A few years back, I attended a kidney cancer conference with a highly eminent kidney cancer doctor. He opened his talk by saying he was no longer treating kidney cancer! The room was stunned, patients already wondering where to go for the next appointment when he finished his statement. “From now on, I will be treating cancers of the kidney.”
Not a small distinction, and a great way to confuse the patient and the newly diagnosed, but is critical.
Just because some growth lands in the kidney, that growth is not the same person to person, and even not from kidney to kidney in one person. In the link below, CURE magazine, May 5, 2017, interviews Dr. Marston Linehan who expands upon the history and future of this work, which I have used as the basis for this report. This research started in the 1980s, when doctors and researchers noted that some families were at greater risk l to develop some growths and tumor, some of which ‘landed’ in the kidney. The early work defined that disease, Von Hippel Lindau hereditary cancer syndrome as to its genesis–an inherited mutational tendency in the VHL gene.
This research started in the 1980s, when doctors and researchers noted that some families were at greater risk l to develop some growths and tumor, some of which ‘landed’ in the kidney. The early work defined that disease, Von Hippel Lindau hereditary cancer syndrome as to its genesis–an inherited mutational tendency in the VHL gene. Given that clue, patients with kidney cancer but from this inherited tendency, most often had mutations in that same gene. These were ‘sporadic’, out of the blue mutations, but that opened the door to treatment improvements. About 90% of patients with the more common clear cell kidney cancer have a mutation in the VHL gene–but not due to any inherited tendency. Much work has been done for these patients and less for those with the rarer cancers of the kidney.
AND…there are more inherited kidney cancers which also enlightened research. One is PRCC, Papillary Renal Cell Carcinoma, defined in the 1990s. The gene that drove this kidney cancer was MET, wh0se mutations make those patients “highly likely to develop bilateral, multifocal, Type I papillary kidney cancer,” per Dr. Marston Linehan of the National Cancer Institute.
Research is being done for these people, as well as those who are affected by the similar disease which is NOT inherited. There disease also comes from sporadic mutations, these from the same MET gene. This work is critical, as the generally available treatments are not as effective with the rare RCCs.
Still another and challenging rare kidney cancer is HLRCC, or hereditary leiomyomatosis with renal cell carcinoma. Linehan says it is not uncommon, and can make the patient vulnerable to develop leiomyomas–particular kinds of growths–and an aggressive form of Type 2 papillary kidney cancer. Quite different genes make this happen, which can be referred to as Krebs cyle enzyme mutation cancers. Obviously, still quite different that the garden-variety clear cell RCC (ccRCC) and requiring quite a different approach as to treatment.
Though there are currently studies underway to find more appropriate therapies for these rarer forms of RCC, some with combinations of agents that have been developed earlier in the decade, and with agents that were not originally envisioned to be used with kidney cancer–oops, cancers of the kidney.
If you don’t really know the pathology of your tumor and its genetic drive, you don’t have a complete diagnosis. And if you relatively young for kidney cancer, the 46 and under group, this is time to discuss it with your kidney cancer cancer of the kidney specialist.
PS According to Linehan, there are at least 13 different types of inherited kidney cancers, and at least 16 known genes that can cause cancer in the kidneys…lots to learn and to discuss with your doctors!
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:
“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.
Looks don’t matter in kidney cancer as much as they used to, as more information comes to us about the molecular or biological nature of the diseases which fall under the “kidney cancer” umbrella. Can those important biological differences be seen in the pathology laboratory? Must we rely on next generation sequencing to determine which of the subtypes we might have?
Recent work by Dr. James Brugarolas and colleagues is reassuring. Even as they found new subtypes of clear cell renal cell carcinoma, they have also determined that these differences can be seen the pathology lab.
Why is this important? So-called similar tumors may behave in quite different and more aggressive ways, so this is vital to understand the threat of recurrence from a very small tumor. The affects monitoring and eventually will be helpful in drug selection.
An interview at the 13th International Kidney Cancer Symposium October 2014
Cut and paste the above youtube address into your browser to be able to hear the lecture, while following along below. The questions are in bold face.
