to work with the trial centres.  In many places, patients get booked for surgery prior to learning about this option.  That would be too late for a trial like this–it gives a drug therapy before the surgery for a brief period.  (In one of the t wo arms, there is medication before the surgery.)

Why Might Patients Consider this Trial?

For years, the standard of care for early stage kidney cancer has been to remove the tumour surgically, sometimes with the entire kidney–either a partial or full nephrectomy. That was the end of treatment and the beginning of surveillance to watch for any signs of recurrence.  (And early stage tumors can be quite large–up to 7cm or about 2 3/4″.)

Now we hope to prevent a recurrence of disease. Since advanced or metastatic kidney cancer is still incurable for the vast majority of patients, this is a worthy goal. With preventive or ‘adjuvant’ treatments, maybe we can stop the disease before it gets to the lungs, liver, bones — to those places where it begins to threaten our lives.  Other cancers use this approach and offer patients a real chance to avoid recurrence.

Adjuvant – and Perhaps One Step Better to Neo-Adjuvant

We’ve seen trials for “Adjuvant” (or preventative) therapy which hope to prevent recurrence (treatments given immediately after nephrectomy). But one trial goes one step better – it’s for “Neo-Adjuvant” (before nephrectomy) as well as Adjuvant (after).

Patients may want to rush to surgery to “get it out”. In reality, those tumours have generally been  growing slowly, undetected for many years. Kidney cancer surgery is rarely an emergency. There is usually time for a second opinion and to check out any newer approaches.

Here’s the thought: given that the tumour cells have gone undetected and tolerated by the immune system for so long, can put those millions of cells to work and make them “show their calling cards” to our immune system before we take them out?

Combining Neo-Adjuvant and Adjuvant Treatment – PROSPER-RCC

The Phase 3 clinical trial called PROSPER-RCC (NCT03055013) is  for patients whose tumors are 7cm (2 ¾”) and larger in size, but not spread beyond the kidney area.  These patients are at greater risk of spread of the cancer than those with Stage I or with smaller tumors.

Based on earlier studies, nivolumab (Optivo) is now approved for advanced kidney cancer. This is a trial to test whether there is a benefit when nivolumab is given immediately before and after a nephrectomy when tumor cells might have spread outside the kidney but are too small (microscopic) to see on scans.  (Typically a patient without spread of disease would not be treated, but monitored.)

The Rationale for PROSPER-RCC: Why It Might Be Helpful

Here’s what I’ve learned:

  • Checkpoint inhibitor treatments with PD-1 blocking drugs like nivolumab seem to work best when the immune system may be being turned off by this cellular growth pathway. Cancer is deceptively clever and some tumours can express a protein, PD-L1. This protein can turn off our immune cell responses that recognize and fight the cancer.  There was a hint of this  with some positive data that indicates that these drugs work best in patients whose tumors were “PD-L1 positive”.  (PD means Programmed Death and PD-L Programmed Death Ligand or connector.  Death to the cells, and the signalling loop that hinders the immune response.)
  • In theory, when the kidney tumour is in place, there are millions of cancer cells. All of those tumour cells send off multiple negative signals to the immune system to stop it from working. However, if a checkpoint inhibitor was used and stopped those blocking signals, the immune system would have a big wake-up call – e.g., lots of targets with which to build an army of T cells. In theory, these newly educated T cells would later turn into memory cells. (If the body can maintain these memory cells, they would continue to fight any return of disease.)This is much like what happens when we are exposed to certain bacteria or viruses. Once we get exposed to the bug, we don’t usually get it again. Our immune cells have learned (“immunity”) how to kill it more quickly the next time before it turns into a full blown cold. Similarly, if these anti-RCC immune cells ever see one of these tumor cells anywhere in our bodies again, they would know to attack and kill them even if there is no drug in the patient and has not been for some time.
  • Surgery is still the main treatment to control early stage kidney cancer. But it will also remove the majority of targets (PD-L1) that the checkpoint drug uses to rev up the immune system. Giving the checkpoint inhibitor before surgery may maximize/optimize the drug’s ability to wake up the immune system and build that T cell army.
  • So the surgery is important. But let’s assume a few cells might be still circulating and have gone undetected for some time. They could still show up later on a scan as an enlarged lymph node or spot somewhere. A boost of the same checkpoint inhibitor right after the surgery could then be used to remind the immune system to continue to look for those cells and kill/eliminate them when they are small. In theory, the immune system will remember what the past “trouble” was: “Hey, haven’t I seen you before?”

From what I understand, this theory worked well in mice. The checkpoint inhibitors worked better if the primary tumour was there to help provide “a target” to activate the immune system first before the tumor was removed.  While we’re not mice, this  makes sense, no?

Trial Design: What Really Happens to the Patient in the Trial

PROSPER-RCC will place patients randomly into two groups:

  • Group One gets two infusions of nivolumab before surgery (at about 28 days and 14 days before surgery). Following that nephrectomy, the patient will receive more infusions of nivolumab. This is for 9 months post-surgery altogether, with 12 more doses.
  • Group Two gets the usual standard of care: upfront nephrectomy, partial or radical nephrectomy, and will be followed by close observation at an expert centre.
  • Two arms/groups:  BLUE arm with surgery  and monitoring by the trial team, the standard of care; the RED arm with  medication before to surgery, followed by more after the surgery.

It is important to note that no patient on this trial receives any intravenous placebo/inactive treatment. Every patient is treated.  Each patient will have either the experimental treatment or the standard of care.  All are under close observation at the trial centre. This trial has been designed and discussed with patient advocates and is supported by the NCI.

