Selecting the Appropriate First-Line Therapy in Advanced Clear Cell RCC


Centering conversation on systemic therapy, panelists review trial data behind the first-line combination regimens for patients with advanced clear cell RCC.

Thomas Powles, MD:
Ulka, it’s over to you next. You’ve got the pleasure of talking about some of the latest data with CheckMate 214, the ipilimumab-nivolumab trial. Do you want to give the group a little background about the ipilimumab-nivolumab study, where we are, and what we’ve seen recently?

Ulka Nitin Vaishampayan, MD: CheckMate 214 was the first immune-based regimen study in frontline metastatic kidney cancer. It was the first 1 to compare to sunitinib, which was the standard at the time. Now there are 5 other regimens that have shown efficacy and have proven and gotten FDA approval. CheckMate 214 compared ipilimumab-nivolumab combination with sunitinib. This was a randomized study on patients with untreated metastatic kidney cancer. The primary end point was overall survival [OS], and this was focused on intermediate- and poor-risk-disease patients.

The results of the study, which have been updated with 5-year follow-up, showed that survival significantly improved with ipilimumab-nivolumab combination compared with sunitinib. Median survival is now in the range of 55.7 months with ipilimumab-nivolumab, which is close to 5-year median survival in these patients. Even at the 4-year mark, there was about an 11% increase in the number of patients who were still alive after ipilimumab-nivolumab combination as compared with sunitinib. It’s remarkable efficacy.

The toxicity has its nuances, and careful management is essential. As we’ve applied that regimen to our average practice, it has become tougher and tougher. The incidence of toxicities is higher, and they need to be diligently managed and acted upon quickly. Because things like colitis—immune colitis is big with ipilimumab-nivolumab—can get worse very quickly and can be potentially life threatening. Immediate immunosuppression and careful monitoring of the patients is critical.

Thomas Powles, MD: We’ve got that regimen. It came out and changed practice. We can all agree on that: long-term durable remissions. Not much later, we saw some axitinib-pembrolizumab data come out. That changed the scene a bit because it got control of disease in some more patients. Rana, do you want an update on the way VEGF–TKI [tyrosine kinase inhibitor] combination has evolved?

Rana McKay, MD: Absolutely. Immunotherapy has demonstrated a track record for excellence and efficacy in RCC [renal cell carcinoma], as has VEGF-targeted therapy. There’s certainly a slew of preclinical data about the combinatorial, immunomodulating strategies of the 2 agents together. There’s still question in the field about whether there’s true synergy or just additive from the 2 components. Nonetheless, KEYNOTE-426 looked at investigating pembrolizumab plus axitinib compared with the gold standard of sunitinib. Patients who were treatment-naïve with locally advanced or metastatic disease and clear-cell histology, and patients were randomized 1:1 to receive the combination with the dosing of axitinib at 5 mg 2 times per day vs sunitinib on a 4 weeks on, 2 weeks off schedule. The primary end point was slightly different from the end point from CheckMate 214, which focused on the intermediate poorest patients. The primary end point was overall survival and PFS [progression-free survival] in the intent-to-treat population. All patients were favorable, intermediate, and poor.

It was a positive study demonstrating improvements in overall survival, improvements in PFS, and improvements in objective response rates. We saw the updates from Dr Brian Rini at ASCO [American Society of Clinical Oncology Annual Meeting] last year. That 42-month follow-up was exciting, demonstrating consistency of that overall survival benefit. The PFS was around 15 months, with the combination and response rates really high: 60% with about a CR [complete response] rate of around 10%. These are exciting data, but they’re a little different from CheckMate 214.

When I have patients in the clinic, and we’re talking about the 2 regimens and trying to think about an I/O [immuno-oncology]–VEGF strategy vs an I/O–I/O strategy, the discussion that we have is, “Do you have to play the short game? Or do you have the luxury of waiting to play the long game?” That’s how I help tease out whether I need to have an immediate up-front response. Or do I have the luxury of being able to give you nivolumab-ipilimumab? That’s the 1 regimen that’s been associated with long-term disease durability. We need additional long-term follow-up from the I/O–VEGF combos. But those are the big discussions we have in the clinic, and I’m sure all of you have with your patients as well.