Dr. James Brugarolas Discusses Biologically Classifying Kidney Cancer
“What we have learned with the development of next generation sequencing (NGS) is that no two tumors are the same. Every tumor has different mutations. Mutations are the drivers of tumor biology. With the advances of next generation sequencing, we have been able to identify and group different subtypes of kidney cancer, according to their mutation status.
Specifically, my laboratory discovered that the BAP1 gene is inactivated in 15% of clear-cell renal cell carcinomas. We found that BAP1 mutations are associated with high nuclear grade. That let us to hypothesize that patients who had BAP1 deficient tumors are going to have more aggressive tumors.
Furthermore, we found that mutations in BAP1 tended to anti-correlate with mutations in the second gene discovered by the Sanger Institute, by Michael Estrada and Andrew Futreal, the polybromo1 gene, PBRM1.
That led us to a classification that about 50% of the patients with clear-cell renal cell carcinoma will have PBRM1 deficient tumors and 15% of patients will have BAP1 deficient tumors. A small percentage of patients will have tumors that are deficient for both genes.
In a very productive collaboration we have had with Mayo Clinic, with Rick Joseph and Alex Parker, we’ve been able to determine that these different subtypes are associated with very different outcomes in patients. Patients that have tumors which are competent (not deficient) for both BAP1 and PBRM1 have excellent survival, whereas the cancer specific survival (CSS) is very poor in patients that have tumors that are deficient for both BAP1 and PBRM1. BAP1 deficient tumors have a somewhat intermediate survival phenotype, and the PBRM1 deficient tumors are similar to tumors that are competent for both BAP1 and PBRM1.
So we think for the first time, we’ve able to identify subtypes of clear-cell renal cell carcinoma that are likely to inform therapy in the future.
There is a gap between the discovery of the gene, to the determination of the clinical implications and subsequently to the therapeutic developments. That is because the therapeutic developments are going to emerge from the biologic understanding which we don’t have yet.
How can improved classification of kidney cancer subtypes improve clinical trial design?
That’s actually a very good question. So, what has traditionally happened is that a trial may be performed and one may find a group of patients–sometimes small, sometimes larger–that appear to do well with that agent. But if the group of patients is small, the trial is considered to be negative and the drug is abandoned. And I would say the problem is not that the drug did not have activity, it is that we were not able to identify the group of patients who appeared to benefit from that agent.
So the classification that we have developed and the identification of these different subtypes will pave the way to be able to do correlations. So then, when a clinical trial is executed when it is able to characterize better those subsets of patients that may benefit from the agent. For instance, as I was alluding to before, the BAP1 gene is inactivated in 15% of the tumors. It is possible that one of the drugs which has been tried in kidney cancer could have activity against that tumor. But there could never be a trial in that is positive that is being active in a small percentage of the patients, in 15% of the patients.
By identifying meaningful biological subtypes, we hope to deconvolute kidney cancer. It probably makes sense in trials going forward to do prespecified analysis of these genes that we now define as different biological subtypes–to be able to get at the question whether a particular treatment is having greater affect in one biological subtype versus the other. It is possible that it may not be that not all the PBRM1 deficient tumors that benefit, that are inhibited by a particular agent, there are other mutations. But it’s the beginning that which will lead us to identify those biomarkers and patients who are most resistant to a particular treatment.
What is the significance of improved disease classification for kidney cancer patients?
That is also an excellent question. These are discoveries that we and others have made over the last two or three years. The implications clinically have begun to be unraveled. It’s going to take significant effort and investment in research for us to go forward. We need to understand how loss of these genes, how mutations in BAP1 and PBRM1, are affecting processes inside the cancer cell, leading to kidney cancer development.
And in particular, we need to understand how BAP1, which is associated with most aggressive type of kidney cancer, is inducing that process. How is it that loss of the BAP1 gene makes the tumor be so aggressive? It’s only once we are able to elucidate the signaling pathways, that we will be able to identify targets for therapeutic invention.