For More Information

Patient-friendly explanation here – http://www.10forio.info/clinical-trials/prosper-rcc

For contact information at over 100 trial sites, dig a bit in the site below:

https://clinicaltrials.gov/ct2/show/NCT03055013

or call the office of the Principal Investigator, Dr. Lauren Harshman, at: 617-632-2429

Deb’s Disclaimer:

As a patient and advocate for kidney cancer patients, I have been delving into the world of clinical trials and trying to understand as much as I can. I’m not a scientist, but I am a patient with this disease, so I bring that lens, along with some abilities to translate science into understandable terms. As a volunteer, I have no financial interest in this trial or any specific medications. @DebMaskensKCC; dmaskens@rogers.com

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Filed under Clinical Trials, FDA Medications, Immune Therapies Old & New, Making a Plan, New Trials, Newly Diagnosed, Patient Resources, Surgery, Therapies, Uncategorized

by | May 28, 2017 · 10:25 pm

New “NEWS!” for Non-Clear Cell re NIVO or NOT? Limited data or a light along the way?

With the headline, “Nivolumab Shows a Substantial Objective Response Rate in Refractory Non-Clear-Cell Renal Cell Carcinoma”, the article should be welcome to all of those in the  in the non clear cell RCC world.  Clear cell  is the most common, the garden variety of renal cell carcinoma.  This is welcome news, as the non clear cell patients get very little attention from the research world. Though the patient with nccRCC might interpret this as, “Good news! Now that they know what to do for me!” , it is just not the case.  Rarely is the news all that good or all that simple.

Let’s back up here and lay the groundwork.  Clear cellRCC, or ccRCC is the most common of about 10 RCCs.  They all land in the kidney, but can vary widely. ccRCC may be about 65% to 85% of the cases of kidney cancer,  with the rarer non-ccRCCs making up the rest.  Maybe 15-35% of the RCCs are considered rare, with the most common Papillary Type I, Papillary Type II, chromophobe, clear cell papillary, collecting duct/Bellini’s, medullary,  translocational (not to be confused with transitional, etc, etc.) and to make it still more confusing, unclassified RCC. But when the most common is described as either 65% of the whole or 85% percent, you have to question if there is clarity in that category!

Clinical trials for RCC have usually only included patients who had clear cell. The reasons are simple; it is the biggest group, the patients can be more readily found, and that is the largest group in need of the medications.  But the patients with nccRCC are really also terribly underserved.    Back in the day, none of us had many options beyond surgery, so little distinction was made.  The prognosis was grim all around, once the cancer had spread.

But the new world of precision medicine, in its name alone, reminds us that the meds need to be developed more precisely, that they be given to the right patients at the right time.  The general crap shoot or “wild-ass guessing”, as a friend says, still remains.  The latest (not necessarily greatest) group of meds are the newish immune therapies.  You have seen their ads, no doubt.

One of those is Opdivo or nivolumab, its research name.  It tries to unblock some of the inhibiting mechanisms that prevent the immune system from doing its job, but it has been tested in trials only with clear cell patients.  BUT,  that does not mean that only clear cell patients are being prescribed the meds–this, thanks to the slightly wild west of the US medical system, that can truly go beyond the FDA approved medication guidelines.

This study, which will be formally presented at ASCO in June, 2017 was announced with the headline above, “Nivolumab Shows a Substantial Objective Response Rate in Refractory Non-Clear-Cell Renal Cell Carcinoma”.  The researchers are NOT in charge of the headlines, so we must dig deeper and see what this study really means to the patients with nccRCC

I tried to sort out what it means–or does not mean. My quick review is that it does not give a great deal of clarity to the majority of those nccRCC patients. A more complete report may improve upon this.  Based on this link, I offer the following:

http://www.practiceupdate.com/news/16132/67/10?elsca1=

“I am always concerned that these new study reports are characterized carefully. They are always more complex and incomplete than I would like. A patient in a forum says this tells of  ‘good’ responses, and especially so for the non clear cell group, but s does ‘good’ really mean generally a benefit to those rarer nccRCCs? Until a fuller report emerges, I can only note the following:

There were 23 patients, from three centers, with a median age of 59. Surprisingly 30% were African -American. This may tell us that there are more African-Americans with the rarer non-clear cell RCCs, or  could reflect the local population of the three centers.  Only 23 patients and with a mix of diseases will never meet the statistically critical requirements to reach the level of excellent evidence–but it may be all we have at this point.

All 23 had non-clear cell, but nearly half had ‘unclassified’ RCC, quite a high rate.  Usually that is considered to represent between 1 to 4% of renal tumors. Most of the rest were papillary, but they generally make up the largest percentage of nccRCCs. No distinction is made here between Papillary Type I or Type II, which are really quite different diseases. Papillary Type I and II are the most common of the uncommon, non clear cell RCCs, and are readily distinguished from each other.  This would be valuable info, and wonder if this was noted in the fuller report. 

Only 3 of 4 patients had nephrectomies before the trial treatment. Were 1 of 4 patients too sick to be given the standard of care of surgery or were their doctors unaware of that? How does this affect the study, and were the no nephrectomy patients from one center or with one subtype?   We do not know the reason for this high rate of no surgery, and at a time in which it is clear that the removal of the tumor is a great benefit to the patient, metastatic or not.

Two-thirds had metastatic disease at the time of diagnosis. Of the total 23, 74% had a prior treatment, mostly Sutent or Votrient. Of these patients with prior treatments, 26% had TWO such treatments.  Thus these patients had already received treatments that were not directly approved for their subtypes.  This is not too rare in the US, where we have greater leeway from our prescribing doctor than do patients elsewhere.  But how does this fit in with the relatively low rate of nephrectomies?

This report does not say how quickly they were treated, i.e., how long from initial diagnosis until treatment with Nivolumab?A patient with Papillary Type II found to have no metastatic disease at the time of diagnosis, but who received a nephrectomy, was monitored for a year or so, then went on one or more systemic therapy is quite different from the patient with an unclassified RCC,  metastatic at the time of diagnosis, not given a nephrectomy, though treated quickly with Nivolumab.  What can be learned when there are such wide variations in just 23 patients that would be helpful to the Papillary Type 1 patient?

The follow up period was a median of 6.5 months, which seems very short, especially when the median Progression Free Survival of the responders was 4.2 months. The median OS is not given. That certainly may reflect an ongoing study situation, or a failure to provide a longer period of follow up.

