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Dr. Vincent Xu: Welcome to The ASCO Post Roundtable Series on Updates in Renal Cell Carcinoma. I'm Dr. Vincent Xu, medical oncologist at the Lank Center for Genitourinary Oncology at Dana Farber Cancer Institute in Boston, and instructor of medicine at Harvard Medical School. Joining me today are two of my colleagues.
Dr. Bradley McGregor: So I'm Bradley McGregor. I'm also at Dana Farber Cancer Institute, where I serve as the Director of Clinical Research for the Lank Center for GU Oncology and instructor of medicine at Harvard Medical School.
Dr. David Braun: And hi, I'm David Braun. I'm an Assistant Professor of Medicine, Pathology, and Urology at the Yale Cancer Center and Yale School of Medicine, and a principal investigator of a tumor immunology lab within the Center of Molecular and Cellular Oncology here at Yale.
Dr. Xu: Today, we'll be discussing recent updates in renal cell carcinoma, and integrating these data into four patient case studies. Our final installment will focus on the treatment of non–clear cell renal cell carcinoma. So in our case number four, a 54-year-old woman with no significant medical history is being evaluated for back pain. She has imaging studies, which show a 6-cm renal mass, retroperitoneal lymphadenopathy, and an adrenal metastasis. She has a biopsy of the adrenal gland, which shows metastatic papillary renal cell carcinoma. What would you recommend for this patient? Should she receive sunitinib, or cabozantinib, or combination cabozantinib plus nivolumab, or the combination of lenvatinib plus everolimus, or pembrolizumab monotherapy? Dr. McGregor what do you think?
Dr. McGregor: Yeah, I think the management of patient with non–clear cell or renal cell of variant histology is certainly challenging. We know that, unfortunately, these patients often do worse than those patients with clear cell, and we certainly need to do better in this situation. These are about 20% of patients with renal cell carcinoma. Papillary actually accounts for 80% of that 20%, so the most common the group. We've actually had quite a few updates in papillary renal cell carcinoma just in the past couple years, starting with the trial run by Dr. Pal, PAPMET, which looked at cabozantinib or sunitinib. There are also arms with savolitinib, crizotinib. Those arms were stopped due to lack of benefit. But when we look at the cabozantinib vs sunitinib, there was actually improvement in progression-free survival and response rate with cabozantinib vs sunitinib, sort of established cabozantinib as a new option in papillary renal cell carcinoma.
And then more recently had data from Dr. Lee, looking at the combination of cabozantinib and nivoluman. And so if you look at that study population, the cohort of those patients with papillary, unclassified translocation RCC, the response rate was over 50%, and it seemed to be quite durable. So very, very exciting. So cabozantinib/nivolumab, at least in the U.S. is approved for patients with advanced renal cell carcinoma, independent of histology. I think the data by Dr. Lee et al is very, very compelling to think about cabozantinib and nivolumab in that situation. But that trial right there, and even PAPMET, highlights that not all variant renal cells are the same. So if you look at the PAPMET, they had to close the savolitinib arm, because it looked like it would not meet endpoint. But then, when we take patients who actually have MET-driven disease in SAVOIR, we look in the small numbers, again, stopped early, but there actually looks like there's an improvement of PFS for savolitinib vs sunitinib, and those patients have MET-driven disease.
And then at the same time, you'll get the data from cabozantinib and nivolumab. There was a group of chromophobe, and that cohort had no responses in their initial group of patients. So that didn't happen. But then you go to, well, that and everolimus, and that situation where papillary actually didn't respond as well to the combination. Those patients with chromophobe, those four of the nine patients, had response, which is the best numbers we've seen in any trial. So it really highlights this idea of histology-directed therapy. And so not all papillaries are truly the same, and even with these different variant histologies, how we treat chromophobe potentially different from papillary, different from FH-deficient RCC. And this idea of histology therapy is important. I think that these trials that include all variant histology remain critical, because we can find signals.
And so I have a trial right now that we're running, looking at the combination of cabozantinib and nivolumab and ipilimumab in patients with variant renal cell carcinoma. I think that's going to be really important. And we may find some signals where this group may respond better than that group. It will help develop the next wave, but it is certainly an area where we need to continue to do work to determine what is the best option for these patients.