On the other hand, we already know that for patients with localized disease, their prognosis is influenced biology of the tumor. I was alluding to this before, those patients who have removal of a tumor, localized to the kidney who deficient for BAP1 and PBRM1, they have a very high likelihood of recurrence in a short period of time. Those patients whose tumors are wild type for PBRM1 and BAP1 can do very well. (Wild type here means that the two genes are competent, or not deficient.)
Importantly, from the important view of translating these findings to the clinic, we have been able to develop assays, immunohistochemistry assays which are routinely performed in tumor samples at most institutions. (This is done in pathology labs).That allows us to very quickly determine whether we are dealing with the wild type tumor, BAP1 tumor, PBRM1 deficient tumor, or one that is deficient for both.
(Transcribed from the above YouTube video by Peggy Zuckerman. Any mistakes are mine alone, but hope this is helpful in understanding this approach to using gene sequencing in kidney cancer.
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.
University of Texas MDACC; KCA Patient Conference; April 14,2012
Treatment Options for Patients with Non-clear Cell Histology
Thank you all for coming, and thanks to the KCA for sponsoring this, which has become a yearly event. So why this talk? The short answer is that regrettably, most of the trials if not all, recruit patients with the conventional histology, that is clear cell RCC.
But up to 20% of advanced renal cell carcinoma patients have these rarer types. That is not one type of tumor, but a diverse group of tumors. It’s not one disease, but heterogeneous diseases. I’d like to show you what has been done so far, and a glimpse of hope going forward.
You heard this morning about conventional type clear cell renal carcinoma, the most conventional; about 75-80% of patients with advanced RCC have this type. But about 20% have these diverse histological subtypes, with papillary 1 & 2 considered about 15%. Of patients without metastatic disease, who get just a nephrectomy for a primary tumor, it is estimated that about 10% will have papillary type 2 and about 5% will have type 1.
In my experience, when patients have recurrence after a nephrectomy, or present with advanced disease at initial presentation, the majority have the type 2 papillary.
Chromophobe is less common than papillary, is indolent, is less aggressive, and it progresses more slowly than the other. But when it is metastatic, it is incurable.
Collecting duct is another aggressive type non clear cell RCC, and renal medullary is a very close type, very similar histologically. However, it is unique in that it affects African-Americans, typically at a young age, who have the sickle cell trait.
Translocation is a newly diagnosed, or a newly recognized entity that is mostly present in young people, adolescents and young adults. We are now conducting molecular research on this unique entity.
There will be about 5-7% patients who will have this report signed by the pathologist, classified as unclassified RCC. This is really a waste basket diagnosis, as it reflects our inability to pinpoint the diagnosis, so “unclassified”. As our molecular insights advance, we will be able to classify the unclassified into more unique and distinct types. There are some rare cases, mucinous tubular and and spindle cell, TS thyroid type. Oncocytoma is usually benign, rarely metastasizes but it is one of those non-clear cell types also.
I added sarcomatoid dedifferentiation because it presents challenges to the treatment of patients with this dedifferentiation. Sarcomatoid occurs with all subtypes of RCC, the conventional clear cell type and non clear cell type. It portrays an aggressive behavior.
This is what papillary Type 1 looks like this under the microscope. This is an inherited syndrome that is characterized by germline mutation of the c-MET oncogene. It is characterized by considerable activation of the c-MET receptor. It is estimated that about 10-15% that are sporadic that are reported as papillary type 1 will have this mutation in the tumor .
The other papillary type 2 is also an inherited syndrome, also characterized by the germline mutation of a tumor-suppressor gene, the fumarate hydratase gene. Individuals that have this, in addition to renal cell carcinoma, have leiomylomas. Females have leiomyomas of the uterus; both sexes will have leiomylomas of the skin. They are referred to as HLRCC hereditary leiomyoma RCC. Sporadic tumors are obviously much more common in type 1 and type2 papillary rcc and the molecular knowledge about this, the molecular characteristics are not well characterized.
This is Chromophobe RCC; usually indolent, compared to the others, unless it is shown with saracomatoid features, and then it becomes virulent. There is an inherited syndrome associated with this, called Birt-Hogg-Dube syndrome, and there is a mutation in BHD genes: follicular is one of these.