As to objective response, 6 of  the 21 evaluable patients (29%) had a Partial Response, which would likely be a 30% reduction in metastases. Another 4(19%) had Stable Disease. Two of the 23 patients died, but not from the treatment. (Assume that had to be due to the disease, but certainly indicates that for nearly 10% of the patients, this was not at all effective.)

When the final analysis was done, nine patients were still receiving Nivo. Newly recruited patients might still be in treatment at that time, but those recruited earlier may have gone out of the trial at the same time.  It is important to not that Nivolumab treatments were stopped in three patients due to intolerance, and six more had postponed treatment, i.e., 9 of the 23.

Certainly we need to find meds which create responses for nccRCC patients. However,  I am concerned we draw any certain conclusions from this study.  Indeed, it is “good” to know that the treatment was tolerable for the majority of the participants, but not so good to read that 6 of the 21 patients had to postpone treatment, and three were removed from treatment due to intolerable/toxic side effects.  We also do not know which subtypes seem to have shown responses, which would have been qutie easy to report.  Did the group with Papillary Type II do generally better that the majority “unclassified” group?  No answer from this stury report. And in the back of my head, I keep wondering why in the world there were so many unclassified patients in this small study?  Was there a standard pathology review, or could these patients been misdiagnosed by one pathologist. Typically there is a single pathologist which can standardize the reporting.  Were all these patients properly diagnosed?

Just wishing there were greater clarity and hoping to get a fuller report, post ASCO.

Without a doubt, the ‘good’ that comes from this sort of report begins with the recognition that the nccRCC group is underserved by the research community> They probably have the poorest outcomes, rarely have a clear diagnosis, and must wait for the ever popular “further research is warranted.”  But all must be aware that these very small observational studies must be reviewed very carefully for what they show or do not show.  Again, one to watch at ASCO, but not enough to make a major change in treatment for any one with a non clear cell RCC.

PS.  Does your doctor know that there are at least four subtypes of clear cell–the big ‘common’ group–which have clearly different survival patterns?  Thought so.

 

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Filed under Basics, Clinical Trials, Immune Therapies Old & New, Rarer RCC Cancers, Surgery, Therapies, Uncategorized

by | April 16, 2017 · 10:35 pm

“Predicting Short Survival” article: A Self-fulfilling Prophecy for the Newly Diagnosed

I thought I had seen enough articles which concentrated on the stats of how poorly kidney cancer patients did, but then, this one came along from Norway.  “A Three-Variable Model Predicts Short Survival in Patients with Newly Diagnosed Metastatic Renal Cell Carcinoma”, just published in 2017, it is shocking and may create barriers to proper care for patients.  The title might have been more accurately titled something like, “How We Fail to Find Kidney Cancer, Therefore Dooming Many to an Unnecessarily Efficient Death”.

Maybe it especially bothers me, in that I have come to expect more of the several Scandinavian health system as I understood them. Also, that I am 1/4 Norwegian, it seems a personal affront.  To lay the ground work, I shall remind you that kidney cancer is often found in the ‘6th” decade of life, or in the 50s, 60s and 70s, most often.  (Any earlier, and there might be a genetic problem, by the way.)  But it is also slow-growing, often can do so without many overt symptoms, but there are often hints.  Of course, if you do not look for those symptoms and search out those causes, you get that slow-growing cancer to establish itself quite thoroughly!  You know the rest of the story, no doubt.

The facts are as follows.  Norway is generally sparsely populated, having about 5.2 million people, with an aging populations, with about 11% over age 70 at present.  There were about 814 cases of kidney cancer in 2014, and more to more, per the stats.  The background statement of the above study notes that it is “important to have realistic perspectives, especially if the expected prognosis is very unfavorable”.  Already I am wondering how expectations by the doctors affect the care they are about to give the newly diagnosed.

In one small area of Norway, Norland data was collected about all newly diagnosed patients, with the stated concern that in trying to select the “best treatment option for an individual, the poor prognosis groups is the most challenging one because aggressive approaches may result in serious side effects in these often frail patients.”  Thus, the researchers wanted to find out how those patients treated within the national guidelines failed.

A central measure of their expectations–no doubt built on the previous years’ patient responses–was the definition of “short survival”, i.e., after the initial diagnosis.  Short survival was for 3.5 months or less…yet the concern from above is in regard to the ‘serious side effects’ in these patients.  Dying within 3.5 months of diagnosis in a modern health care system seems a pretty serious side effect as well!  In this small area there were 48 patients identified in this recent study, 10 of whom died within 3,5 months.  Those 38 patients who lived four months or longer were deemed to have had long survival.  Obviously those patient who were doing badly at the time of diagnosis seemed to die  more quickly.  This seems at odds with the American experience, with much long general overall survival, but it is hard to get those stats, as the US measurements are in terms of YEARS of survival.  A metastatic kidney cancer patient is a Stage IV patient, with the 5 YEAR survival at 8%, per the American Cancer Society–whose stats are necessarily behind the times.  They modify that to note that low-risk patients have a 41% survival rate, intermediate risk patients have a 18% survival rate, and the high-risk patients have the 8% survival rate at five years.

Why such a difference?  The disease is similarly divided 2 to 1, male to female, and there is a near-similar mix of subtypes, such as clear cell, papillary and chromophobe.  The median age at time of diagnosis is 68, slightly higher than in the US. However, in the US, only about 30% of patients are found to be metastatic at time of diagnosis, but in this small study, 70% were found to be with metastatic disease upon diagnosis or within 3 month of that time.  Most important is to note that only 65% of patients in this study were given a nephrectomy, either full or partial.  And post diagnosis, only about 56% of those patients received any systemic treatment.

That seems enough to tell me that these patients were treated very differently that most US patients in terms of surgery, but other statistics were striking. Though the 60-69 age group represented 58% of the patients, only 3.3% were found under 60 years of age.  Was nobody looking for cancer in this group? Imaging for other diseases often reveals kidney cancer, so the 3.3% seemed off the statistical mark.