Dr. Braun: Yeah, I think that was really a wonderful discussion, and some points to just emphasize and highlight as well. I really like the idea of using the term “variant histology,” just because it sort of conveys that these are not all one thing, that FH-deficient RCC is certainly very different from a chromophobe, is certainly very different from a classic MET-driven papillary. And so really, ultimately getting to a point of histology-directed therapy I think is going to be the goal as we learn more about their biologies. But in the meantime, having trials where we can get general signals from these big buckets, like the trial that Dr. McGregor is running, the cabozantinib/nivolumab/ipilimumab trial, I think is going to be incredibly, incredibly useful. So when I see a patient with variant histology, there's a few things I look at. One is, I look to my trusty pathologist to make sure I have a good pathology colleague, because these can often masquerade or mimic as other things.
And so what used to be referred to as papillary type 2, I think has now been sort of divided up largely into other subtypes. So what used to be papillary type 2, when we recall that, a lot of those actually ended up being FH-deficient, and those might be treated really differently than what would consider a classic papillary. The second is, I'm always looking for opportunities for local therapies, just because our knowledge of effective systemic therapies for varying histologies is less. If there is an opportunity to do local therapies, it's not for every variant histology. I don't think of this for FH deficient or certainly not for something like an RMC or renal medullary carcinoma. But for a papillary or for a chromophobe, if there's ways to really surgically debulk and get even to a point of NED, I think that's worth considering. So a patient like this who has a 6-cm renal mass, some adenopathy in the area, an adrenal metastasis, there's a chance that patient could surgically get to NED. That's actually at least a reasonable discussion to have.
And then if that's not possible, then thinking about systemic therapies. And my first thought is, oh, is there a trial that's available? Because I think that's ultimately going to be beneficial for the patient, and ultimately how we're going to learn for the patients ahead of us. In the absence of trial data or an available trial using the data we have, using, as Dr. McGregor, mentioned the data from Dr. Pal on cabozantinib, or I think some of the really compelling data from Dr. Lee’s study in papillary specifically, and then unclassified as well of using a nivolumab/cabozantinib combination, I think is really appealing.
Dr. Xu: Great. So great thoughts, really important now in this day and age to make sure we get the histology right, and more and more important to also look at molecular markers, such as MET amplification, FH deficiency. And many of these, as we've learned, can masquerade even as clear cells, especially in the community where patients are seen at centers where there's lower volume of renal cell carcinoma. Maybe a clear cell which is not responding to treatment may not actually be a clear cell.
Dr. McGregor: And I would just add, this idea of histology-directed therapy can really go to extremes. So if you have someone who has medullary renal cell carcinoma, they do not respond to a TKI immunotherapy at all, and you're really looking at cytotoxic chemotherapy, like carboplatin/paclitaxel or gemcitabine-adriamycin. Collecting duct carcinoma, you're looking at maybe a platinum/gemcitabine, maybe cabozantinib based on the BONZAI trial. But this idea, those are two extremes where we already have seen that these behave very differently from everybody else. So to that point of getting that pathology view up front is really, really critical, because sometimes these can have huge implications for treatment.
Dr. Xu: So a few key clinical takeaways for non–clear cell kidney cancers. All patients with non-clear cell kidney cancers should receive histology-directed therapy. Non–clear cell RCC or variant histology RCC is not all the same. Among patients with papillary kidney cancers, cabozantinib is the preferred VEGF receptor TKI, given randomized data showing that cabozantinib is superior to sunitinib in this setting with better progression-free survival and higher objective response rate. Cabozantinib plus nivolumab, lenvatinib plus everolimus, and pembrolizumab have all shown activity in papillary and unclassified RCC and are reasonable regimens in the absence of forthcoming clinical trials. And specifically in chromophobe RCC, everolimus has seemed to have increased activity in this particular variant compared to other types of kidney cancer. Patients with medullary renal cancer or with collecting duct cancers tend to be less responsive to traditional clear cell regimens, and may respond a little bit better to cytotoxic chemotherapy. So this brings us to the end of this case. Please see the other segments for further discussion about the latest data in renal cell carcinoma or visit ASCOpost.com. Thank you.