Collecting Duct carcinoma of the kidney is highly aggressive, and it is a disease hybrid between renal cell carcinoma and transitional cell carcinoma TCC of the pelvis, which behaves like bladder cancer. You will see features of the RCC and TCC in patients that have this tumor. It is invariably an aggressive type of cancer and invariably presents at an advanced state. Renal medullary RCC is very closely associated with collecting duct, and affects young African Americans with sickle cell trait.
This is what unclassified RCC looks like under the microscope; with refinement of our technology we will be able to sub classify more the unclassified.
Translocation RCC is typically a disease in young females. Patients, young women and adolescents often present with advanced disease, with extensive lymph node metastases. The TFE 3 protein product of translocation has been studied.
This is what the sarcomatoid RCC looks like, and again it is associated with both clear cell and non-clear cell RCC histologies. Chemotherapy plus targeted therapy trials are ongoing but prognosis remains guarded.
Outcome of Patients with Advanced nccRCC
This is historical data, from the pre-targeted therapy era, when chemotherapy, interferon and interleukin 2 were the mainstay of therapy of patients with RCC. This is a retrospective study from the Sloan Memorial in 64 patients with non-clear cell histologies. The majority were reported as having collecting duct, then chromophobe, papillary and then unclassified. The median survival was about 2 ½ years in patients with chromophobe RCC, but worse in patients with collecting duct and papillary, and very dismal median survival with advanced papillary. Again, this is pre-targeted therapy.
We look at our own experience. These Kaplan-Meier curves represent patients treated;, the ones here (on the upper line) were treated with conventional. This is group (on the lower line) with the non-clear cell, the non-conventional. Survival is about 10 months median with the non-clear cell vs patients with clear cell. Again, patients treated in the era of immunotherapy.
Current Therapy of Metastatic Non-clear Cell RCC
So what about the current therapy of patients now with advanced non-clear cell RCC? I think that you may already have heard about this earlier from speakers.
Temsirolimus was tested in patients in a phase III trial, with advanced poor-risk patients, with advanced RCC, and with multiple risk factors such as poor performance status, anemia, hypercalcemia, and high serum LDH. Patients were randomized to receive either Temsirolimus, the mTOR inhibitor given intravenously weekly versus interferon as a comparator, or the combination of these two. Survival was the primary endpoint of this study. Of these patients, 20% had non-clear cell RCC histologies. Results were in favor of Temsirolimus with a median survival of 10.9 months with Temsirolimus vs 7.3 months median survival treated with interferon. This is an improvement of 49%. So you can say that for patients with non-clear cell histologies with poor risk factors, that Temsirolimus is a reasonable option as first line therapy.
This is a retrospective study conducted and published by the French and Cleveland Clinic, with investigators looking at the Sunitinib and Sorafenib. (Sutent and Nexavar) The majority of these patients (41 or 77%) had papillary, and 12 or 23% of patients with Chromophobe. The take home message on this retrospective analysis is that there was no central pathology review to really confirm that in fact, these patients had the reported pathology. Also, there was no central independent radiology review to confirm the responses. But the investigators reported a decent median progression free survival in patients with papillary, 7.6 months, but obviously shorter than what we see in patients with conventional type RCC. For chromophobe, the median PFS was even better at 10.6 months. Retrospective studies and again, patient selection biases are inherent in this.
The French conducted a Phase II trial with Sunitinibin papillary RCC. The majority of these patients had type 2, the most frequent type of non-clear cell patients with advanced disease. They observed only one patient achieving a partial response, 1 among 23 with type 2. None of the five patients with Type 1 had a response.
The Sloan Memorial group published their experience. This was a single arm phase of the trial, but unfortunately was closed to patient accrual prematurely, due to slow accrual. That brings up the point about the importance of patients’ participating in clinical trials. If we don’t really have robust participation in trials, we end up with trials that take a long time and many of them close before the end point is realized. Thus we really cannot make robust claims about the results. But among 22 evaluable patients, 8 had papillary, 5 unclassified and 10 were reported as having others. Only one patient had a positive response; that was one with unclassified rcc. The median PFS was just 5.5 months, basically half of what we would expect with patients with conventional cell histology. In patients with papillary, the median progression free survival was 5.6 months.