Only 30% were found to be in ECOG Performance status 0-1, with 70% already struggling with the effects of their disease. Another measure indicates that only 18% had good performance status.  This causes me to wonder how long those patients struggled as well to get a necessary imaging study to verify the presence of a kidney tumor.  (Only 65% of those got the darn things removed!)

Over 55% of all these patients had low hemoglobin, one of the simplest measures found in every blood test.  A pretty good clue that something very fundamental was amiss with these patients. In the group who died within the ‘short survival’ period of  three months, 50% of them had SKIN metastases.  Again, a very visible symptom, and hard to ignore when found with the low hemoglobin.

So how did they do in terms of median Overall Survival?  That was only 13.2 months, and with a 2 year survival rate of 40%.

Perhaps late to be diagnosed, with far fewer nephrectomies than in the US, and with far fewer systemic therapies applied post the time of diagnosis–no wonder the outcomes are so poor! Does this influence the doctor as he diagnoses a patient with low hemoglobin and some odd skin manifestations.  Does he recommend a nephrectomy–and how long does it take to get into such a surgery?  Does the likelihood of a poor outcome prevent the doctor from taking a more aggressive approach, not to recommend any systemic treatment for 43% of those patients? Does he just assume the patient will succumb very quickly to the disease!  Does that create the poorer outcomes in these patients?

A self-fulfilling prophecy is oddly reassuring to the party who makes the prediction, as he unwittingly works to make that prophecy come true.  Poor expectations for survival may well lead to that very outcome.  Wish it were otherwise.

 

 

 

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Filed under Guidelines, Newly Diagnosed, Surgery

by | May 16, 2016 · 7:33 pm

Lenvima/Lenvatinib with & without Everolimus–New FDA approval

Another new drug for those of us with ‘unresectable and advanced” kidney cancer!  YEA or is is just, yea? What does this mean to the patient in this situation as he struggles to get the best treatment possible?

The approval is for Levatinib in combination with Everolimus (Afinitor) for advanced kidney cancer or unresectable (surgery not possible) kidney cancer in patients who have had previous TKI treatment–Sutent, for example.  This was based on a Phase II trial, so a bit unusual in that regard.  Generally the FDA waits until there is a larger Phase III trial, so this reflects the  need for better second-line treatments.

It is always great to have another tool against kidney cancer, and on top of the recent approval of Nivolumab (Opdivo) and Cabozantinib (Cometryx), but do note that all three are for second line use, after the first line meds have failed.  Current first line drugs include high dose interleukin, Sutent and others.

All the patients in this trial had previously used and quit responding to the first line TKIs, and are compared in three arms

Arm 1)  Lenvatinib alone–52 patients—didn’t make the grade

Arm 2) Everolimus alone–51 patients—standard of care for second line

Arm 3) Lenvatinib & Everolimus in combo–51 patients–the new approval.

Not a very big trial, so harder to make broad judgements!

Everolimus is already approved for second line use, and Lenvatinib alone was NOT approved except in combination with Everolimus.  With that, just ignore Arm 1.  The big news is that the combo improved median Progression Free Survival (PFS) in the combo to 14.6 months vs 5.5 months with Everolimus. The median gives us the POINT in time at which half got “progressed” on their disease, ie, the damn stuff grew, while the other half had not yet had progression.  Not an average, so half of the combo patients had PFS by 14.6 months, and the other combo half did not have PFS until after that time.

The median Overall Response Rate (ORR) was not very high–but quite typical–and important to understand.  The combo patients had a 37% ORR, so about 1 in 3 had a measurable response.  That compared to just 6% with everolimus.  The most important measure to patients is median Overall Survival. This is usually measured when one-half of a patient group has died, so there are always patients who live beyond that median point. The combo OS was 25.5months vs the Evero alone OS of 15.4 months.  There was no mention I could find whether there were patients alive at this point, but assume there were. Love to know if there are very long term survivors in the combo group, and what makes them more likely to have that response!

In the combo, 29% of the patients discontinued treatment due to side effects and with Everolimus alone, 12% discontinued.  However, both groups had large number of reduced dosages and/or dose interruptions, 89% in the combo group, and 54% in the evero group.  Read: some tough side effects.

The most serious side effect in my opinion was that renal failure occurred in 11% of patients in the combo, 5 of the 51 patients.  Grouping ‘renal impairment with failure”, the combo caused such problems in 18% of those patients, 12% i the evero group. Not good news for those of us with one kidney, so something to be monitorly VERY carefully.

The other ‘usual suspects’ in the side effects in the combo were hypertension 42% vs 10%, diarrhea 81% vs 19%.  Not surprising was a fairly high rate of ‘hemorrhagic events”, ie, bleeding problems in both groups, 32% vs 26%. And more.

Again, not easy, better than no treatments,or using everolimus alone.  All these meds demand good communication with the treating team and patients.  Sadly missing in this trial and in every other one is any real guidance as to which patients might best respond to this combo. Neither is there a neat comparison to the second-line use of Nivo or Cabo.  Practice, practice, and be aware of your own health issues as to side effect potential as you look at these trials and your own situation.

http://www.multivu.com/players/English/7690031-eisai-lenvima-fda-2/  for the company’s review and videos by Dr. Sumanta Pal at the City of Hope and a spokemans from Esai.

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Filed under Clinical Trials, FDA Meds & Trials, Medications, Patient Resources, Targeted Therapies, Therapies

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by | November 13, 2015 · 10:04 pm

Immune Therapies: Headlines, Hype or Hope?

Recent headlines called a new medication, Nivolumab, both a miracle or breakthrough and more.  Is it hype or hope?Why is it so hard to sort out the reality?

Let’s go through the facts from the New England Journal of Medicine and ignore the headlines. First, its being  in the NEJM is important, as it has passed review by other researchers.  (Sadly missing in too many ‘breakthroughs”).