Thomas Powles, MD: Give me the cabozantinib-nivolumab data, a quick summary of where we are with that, and some of the points that differentiate it from axitinib-pembrolizumab.

Eric Jonasch, MD: Cabozantinib is a small molecule inhibitor of VEGF, but it’s also a small molecule inhibitor of AXL, MERTK, and TYRO3, so the TAM family members as well as MET. It ends up being somewhat more of a complex TKI, which in and of itself is interesting and may have immune modulator theory effects. This study took 40 mg of cabozantinib-nivolumab given IV [intravenously] every 2 weeks vs sunitinib. The primary end point was PFS, although the secondary end points are the usual suspects. You presented the update at GU ASCO [ASCO Genitourinary Cancers Symposium], where these data showed that not only did it meet its PFS end point, which originally a doubling of PFS with a hazard ratio of 0.51, but the overall survival was positive. Even with this update, the hazard ratio remained 0.7. It’s still very good. Objective response rates were in the mid-50% range vs 20s for sunitinib.

CR rates went from around 8% initially up to 12%. It’s interesting to see the evolution of these data. We’re seeing that with the maintenance of the progression-free survival, there’s a maintenance of superiority from an overall survival perspective—this intriguing complete response rate. To Rana’s point, is this additivity? Is this synergy? We don’t know. The problem is we haven’t done presurgical studies or neoadjuvant studies to look at the interaction of these agents biologically.

Thomas Powles, MD: I’m going to round this off with the lenvatinib-pembrolizumab data, which came out last from the CLEAR trial and has the shortest follow-up. The response rate is high, about 70%. The PFS is long, above 20 months. The OS signal looks identical to the other OS signal, which is important. There are more similarities and differences among these regimes as I see it, and I find it hard to differentiate, to be honest. I can find an argument for each. I can say cabozantinib-nivolumab, ...axitinib-pembrolizumab, …lenvatinib-pembrolizumab…. I can see all 3 of those. But I also see—as you suggested, Rana—a distinction with the ipilimumab-nivolumab data. No. 1, it’s a more confined label to intermediate…disease. No. 2, it’s less good at getting initial control of disease.

The question I’d like us to contemplate is, how important is CTLA4? We saw an ipilimumab-nivolumab adjuvant trial, which didn’t look positive. You said it’s the long game, and I want to get ipilimumab-nivolumab for the long game. Obviously, ipilimumab-nivolumab has the longest follow-up because it’s been going for the longest period. We’re always going to have that discussion. The question is, how much do we think ipilimumab is contributing? How important is it that we give it to our patients? If you’re going to give it, you can only give it in the beginning.

Eric Jonasch, MD: There’s a study that’s ongoing,…looking at nivolumab vs nivolumab plus ipilimumab in the European context. That’s going to answer that question. If we extrapolate from pembrolizumab, there have been the KEYNOTE-427 data. What’s great about this monotherapy nivolumab is you’re seeing these objective response rates, which are reasonably high. What’s not great about them is the PD [progressive disease] as best response, which is already a little hazardous with 214 [patients] at 18% to 20%. There, it was in the low-30% range. I’ll hypothesize that you’re de-risking the PD as best response to some degree, and you’re probably nailing down the durability of complete response with ipilimumab. Fortunately, we have studies that are going to be able to resolve the speculation.

Rana McKay, MD: I don’t mind chiming in.

Ulka Nitin Vaishampayan, MD: She did the study.

Rana McKay, MD: Building on that KEYNOTE-427 data, there was also a series of adaptive studies in which patients were started on nivolumab up front and the ipilimumab was layered in later, depending on whether they had a response. That data demonstrate that using I/O by itself, PD-L1 or PD-1 inhibition alone is inferior. We saw lower response rates and complete response rates. The objective response rate was lower. We don’t want to compare across these trials, but the ipilimumab is adding to the complete response rate, the objective response rate, and the durability.

Thomas Powles, MD: I’m talking about peak ipilimumab. In 2019, there was a fantastic PFS. We’re beginning to see some uncertainty. I’m really excited about this CA209-8Y8 trial.

Transcript edited for clarity.

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