Nivolumab Plus Ipilimumab Sparks Hope for Patients With RCC and Sarcomatoid Features

Nizar M. Tannir, MD

The use of targeted therapy has thus far achieved suboptimal outcomes for patients with renal cell carcinoma and sarcomatoid features in their tumors (sRCC). These patients make up 10% of the RCC patient population and finding novel strategies for their treatment is important. 

A post hoc analysis of the phase 3 CheckMate 214 clinical trial evaluated the efficacy of nivolumab (Opdivo) plus ipilimumab (Yervoy) versus sunitinib (Sutent) in patients with sRCC. Of 1,096 included in the study, 139 patients had sRCC and intermediate/poor-risk disease and 6 had favorable-risk disease. The study found that led to unprecedented long-term survival, response, and complete response when compared with sunitinib. Based on the results, investigators support the use of nivolumab plus ipilimumab as frontline treatment of patients with sRCC.

In an interview with Targeted Oncology, Nizar M. Tannir, MD, professor of the Department of Genitourinary Medical Oncology, in the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, talked about how the introduction of nivolumab plus ipilimumab to the front-line setting of sRCC impacts the treatment paradigm.

TARGETED ONCOLOGY: Can discuss the prevalence of renal cell carcinoma with sarcomatoid features? And what are outcomes generally like for these patients?

TANNIR: Approximately 10% of patients with renal cell carcinoma will have sarcomatoid features in their tumors. I think the best way to really identify those with certainty is by looking at the effect of the specimen rather than doing a biopsy of the primary tumor in the kidney or a biopsy of the metastatic site. Which you know, often may miss the underlying sarcomatoid differentiation.

The outcome traditionally has been poor in the days of targeted therapies, and the old cytokines, IL-2 and interferon. The outcomes for these have improved, with the introduction of the immune checkpoint inhibitors. If you look at our data that we had published in Journal of Urology a few years ago, the outcome of patients with sarcomatoid differentiation and kidney cancer, the median survival was around 14 months. That was in the era of cytokines and target therapies with VEGFR tyrosine kinase inhibitors (TKIs) and mTOR inhibitors. Is was only recently with the approval of new checkpoint inhibitors such as nivolumab plus ipilimumab from the phase three CheckMate 214 that the survival of these patients has dramatically improved.

What ongoing challenges have to be addressed to optimize the treatments we have available for these patients?

TANNIR: As I mentioned, the availability of the immune checkpoint inhibitors has really improved the outcome of these patients. I think it's important to start with proper review of pathology. As with everything else in oncology it’s important to make the correct diagnosis because, again, as we know, RCC is not one type. There are many types with clear cell being the most common type, but of course, the others are papillary and chromophobe. The survival and the outcome, the way we treat those patients with sarcomatoid differentiation depends on the underlying histological epithelial component of the tumor. Patients with clear cell RCC will have sarcomatoid differentiation will have a better outcome with immune checkpoint inhibitors than those who have, for example, chromophobe with sarcomatoid differentiation, we still have a poor outcome even with immune checkpoint inhibitors, and also papillary RCC who have a better outcome than patients with chromophobe when treated with immune checkpoint inhibitors. So, I think starting with the correct diagnosis is important. Also, recognizing that these patients are best treated with immune checkpoint inhibitors is important. Particularly, the clear cell type and the papillary type.

Can you give a key takeaway from the primary analysis data from Checkmate-214?

TANNIR: The primary analysis was published in the New England Journal of Medicine in 2018, which led to the approval of nivolumab plus ipilimumab for patients with advanced RCC with intermediate risk, showed that the overall survival and the response rate was superior with nivolumab plus ipilimumab compared to sunitinib. This Checkmate-214 study recruited 1096 patients with advanced clear cell RCC or treatment naive and there were randomized to receive either nivolumab and ipilimumab or sunitinib. All patients with favorable intermediate or poor risk, by advocacy were included.

The primary analysis was focused on patients with intermediate and poor risk, and there were three co primary endpoints for that study: the objective response rate (ORR), progression free survival (PFS), and overall survival (OS) . But if you look also at the intensity, that's all those patients. Then, the beta trial, randomized around 550 of those patients to 1:1 and treated them with nivolumab ipilimumab. Five hundred forty six were treated with sunitinib. If you look at the overall population in that trial, the intent to treat, the OS was superior with nivolumab and ipilimumab compared to sunitinib and the response rate was higher with nivolumab and ipilimumab compared to sunitinib with approximately 10% of the patients achieving CR with nivolumab and ipilimumab.