The new med, Nivolumab was compared against Everolimus, a second-line treatment. Therefore Evero is thought to be of lesser effectiveness than the first line meds.  Second-line meds are generally used when others meds quit helping or their side effects are too hard. Automatically NOT the miracle cure, but another option when first-line treatments fail.

Should Nivo have been compared to the first-line meds?  Being better in the first-line would be bigger deal, but we need more approved meds. Second-line treatments usually are easier to ‘beat’, as the new med must be better or less toxic.  Again, more likely to be approved!

PATIENT CHARACTERISTICS

The study had 821 patients 24 countries, half using Nivo and half Evero. Patients were similar, 90% having had a nephrectomy, removing the tumor and some or all the kidney. Then the cancer spread, making metastases, (mets, for short). These patients had 1-3 treatments, first-line drugs like Sutent, a targeted therapy, and a few had used cytokines or even chemotherapy.  Having had an mTOR inhibitor like Everolimus was not acceptable. Most had lung mets (67%), followed by liver(12%) and then bone mets (18%). Most with 2 or more sites of mets.

To enter the trial, the patient had to have had disease progression after their last treatment, within six months of enrolling in the trial. No doubt, some patients had greater disease progression than others, but had relatively good performance status, not completely bed-ridden or unable to function.

The median time from initial diagnosis of kidney cancer at any stage to entering the trial was 31 months;  half had been diagnosed less than 31 months ago, and half more than 31 months before the trial. That range of time from diagnosis to trial was 1 to 392 months. That means that for some patients, they went a long time either fighting the disease since diagnosis, having a later recurrence, being treated, yet having disease progression years after the intial diagnosis.  At least one person was diagnosed 392 months earlier. This is a good reminder to patients who have been told, “I got it all”. This darn stuff can return, so having a plan B is important. Again, the previous treatment failed and these patients got directed into this trial.

GENERAL RESULTS

Median Overall Survival (OS) is a measured when one-half of the total number in the group dies. Median OS for Nivo was 25 months with some patients still surviving at time of report, beyond the 25 months. For Evero, OS was 19.6 months, some of who were also likely surviving, as well.  The OS of 25 months was clearly better with the Nivo group by this analysis. Nevertheless, half of all the 821 patients total died while on this trial from progressive disease.  Of  183 of the 410 Nivo patients, 183 has died by 25 months, and 215 of the 411 Evero patients had died at 19.6 months. 

 

There is no report of ongoing response here, but many went on to other meds, as explained below. 

Median Progression Free Survival (PFS), measurable growth of disease,  was 4.6 months for Nivo, 4.4 months for Evero.  The median shows that half of each group, roughly 200 each had return of disease in less than 5 months!  Again, these trial patients were pretty sick or at risk. All had been treated earlier, and had to stop previous treatments due to recurrence of disease. However, this shows a pretty quick return of disease or new growth from the base CT scan for nearly  65-70% of all patients.

One subgroup did a bit better than the 4 1/2 months median PFS.  At six months after the start of treatment, there was a special subgroup was noted,  about 1/3 of those patients–145 pts (35%) with Nivo, and 129 (31%) with Evero. Obviously they did not die or have Progressive Disease until after six months.  The Nivo group had eventually had a median PFS of 15.6months, and the Evero group, 11.7 months.  Their success pushed the median OS higher, especially for the Nivo group.

Obviously, there were some patients with far more aggressive disease in both groups, some dying before six months, and others not progressing to more disease until after six months.  In contrast, nearly 1/3 of all the patients had PFS of 12-15 months, and much longer OS. What is the common characteristic in the most successful two groups in both arms of treatment?  Not answered by this trial report.

The duration of treatment was longer with Nivo, and likely easier to tolerate. Since Nivo was given by IV every two weeks, the doses were most consistently received. Even so, 51% of them had dose delays, but no per dose reductions.  Those people were seen by the medical team every two weeks.

The Evero group took oral meds, and 66% had dose delays or interruptions with 26% with at least one dose reduction. This would indicate that these meds could be hard to take, or perhaps lacking the same interaction with their medical team.  Of course the Evero patients may have underreported how much of the medication they actually took!

However, the reported types of side effects were generally similar, but the more severe grade 3 and 4s effects in the Evero group.There were 2 treatment related deaths in the Ever group, none in the Nivo group.

POST PROGRESSIVE DISEASE

Even after the disease did progress, about half of  patients in both groups stayed with their meds–despite ‘failing’, the researchers hopes that would continue to benefit, perhaps slowing the disease.  In a local clinic setting or with a less experienced docs, their meds might have been stopped or changed. Afterall, those meds were no longer “working” and  mets are growing. This approach is significant to consider, especially after multiple treatments.  (The decision to keep giving a medication or increasing its dosage where tolerable is causing some changes in treatment in a number of the targeted therapies.)

Perhaps because of being in a trial or getting care than was more expert than most, one-half of  patients chose to keep on the trial meds.  Others crossed over to the med in the other arm or returned to existing non-trial meds. In some countries, there were likely fewer choices than in the US.  There are no real stats as to survival for those on those who stopped taking the meds. It is reported that indicate that 55% of the surviving Nivo group and surviving 63% of the Evero group went on to other agents. About one-quarter of the Nivo group shifted to  the Evero. Of the Nivo group, 36% shifted to axitinib.

Sadly, as per the chart in the New England Journal of Medicine, all these patients had died by 30-33 months post enrollment.  However, it is again not clear what was effect, if any on that period from the non-trial drugs.  Of the 227 who stopped Nivo for any reason, nearly half shifted to Evero. Of those who stopped Evero, 140 went to Axitinib.

DURABLE RESPONSES?  HOW LONG? FOR HOW MANY?