We at MD Anderson conducted our own study with Sunitinib. With 57 patients, this is one of the larger Phase III trials of Sunitinib–or any targeted drug in non clear cell RCC. The median age was typical of trials, about 60. We have different risk groups, good, intermediate and poor. Two-thirds of our patients had prior nephrectomy and we allowed prior systemic therapy. Eight patients had prior systemic therapy. We did not exclude patients with brain metastases, if the brain metastases were controlled.
HISTOLOGIES
This is the breakdown of the different histologies of the patients involved in that trial, with papillary constituting about half of the patients, 27 of the 57. Eight had unclassified, 7 had sarcomatoid, 5 chromophobe, 4 renal medullary and 2 collecting duct.
And there was one each of these rarer tumors. (slide reads tubulocystic, translocation, thyroid-like follicular carcinoma and mucinous/tubular/spindle cell.)
This is a summary of the efficacy data with the median follow up of 21.7 months. We observed 5 responses, less than 10%. Two of these responses were in chromophobe 2 of 5, that is, 40 %. That seemed to mirror the experience with conventional histology, and there was one patient each that had response, 1 of 25 in papillary, 1of 8 unclassified, 1 of 7 sarcomatoid. The important point to mention about this trial is that all the slides–the pathology specimens–were reviewed by one GU pathologist and all the scans, baseline and subsequent scans throughout therapy were reviewed by a single, blinded radiologist. So we are pretty confident of these results we report here.
The progression free survival and the overallsurvival of this data are in this slide. For the 55 patients evaluable for response, the median PFS was 2.7 months, absolutely very disappointing. You can see that the confidence interval is quite narrow, meaning we think that this reflects reality. For the 25 patients with papillary RCC evaluable for response, two were not evaluable for response. The median response for PFS was 1.5 months, again, a narrow confidence level.
For all 57 patients, the median overall survival was 16.8 months, perhaps reflecting maybe patients lived longer because they received maybe some subsequent therapy that they benefited from more than they benefited from Sunitinib. For the patients with papillary RCC, the median overall survival was 12.5 months.
The progression free survival and the overall survival of this data are in this slide. For the 55 patients evaluable for response, the median PFS was 2.7 months, absolutely very disappointing. You can see that the confidence interval is quite narrow, meaning we think that this reflects reality. For the 25 patients with papillary RCC evaluable for response, two were not evaluable for response. The median response for PFS was 1.5 months, again, a narrow confidence level.
For all 57 patients, the median overall survival was 16.8 months, perhaps reflecting maybe patients lived longer because they received maybe some subsequent therapy that they benefited from more than they benefited from Sunitinib. For the patients with papillary RCC, the median overall survival was 12.5 months.
Phase II study of Everolimus in Advanced Papillary RCC (RAPTOR)
There is now an ongoing trial, the RAPTOR study, with Everolimus, the mTOR inhibitor mentioned earlier. It’s occurring in Europe at multiple sites, and is a single-arm study of Everolimus in patients with papillary RCC. The primary endpoint of the trial is progression free survival at 6 months, and secondary endpoints are disease control rate, objective response rate (ORR), and median progression free survival (PFS) and safety.
Randomized Phase II Trial of Everolimus vs Sunitinib
There are two phase II trials of Everolimus versus Sunitinib, led by Duke and recruiting patients from Canada and the United Kingdom and one of our own, led by our institution with contributions from the Harvard Consortium.
A Phase II trial of Everolimus vs Suntinib in Non-Clear Cell in MDACC
The two trials are very similar in design except the Duke study–the ESPEN trial–does ot have a cross-over at progression with first-line therapy. This is the schema of treatment of the trial ESPEN, with Everolimus vs Sunitinib in prospective evaluation with patients with non-clear cell RCC. Patients with non clear-cell RCC after stratification, whether they have papillary or the other non clear cell subtypes.
