Successful ESMO Studies to Likely Trigger Sequencing Shakeup in RCC

Rana R. McKay, MD

On the heels of the pivotal CABOSUN and CheckMate-214 studies demonstrating the promise of cabozantinib (Cabometyx) and nivolumab (Opdivo)/ipilimumab (Yervoy) as frontline therapies for patients with metastatic renal cell carcinoma (mRCC), respectively, physicians are already considering how potential regulatory approvals of these therapies could impact sequencing in the field.

“The treatment landscape for metastatic RCC is rapidly changing,” said Rana R. McKay, MD. “Though there are a lot of new agents that are out there, I would still encourage clinical trial enrollment because that’s how we move the field forward and improve treatment options for our patients.”

An independent review of the phase II randomized CABOSUN trial confirmed the PFS benefit in the frontline setting with the multikinase inhibitor cabozantinib (Cabometyx) over sunitinib, showing that cabozantinib was associated with a 52% reduction in the risk for progression or death.²

OncLive: How is the treatment landscape for patients with mRCC expected to evolve once again?

McKay, an assistant professor of medicine and medical oncologist at the University of California, San Diego, highlighted the promising findings from the CheckMate-214 and CABOSUN studies in an interview during the 2017 OncLive^® State of the Science Summit^TM on Genitourinary Cancers.McKay: We have seen a world of riches in this space. First, in the tyrosine kinase inhibitor (TKI) era, with the approval of TKIs and a monoclonal antibody against VEGF, and now we’re really entering the immunotherapy era with the approval of nivolumab and recent data that were presented about the efficacy of nivolumab and ipilimumab for patients with advanced disease. The treatment landscape is rapidly evolving.

The CABOSUN trial and CheckMate-214 trials drew excitement at the 2017 ESMO Congress. Can you reflect on the importance of both studies?

With regard to the frontline space, the nivolumab/ipilimumab regimen throws a wrench into our standard VEGF TKI paradigm. Then, with regards to agents in the second-line space, we have nivolumab, cabozantinib, everolimus (Afinitor)/lenvatinib (Lenvima), and other VEGF TKIs, such as axitinib (Inlyta) and sorafenib (Nexavar). There is a lot to be learned; we’re not there yet with regards to outcomes for our patients. Novel combinatorial strategies are being explored as well as novel treatment sequences. Biomarker studies will hope to inform which patients are the right patients for the agents that are out there and guide therapy. CheckMate-214 is an important trial in this space; it’s a large phase III trial that was evaluating the combination of nivolumab plus ipilimumab for patients with metastatic clear cell RCC. The comparator arm was the gold standard of sunitinib; this was the first time that an agent has beat sunitinib in the frontline space, so this is groundbreaking. The objective responses were higher than seen in a VEGF TKI, up in the 40% range.

However, there are a lot of questions to be had about which patient population is the best one. It seems, through an exploratory analysis, by looking at those patients with favorable risk, that those patients who received sunitinib fared better compared with patients receiving nivolumab/ipilimumab. We still need to learn about how to use this combination, which is the right patient population, so there is a lot to be learned. But, it is very exciting data.

What about the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin)? How could that be incorporated into the paradigm?

What are the novel combinatorial and treatment sequencing studies on the horizon?

With regards to the CABOSUN data, this was a phase II study that was evaluating cabozantinib versus sunitinib in the frontline space for patients with intermediate- or poor-risk RCC. Cabozantinib demonstrated an improvement in objective response and PFS. The updated data were presented at the 2017 ESMO Congress, and the hazard ratio continues to improve with regards to the PFS benefit of cabozantinib over sunitinib. The phase II study of atezolizumab and bevacizumab was reported in the intent-to-treat population. There did not seem to be a benefit with regards to response or PFS of the combination over sunitinib; however, when looking at patients who were PD-L1 positive, there did seem to be a potential benefit in that population. There could be a role for the combination in a select patient population, but data are still to come regarding that. Regarding novel combinatorial studies, the phase I data of axitinib and avelumab (Bavencio) were recently presented at the 2017 ASCO Annual Meeting. Those data are exciting. There are other studies that are evaluating the combination of cabozantinib with nivolumab, and cabozantinib with nivolumab/ipilimumab that we are also excited about to be reporting out in the future.

References

1. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Presented at ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA5.
2. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.

The CheckMate-214 trial explored the combination of nivolumab plus ipilimumab versus sunitinib (Sutent) monotherapy as first-line treatment of advanced or metastatic RCC.¹ In intermediate- and poor-risk patients, the median overall survival (OS) was not reached in the nivolumab/ipilimumab arm and was 26.0 months with sunitinib, and progression-free survival (PFS) was 11.6 months and 8.4 months in the 2 arms, respectively.