The writers of the study say that there was a higher number of objective responses with Nivo vs Everolimus, and that many (of the Nivo group) “were durable”.  There is no definition of ‘durable’.  My question is “What equals durable?”.  We patients really want a cure, but are very grateful for anything that pushes the cancer back, slows it, stops in from growing any further. Nevertheless, we do want those responses to last.  The clearest reference to durable responses is a note that 32 of the Nivo patients and 6 of the Evero patients had a response that lasted more than 12 months.  But in an unexplained statement, the median duration of treatment was just 5.5 months for the Nivo patients, 3.7 for the Evero group.  It seems that there was not an extension available, or that the patients moved on to a different treatment or passed away.

CONCLUSIONS AND EDITORIALIZING AGAIN

It seems that Nivo is more helpful for some patients than others in this group previously been treated with other TKIs. This is NOT A SILVER BULLET.  There would be greater value to know more about the molecular nature of  the tumors of the responding and the non-responding patients.  We desperately need to know for whom any of these drugs is likely to be more effective.  The headlines that don’t discuss that challenge underserve us, as does the design of the trial that does not elicit the more nuanced, genomic data that could be forthcoming!

We all know that headline claims are more wonderful  than the reality.  The story of RCC medication development is that of more and more help in a difficult disease, making mixed progress, while the other researchers find out that RCC is really many diseases.  Clear cell is probably better defined as being made up of four types, Papillary Type 1 and Type 2 being further divided into three Type 2, then there is chromophobe, clear cell papillary and the really odd versions of RCC.  I known this, and so do you.  But why don’t the researchers incorporate those definitions and monitor the patients with those various subtypes as they go forward?

Good luck to all of us.

 

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by | May 7, 2015 · 12:06 pm

Younger Patients & Kidney Cancer: Your Genes or Your Luck?

Once you reach a ‘certain’ age, you are horrified, but not surprised to get a cancer diagnosis, or hear about it in a loved one.  That same cancer in a young person is even more horrifying, we instinctively know.

Most kidney cancers (and there are more types than we previously knew) are found in people in their 60s and 70s.  Bad enough, but a cancer called by the same name and found in a younger person is often a very different cancer, with a very different prognosis.

Some new research recognizes that special attention should be paid to those RCCs found in patients 46 years of age and younger.  Why is this?

The quick answer is that this may represent a more aggressive kidney cancer and/or be of a familial or hereditary nature.  That important distinction has researchers strongly recommending that young patients be referred for genetic testing.  This can explain those special risks and create more appropriate treatment plans, and alert other family members as to special monitoring. Critically it may change the approach to any removal of the kidney and/or tumor.

Typically a small renal mass might be monitored or removed by either surgery or some laser ablation.  If removed, the tumor can be assessed by a pathologist–a look under the microscope.Without a prior biopsy, the ablated tumor will not be examined, and no genetic testing can be done.

BIG HOWEVER HERE: even with a good pathology report, that may tell only what that tumor looks like–not what pushed it to grow, i.e., the genetic drivers. And those genes don’t go away with the tumor, so the risk remains that more tumors will grow, maybe in the second kidney, or in the partially removed kidney.  Plus the rest that can happen with cancer…

An 75 year old whose small renal mass is removed will likely function well with one kidney.  That same tumor  in a 35 year old creates another challenge.  If that tumor is driven by familial genes–not just by sheer bad luck–more tumors on the other kidney may be in the works.  A partial nephrectomy   must be considered. The risk of more tumors emerging in that kidney AND the other kidney is high.  The younger patient needs decades of good kidney functioning, but those decades carry the risk of the emergence of more mets.

What else should trigger a genetic testing?

Quick answer: anything that doesn’t look like the senior  citizen with a single tumor in one kidney.  More officially below:

Early onset of kidney cancer is 46 years or less.

Bilateral (two-sided) or Multifocal (many locations) kidney tumors

Family history of kidney cancer, 1 or more close relative, 2 or more in more distant relatives

Kidney cancer with either a mix of other tumor types roughly related to kidney cancer or with lung cysts or pneumothorax (air leaking out of lung into chest cavity)

Personal or family history of kidney cancer syndromes.

The above list is from Yale  School of Medicine, Professor Brian Shuch, who work includes dealing with heredity forms of kidney cancer.

More small renal masses found at an earlier age in more patients, as our imaging techniques improve and more CTs scans are done. Not all will be hereditary, and many will be sporadic or out-of-the-blue kidney cancers.  Those are likely due to the sheer chance. Things go wrong as trillions of cells divide and make DNA mistakes along the way. Years of environmental damage may overwhelm the body’s ability to correct those DNA mistakes–i.e., the immune system gets overwhelmed, tricked, tired, etc.

Kidney cancer found at an early age or with the bilateral/multifocal tumors simply must be tested as to it genetic origins.  This gives information critical to protect the rest of the kidney(s) and to participate in treatment that is more helpful.  Finding an effective treatment will still be a challenge, but proper treatment requires knowing exactly which kidney cancer you have.  From there, a real plan can be developed.

Just as I remind all readers to work with an experienced RCC oncologist–not just a surgeon and/or urologist (sorry guys, we need a team)–those who fall into this early and hereditary renal cell carcinoma category must also work with super specialists.

The person to contact at NIH is genetic counselor Lindsay Middelton at (301) 402-7911. She is with the National Cancer Institute’s Urologic Oncology Branch.  An introductory link is below to the NCI and two other rare kidney cancer organizations.

http://www.cancer.gov/cancertopics/causes-prevention/genetics/genetic-testing-fact-sheet

Birt-Hogg-Dubé syndrome:
http://www.bhdsyndrome.org/for-families/what-is-bhd/

Other syndromes causing kidney cancer:
http://www.bhdsyndrome.org/for-families/kidney/other-causes-of-hereditary-kidney-cancer/

 

 

 

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by | March 4, 2015 · 1:47 pm

Recurrence? Is There an App for That–or a Medicine?