We recently published the latest follow-up which was a minimum of four years in ESMO Open. Prior to that we published 42 months minimum follow-up in the Journal of immunotherapy for Cancer. The data with a later follow-up continues to show us what we've published initially in the New England Journal of Medicine that these survival and ORR were superior with nivolumab and ipilimumab compared to sunitinib.

I think the key message here is, at four years minimum follow up more than 50% of the patients treated with nivolumab and ipilimumab remain alive. And I think that's much higher than patients treated with sunitinib. Obviously, there are still patients who continue to relapse over time. But I think this is encouraging data with approximately 30% of patients on the nivolumab and ipilimumab are remaining progression free at minimum follow up or four years.

What was the rationale for carrying out this post hoc analysis?

TANNIR: As mentioned, the outcomes and survivals of patients who have RCC and sarcomatoid differentiation in their primary tumors remained really dismal. And it was important because of the poor outcome historically of these patients when treated with targeted therapies such as sunitinib. I think it was important to look at those patients who were recruited to the trial and enrolled and treated with nivolumab and ipilimumab versus sunitinib to look at the outcomes of those patients who had sarcomatoid.

We identified approximately 60 patients I believe, in the trial of nivolumab and ipilimumab and around 52% of patients who are treated with sunitinib, who had succumbed to it. We looked at this was an analysis based on the local pathology report from the institution where the patient was enrolled, as well as we did a thorough review of all available pathology slides by expert pathologist Sabina Signoretti, MD from the Dana-Farber Cancer Institute. I think the data showed impressive results with around 60% of patients who had nivolumab and ipilimumab who had sarcomatoid differentiation, 60% achieved a response in 19%. So, about a third of those responders were complete responders so achieved a CR and compared to 30% with sunitinib, and then also the survival of these patients was the median was 31 months versus 13 months with sunitinib. So, I almost tripled the median survival with nivolumab and ipilimumab to sunitinib. So clearly a higher ORR, higher complete responses (CR) rate. This is really impressive unprecedented to have approximately 19% of patients treated with nivolumab and ipilimumab who had intermediate risk answer commodity differentiation to have a CR that’s really unprecedented. So, there was a higher ORR, higher CR rate, and almost triple the survival with nivolumab and ipilimumab compared to sunitinib. I think this was really encouraging to find, to analyze and in the trial and then to publish that just A few months ago in 2020 in Clinical Cancer Research journal.

Are there any implications to these data that you would like to highlight?

TANNIR: I believe patients with clear cell RCC, who have sarcomatoid features in the tumor should be, in my opinion, nivolumab and ipilimumab if you're doing that for treatment in first line setting, I think the data we have from Checkmate-214 support this recommendation as the preferred first-line therapy for these patients.

Are there any next steps for moving this combination forward as treatment of this patient population?

Tannir: Of course. I think, we're not going to stop with just nivolumab and ipilimumab. It is a good regimen, as are other immune-based therapies. But this should serve as a backbone to build on these regimens and add novel agents. I think there is a trial of patients with intermediate risk to high risk on treatment with nivolumab and ipilimumab plus a VEGFR TKI cabozantinib (Cabometyx) versus nivolumab and ipilimumab plus placebo. That's the Cosmic-313 trial, which is ongoing. I think the results will be of interest and will be awaited in the next year or two years to see if adding a VEGFR TKI such as cabozantinib to this nivolumab and ipilimumab will even improve the results not just of clear cell and in general, as well as the the sarcomatoid cohort.

Again, I think while the results from Checkmate-214 with an ORR of 60%, a CR 19% and tripling of the survival are very impressive and good news for our patients. Many patients with even sarcomatoid differentiation of clear cell RCC, unfortunately do not respond to nivolumab and ipilimumab or relapse after an initial response and therefore, we do need to improve the results. Hopefully also there are some other agents such as the IDH2 inhibitors that may play a role in this disease. Maybe some other immune agents. There are some trials, phase one, still in the phase one early phase testing, looking at CAR-T therapies in patients with RCC, so I think the field is moving in the right direction we hope to bring new therapies to help our patients with RCC.