A Phase II trial of Everolimus vs Suntinib in Non-Clear Cell in MDACC
The two trials are very similar in design except the Duke study–the ESPEN trial–does ot have a cross-over at progression with first-line therapy. This is the schema of treatment of the trial ESPEN, with Everolimus vs Sunitinib in prospective evaluation with patients with non-clear cell RCC. Patients with non clear-cell RCC after stratification, whether they have papillary or the other non clear cell subtypes,will be randomized to receive either Everolimus 10 milligrams a day or Sunitinib at the standard dose and schedule, 50 mlgr/day, four weeks on, two weeks off. They stay on therapy until they have progressive disease. At progression, they cross over to the other agent that they did not receive as first-line therapy.
Therapy of Papillary RCC; A New Way Forward?
Now moving forward. I hope the future will be brighter than what I showed you. There are a couple of interesting trials that I would like to present to you, what hopefully what the future will bring.
EGFR is being recognized as an important pathway to block several malignancies, epithelial malignancies, and kidney cancer is one of them. Evidence for EGFR over-expression or aberrant function has been reported in many of these epithelial malignancies.
Rationale for EGFR Inhibition in RCC
And there is a rationale for EGFR inhibition in RCC. This was from pre-clinical in vitro work in RCC cell lines. This was work done by Dr. Mendelsohn, our former president here, where they transfected VHL into VHL-negative cell lines and showed that restoration of the response to the antibody to against EGFR, the C225 antibody or Cetuximab was blocked the tumor growth, indicating that presence of wild-type VHL is required for effective EGFR blocking.
Phase II trial of Erlotinib in PRCC
That constituted the hypothesis for this Phase II trial, conducted by South West Oncology Group, published three years ago. They had 52 patients enrolled from 27 SWOG sites and 2 ECOG sites, seven of those 52 patients were ineligible for different reasons. Only 45 patients were evaluable.
Efficacy Median Follow Up
And this is the efficacy slide, with a median follow up of 21 months. There were 5 partial responders, four were confirmed, one unconfirmed. There was an 11% response rate with a wide confidence interval, as you see. (Wide confidence interval means less confidence in results)
EfficacySecond Endpoint OVERALL DISEASE
The overall disease control rate, a second endpoint of the study, and that included partial responders as well as patients with stable disease and this was 64%. The probability of freedom from progression or treatment failure at six months was 29%. The estimated fractions at 2, 4 and 6 months of patients who were stable or responding were 71%, 44% and 31%, respectively.
Overall Survival
Overall Survival at six months was estimated to be 87%, and median overall survival estimated to be 27 months. This is pretty encouraging, but again, a single-arm study of 45 patients, where you could bring up some patient-selection biases.
Study Limitations
These are the study limitations. They did not look at tumor grade. We know very well that papillary RCC is not one disease, as I mentioned and that patients with tumors which have high grade have more aggressive disease than patients with lower grade.
They also did not differentiate, did not characterize how many of those patients of the 45 recruited had Type I or Type II. There was no comment on what second-line therapy these patients might have received later after they received Erlotinib on this trial that could have confounded/compounded the survival and showed the survival to be better than what we have been accustomed to seeing. No mention of how many patients has prior nephrectomy or metastatectomy prior to enrollment in the trial. There was no correlation at all between EGFR expression with PFS or OS. And again, there were several patients who did not have central pathology review.
Erlotinib in RCC
As to Erlotinib in papillary RCC, Erlotinib appears to have some activity in papillary RCC. Overall, Erlotinib is a well-tolerated therapy, but is inhibition of this pathway beneficial to all patients with papillary RCC? That remains to be seen. Which subgroups of papillary would benefit most from the EGFR inhibitors? I think the story is similar to the story with non-small cell lung cancer, adenoma carcinoma of the lungs, where EGFR mutation has been linked to faster response among these patients. Which molecular markers will be predictive of response? We wait to see. Only through larger, prospective, randomized trials, will we be able to answer many of these questions. We need an ongoing, a future trial, looking again at Erlotinib (Tarceva) in patients with papillary RCC.