Being diagnosed with kidney cancer is a stunner.  Facing surgery and endless, oft unanswered questions changes your life.  Patients with small tumors, easily removed, are often told not to worry about it coming back.  Of course, there is ALWAYS the possibility that even small “I got it all tumors” can recur.  Sadly, the current guidelines fail to catch about 30% of recurrences, using the 2013, 2014 guidelines.  These guidelines were from an earlier era, where there were fewer small tumors found, so there was data lacking on long-term follow-up.

We patients ask? “Why not just take the meds that the patients with metastatic disease do?  Wouldn’t that prevent it from coming back?  If it works to fight the mets, why wouldn’t it prevent new ones from getting a foothold? “

Why not use the meds that they use now against metastatic disease? Why wouldn’t that work?  Have they tested that idea?

In February of 2015, a study was released which comparing patient response to 1) sunitinib (Sutent),2) sorafenib (Nexavar), or 3) placebo (no real medicine).  This  three-arm study included 1,943 patients who had locally advanced clear cell and non-clear cell histology RCCs. They were thought to be at high-risk for recurrence of their cancer, and might benefit from “adjuvant” therapy.  The researchers hoped that they would see a 25% improvement in time to recurrence of disease with the meds vs no meds.. That would means that the typical 5.8 years median Disease Free Survival (DFS) would go to 7.7 years.

Sadly, there was no benefit to taking the active drugs compared to the placebo.  More sad is that the patients had side effects associated with the drug, referred to as “adverse events”. In fact, many dropped out of the active agent arms into the placebo arm, certainly knowing that the med they were taking were anti-cancer meds.  Those “adverse events”, severe fatigue, hypertension or hand-foot reactions, were observed in those taking the active agents and rarely in the placebo patients.

The median time on the drugs was 8 months.  That means half the patients  were on drugs more than 8 months and half were on the drugs less than 8 months.  Even those patients starting with lower doses of the drugs fared worse than the placebo group.

Despite taking the medications and enduring the side effects, the recurrence was about the same.   With medication or without, these patients, as groups, did the same.  Those taking the meds had Disease Free Survival of 5.6 or 5.7 years, similar to those not taking any real meds.  There was no real added benefit to these patients.  Certainly the quality of the life was affected by the side effects, and the constant reminder of the spectre of more cancer.

What can patients learn from this study?

The fear of recurrence is real. After all, the expected time until the disease progressed (love using that term for cancer!), was about 5 1/2 years.  These patients were carefully monitored with CTs on a regular basis, which caught their recurrences as soon as possible. Had they not been in this trial, it is reasonable to expect that many would not have received those scans and not know of the recurrence as it happened.

The reality is that the typical patient may or may not continue to be monitored. Even those who passed the 5 1/2 year mark without recurrence may not realize that RCC can come back.  Again, 30% of recurrences in small, non-metastatic disease are not caught.  One can assume that the higher risk group in this trial would also be at risk for that level of recurrence.

Take-home message: At present, nothing has been shown to prevent recurrence of this locally advanced disease. Even the non-metastatic small tumors that have sent out invisible “wanna-be mets”, and no one can yet guess who is at the most risk.

The best approach is to monitor yourself and your general health and to demand CT scans, especially in the lungs, where metastatic RCC is most likely to start.  That does NOT mean an x-ray, as those mets would have to be about 1/4″ in order to be seen.  My own lung mets were under that size when first found, but there were hundreds of them, and they grew quickly.  Not visible on an x-ray, but growing every day.

Despite the disappointing study above, the ASSURE study, more clinical trials are recruiting patients for similar studies using drugs that have already been shown to be less active than those in the ASSURE study.  I would be cautious in getting into such a trial, and would spend my energies seeing that my monitoring is extended at least until 10 years past my surgery–even with those “got it all” primary tumors.

 

 

 

 

 

 

 

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by | November 17, 2014 · 3:02 am

HD IL2: Cures, Partial Response or Stable Disease=Clinical Benefits to Patients

Is it a cure or nothing for cancer patients? 

Is there another way to measure the benefit from any medication?

We all want the cure, the Complete Response (CR) that can lasts many months or years.  Often we have to settle for some reduction in our tumors or mets, a Partial Response (PR). But even “Stable Disease” is welcome news.  To get that cancer back in its cage, even for a time, is  better than “Progressive Disease”.  When the cancer is progressing, your life may be regressing, and that isn’t what you want to hear.  That Progression Free Survival (PFS) has to start with stopping the cancer.

As complete and durable (ten years) responder to high dose interleukin 2 (HD IL-2), I welcome any discussions of “Clinical Benefit (CB)”.  CB includes all the good responses with any cancer treatment, CRs, PRs, and SDs.  We and our doctors need this information to make informed decisions about treatment, for IL2 or other meds. The value of Stable Disease has been ignored in many studies.  Maybe there are lessons here for you and your doctors, especially about the under-utilized HD IL2.

Clinical benefit (CB) of high-dose interleukin-2 (HD IL-2) in clear cell (cc) metastatic renal cell carcinoma (mRCC).

Source URL: http://meetinglibrary.asco.org/content/123909-142

(Abstract is below)

There are few new studies about the use of HD IL2 following the approval of the targeted therapies. The ease of use of these agents, along with the desire not to send patients to specialty centers for IL2, limited its use. It was difficult to select patients, and the CR and PRs were relatively small in number. Doctors often did not discuss the possibility of a cure with their patients.  Did patients also miss the chance for Stable Disease, and with it, a  “Clinical Benefit”?

Patients in this study who did not have a CR, but whose cancer stopped growing benefited.  That CB was not counted in terms of the approval of the drug, nor do doctors consider it in their recommendations. Should this possibility be discussed with patients?  Most patients would surely answer, “Yes!” to that question.

The researchers recognize of the value of Stable Disease (SD) as an outcome, versus only Complete Response (CR) or Partial Response (PR). The usual outcome measures, Progressive Free Survival (PFS), or Overall Survival (OS), are noted, as isTime to Next Treatment (TNT). TNT implicitly recognizes that a failed or limited response will likely be followed by another treatment.  Early on, there were no subsequent treatments, sad to say.