The C-MET Signaling Pathway
Now an interesting pathway is the C-Met pathway. This pathway seems to be operational, operative in some patients with papillary RCC. You see that hepatocyte growth factor is the ligand that signals through the receptors–the MET receptor–and causes down-stream effects. There are several agents in the clinic in phase I and Phase II that are targeting this pathway. This is an antibody (referencing AMG 102) against the hepatocyte growth factor, by AMGEN. There is another drug similar to this that targets the ligand, that is from AVEO and then there are several of this small molecule tyrokinase inhibitors that block the pathway here, intracellularly. I will focus now on one called Foretinib, XL880.
Phase II and Biomarker of the Dual MET/VEGFR-2 Inhibitor Foretinib in PRCC
This is a phase II trial that was conducted at multiple centers in the US. There was a biomarker initiative in this drug to study the effectiveness of the MET and how it was modulated and MET correlated with outcome.
We have already covered that the oncogenic events in PRCC are unknown, but do not involve the VHL-HIF-VEGF axis. Activating mutations of the MET gene have been identified in hereditary PRCC and about 10% of sporadic PRCC. Seventy five percent of sporadic PRCC may have duplication in the chromosome 7, at the location of MET, which enhances MET signaling.
Foretinib
What is Foretinib? It is a multi-tyrokinase inhibitor, and predominately blocks two pathways that may be critical in patients with papillary RCC, the C-MET pathway and the VEGF-R2 pathway. It was shown to have activity in xenograph models and in a phase I trial, two patients with PRCC had a durable partial response. One lasted more than forty-eight months. Based and encouraged by this, and on the rationale of blocking the MET pathway in papillary RCC, a phase II trial was then conducted.
Study Design and Treatment
This is the study design, the treatment plan for Foretinib. There were two dosing cohorts, one intermittent with 240 milligrams a day, given every five days for two weeks, and a daily dosing of 80 milligrams a day. The important thing about this design and its design in this trial is that patients were stratified by whether they had evidence of germline mutation of the MET oncogene or if they had other MET pathway aberrations such as somatic MET mutation, or duplication of chromosome 7 and/or 7q31 amplification. The study was designed to have at least 30 patients per dosing cohort.
Study Endpoints
The primary endpoint was objective response rate, and the secondary endpoints included progression free survival, overall survival, safety and tolerability and pharmacokinetic and pharmocodynamic markers, and the correlation of the MET status with outcome.
Primary Endpoint ORR
This is a summary of the efficacy, looking at the objective response rate. Thirteen point five percent had partial response; it was the same with the two cohorts, with intermittent dosing or daily dosing. Duration of the response was a year and a half, and 88% of the patients had disease stability, either partial response or stable.
Secondary Endpoint: PFS
Looking at the Kaplan-Meier curves of progression free survival, we see in blue the overall cohort of 74 patients, in yellow those receiving intermittent dosing and in red the patients treated with daily dosing. As you can see, compared to what we discussed earlier with Sunitinib and others, this is very encouraging, to have nine months of progression free survival in these patients.
Secondary Endpoint Overall Survival
In this slide of secondary endpoints, the median is not reached across both cohorts, and about 70% of patients were alive at one year.
Tumor Shrinkage in 50 Out of 68 Patients
This is a waterfall plot on the right, showing best % change of tumor from baseline. You see that 50 of 68 of patients had tumor shrinkage. Even though the response rate was low and did not meet the primary endpoint that the investigators set, fixed at 25% to make it more interesting and move forward with this drug, but at 13.5% , this was about half of what they aimed at. When you look at the tumor shrinkage, I think this is impressive to see this in a disease where we have no established therapy.
MET Status and Outcome
Now I think this is very important slide, as it illustrates a proof of concept, that when you target a particular pathway that drives the disease such as the type I where you have the germline MET mutation, five of ten patients, that is 50%, had partial responses. When you look at sporadic cases, only one of the five or 20% of those with the sporadic MET mutation had partial response, and the others did not respond. So I think this represents a progress, a map forward, to try to bring this company to sponsor a large trial, testing this in a large number of patients.