The original clinical trial which led to FDA approval of HD IL2 recognized only CR, which was 5%, with the median not reached during the trial, and PR, which was 14%. Study footnotes indicate that three of the PRs had surgery which rendered them disease free at the time of the publication. This would now be called a “salvage therapy”, and put them in the No Evidence of Disease (NED) class. A different analysis of this data would have upped the CRs some small percentage, and some SD would also have been found.

Also the definition of PR was 50% or greater reduction in measurable tumor size, the sum of the perpendicular diameters of all lesions, with no new increase of size of any other mets. Far less strict measurements of PR were used in the targeted therapy trials, with a 30% tumor reduction defined as a Partial Response.

 With those definitions in mind, note that there are CRs in 11% of patients, with a PR in an additional 6% of patients. Most important is the SD category, which was achieved for 31% of all patients.   This total of 47% is described for the group as being of Clinical Benefit (CB). Certainly patients value the responses of SD, which seems to have provided slightly over one year versus 3-4 months benefit to those who did not have SD.

 When comparing the value of Objective Response (OR) with its median of 1616 days to that of Stable Disease (SD) measured as 1476 days, one can clearly see the value of achieving Stable Disease. Unfortunately, those patients with Progressive Disease, or with responses Not Evaluable (NE), showed OS of 365 days.

Patients should be aware of these definitions and the impact the lack of parallel comparisons in making these critical decisions.  Ten years ago, the patients reminded one another to stay alive until the next treatment.  Having Stable Disease made that possible.  Let’s apply the same tests to all the available treatments when making these life-changing choices of treatment.

ABSTRACT FOLLOWS Citation: J Clin Oncol 32, 2014 (suppl 4; abstr 461)

Author(s): Neeraj Agarwal, David D. Stenehjem et al University of Utah, Huntsman Cancer Institute, Salt Lake City, UT; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Pharmacotherapy Outcomes Research Center, College of Pharmacy, University of Utah, Salt Lake City, UT

Background: HD IL-2, an immunotherapy, is a standard of care for a select group of patients (pts) with mRCC. Generally objective response (OR) rates, i.e. complete response (CR) + partial response (PR), of 16-20% are discussed with pts, but not disease stabilization (SD). Recent data suggest that cancer immunotherapy may improve survival without inducing OR. Thus, treatment with HD IL-2 may provide survival benefit to an additional group of pts not experiencing OR, but only SD as the best response. Here we report CB (OR+SD), and specifically report outcomes of cc mRCC pts experiencing SD as the best response, on treatment with HD IL-2.

Methods: All sequential cc mRCC pts treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000-2012 were included. Pts were evaluated for best response, progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS). Two practitioners independently reviewed HD IL-2 response with discrepancies adjudicated by a third reviewer.

Results: 85 pts, 79% male, were identified with a median age of 56 (range 32-76) years. Pts belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. A CR was identified in 9 (11%), PR in 5 (6%), SD in 26 (31%), progressive disease (PD) in 38 (45%), and unknown/not evaluable (NE) in 7 (8%) pts; yielding a clinical benefit in 40 (47%) pts. The median PFS, TNT, and OS in these individual groups of pts are compared in the table.

Conclusions: A clinical benefit of HD IL-2 was achieved in nearly half of all clear cell mRCC patients. OS was not significantly different in OR and SD groups. Even though OR favorably determine outcomes, SD is also an important response criterion, and may be discussed during counseling patients for treatment with HD IL-2.

  PFS, days TNT, days OS, days
Overall 152 264 817
SD vs PD and NE 337 vs 78 (p<.0001) 373 vs 110 (p=.0001) 1,476 vs 365 (p=.0003)
CB vs PD and NE 791 vs 78 (p<.0001) 735 vs 110 (p<.0001) 1,616 vs 365 (p<.0001)
OR vs SD, PD and NE NA vs 99 (p=.0003) 953 vs 166 (p<.0001) 1,616 vs 603 (p=.0021)
OR vs SD NA vs 337 (p=.0234) 953 vs 373 (p=.0015) 1,616 vs 1,476 (p=.2094)
Abbreviation:PFS, Progression Free Survival; TNT, Time to Next Treatment, OS, Overall Survival; NA, not achieved;SD, Stable Disease; PD, Progressive Disease; NE, Not Evaluable; CB, Clinical Benefit;CR, Complete Response; PR, Partial Response;OR, Objective Response
 

Abbreviation: NA, not achieved.

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by | November 8, 2014 · 6:24 pm

My Radiologist or New Best Friend

In our kidney cancer world, it is unusual even to know the name of the radiologist, and most patients rely on his report, as given to the doctor. Many kidney cancers are “incidental findings” on CTs given with another diagnosis anticipated, broken rib, for example. Thus, it is the radiologist who recognizes the cancer long before either the doctor or patient. It may be a metastases that is found, with the primary tumor not yet imaged, or vice versa. If the tumor is relatively small, and no mets are seen in that initial scan, most patients are assumed to have localized disease. Often there are sudden plans for surgery, but not necessarily to search for other distant mets. The patient may be told, “I got it all.”

Of course, that is the best news, and the only news we want to hear.  But we are wrong, as what we NEED to know, even before the surgery, is whether or not there has been a spread of the cancer.  Treating kidney cancer is already a guessing game, and without knowing the whole game and all its rules, the patient is too often the loser. (Look for a longer, somewhat geeky post on small primary tumors and their potential to metastasize, both quickly and years later.  Ain’t a pretty picture.)

Any good radiologist will know that even small primary tumors can have already produced distant mets. That radiologist likely knows  that additional imaging should be done in such cases. The GP or even the urologist without RCC experience may NOT know that.

Too often small, overlooked mets in the lungs or on a bone can go unnoticed for months or years. Only the radiologist can provide a complete understanding of the extent of the cancer, and only with imaging outside the area of the “incidental finding”. He is the first line of defense, and often the first real expert in determining the extent of the disease. Thanks to those unsung heroes!

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