I told you I would mention sarcomatoid because it presents challenges to our management of sarcomatoid RCC.
Phase II Doxorubincin/Gemcitabine
Just briefly, the backbone of treatment for sarcomatoid treatment remains chemotherapy. People have looked at adding target therapy. This is the backbone of the treatment, two cytotoxics. In this trial conducted by ECOG, published in Medical Oncology Journal lately, the response rate and efficacy were not very encouraging. Median PFS, less than four months, median overall survival, less than nine months with chemotherapy for these patients.
Phase II Sunitinib/Gemcitabine
There is an ongoing trial at the Harvard Consortium, looking at combining Sunitinib with Gemcitabine in patients with either sarcomatoid RCC, or poor risk disease. This was presented with preliminary results two years at ASCO GU. There was a 25% partial response in 3 patients, but again looking at the time to progression of 4.8 months and then there was a high toxicity, with 25% of patients dropping due to high toxicity. This is ongoing with a total of 80 patients accrued on this trial.
Phase II Trial of Gemcitabine/Capecitabine/Bevacizumab at MDACC
This is our own experience on this trial. We just recently closed this trial with 34 patients accrued, combining Gemcitabine and Capecitabine, two cytotoxics with Bevacizumab, a targeted agent blocking VGEF. Again, our results are in keeping, in the ballpark with other trials.
Summary
In summary, non-clear cell renal cell carcinoma presents diverse rare tumors, and unfortunately, still we have no established effective therapy. This is why I believe that patients with advanced non-clear cell RCC would be best treated on clinical trials, as I believe you heard Dr. McDermott say earlier. There is no place where this is more urgent than patients with non-clear cell RCC, because the other FDA-approved treatments that work with conventional clear cell cancer, unfortunately do not work as well in non-clear cell. But the point the importance of collecting tissue. This is crucial to advance our knowledge.
Pedro
I want to finish with a glimmer of hope as I always try to in these presentations, where we don’t always have that much good news. This is one of my patients from ten years ago. This patient had a conventional cell carcinoma with sarcomatoid, had his surgery in the Valley, came two months after his surgery with metastases to bones, lungs, and lymph nodes. I show you this scan of Pedro. Pedro came in with a large family, 15 members, in a wheel chair. He had compromised performance status, required transfusions weekly, he had constitutional symptoms, with weight loss and sweating. This was ten years ago when we did not have any of these therapies.
Pedro wanted to be treated, his family supported him and we treated him with what we had at the time. That was chemotherapy with F/U, Gemcitabine, and low dose interferon. As you can see from this slide scan to the right, from recently, Pedro is alive and doing well in complete response, ten years later. He is celebrating ten years’ anniversary beating kidney cancer with his family.
Acknowledgement
We salute you, the patients and the families. You are the heroes who inspire us to continue our research to make RCC a history. Thank you. (said with great emotion)
Questions from the audience follow:
I want to say it is good to see some of you, patients of mine and families, you inspire us. I want especially to mention Teresa and Matt. We wish you all the best. Matt keeps me updated; he is my best source as to what is going on in the world, whether it is on Wall Street or any countries. I am going to ask him to join our research group, we need people who are motivated, and there is nothing better than the spouse and the patients. So I hope
that our partnering, academic centers and people like you, the patients and families –I think we can partner and be a force to push Congress, to push the drug companies to support, to bring in new drugs, new therapies, that we badly need for our patients.
Matt: I appreciate your efforts, Dr. Tannir, and any help with papillary would be great, and XL880 is stuck in limbo and XL 184 I think represents a lot of promise for papillary and also clear cell, in making those medications, making them available for our patient group, for patients with clinical trials and off label, where they are approved for other types of cancer.
Tannir; “I don’t want to forget that when we partner, also with insurance companies, because I know you, many of you struggle. I’ve had patients with papillary, as Matt mentioned, and there are no clinical trials available right now, and they reject that, and I think that is unfortunate that insurance companies. This now politics, but insurance companies, when you have gone through all the standards of care, you think that there is drug that might help them and they deny that. But I think that we can, by joining forces, that we can hopefully make that important change.
