Immunotherapy Combos on Horizon in First-Line RCC

Robert J. Motzer, MD

Immunotherapy combinations have significant potential as treatment for patients with renal cell carcinoma (RCC), says Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center.

“I am quite optimistic that these combinations will change our approach to kidney cancer in the first-line setting for years to come,” says Motzer.

Much of the current focus is on the combination of nivolumab (Opdivo)—which was approved in November 2015 for second-line RCC—with ipilimumab (Yervoy) in the first-line setting, he adds.

Other immunotherapy agents are being explored in combination with VEGF inhibitors, such as the combination of the PD-L1 inhibitor atezolizumab (Tecentriq) and the VEGF inhibitor bevacizumab (Avastin).

OncLive: What are the benefits of nivolumab as a treatment for patients with RCC?

In an interview with OncLive, Motzer, who is also a 2016 Giant of Cancer Care in Genitourinary Cancer, discusses the potential of these regimens and other combinations, as well as the benefit of nivolumab in RCC as a single agent.Motzer: Nivolumab was studied in a pivotal phase III trial compared with everolimus (Afinitor) in patients who had progressed on drugs such as sunitinib (Sutent) and pazopanib (Votrient). The primary endpoint of the trial was overall survival (OS) and that was reached, showing a benefit of OS for nivolumab compared with everolimus. This trial established nivolumab as a new standard of care for these patients.

The other endpoint we looked at was response, and there was a higher response rate associated with nivolumab compared with everolimus. What is most noteworthy is, in addition to the high response rate, many of the responses were durable. The median duration of response at 12 months at the time of the data analysis and many of the responses were continuing.

We also examined progression-free survival (PFS) and did not find an improvement in PFS over everolimus. There are several possible reasons for that. One is this phenomenon of pseudoprogression with immunotherapy, where sometimes the tumors actually get a little larger. The other is that the mechanism of immunotherapy is different than that of VEGF-targeted therapies, so some of the responses may be later. The benefit may also only be seen in a group of patients that achieve a long-standing response rather than the majority.

Is there potential for nivolumab to be used in combination in RCC?

The other notable aspect of that trial was the favorable safety profile for nivolumab; there were a few grade 3 or 4 adverse events. This was reflected by an improvement in quality of life for patients treated with nivolumab compared with everolimus. This is a big step because it has been very difficult to show improvements in the quality of life for any of the drugs for patients with kidney cancer.There was a phase Ib trial that showed promising activity for ipilimumab in combination with nivolumab. We looked at different dose levels and 1 thing that really stood out was that there was a particular dosage and combination that was well tolerated and effective. That was the nivolumab at 3 mg/kg with ipilimumab at 1 mg/kg. When we used the higher dose of ipilimumab we found that there was more toxicity. That is really the best dose to move forward.

Are there other immunotherapy combinations that you see potential for in RCC?

That led to a large randomized phase III trial—CheckMate-214—that compared sunitinib with nivolumab/ipilimumab in first-line therapy. That trial has completed accrual and we are hoping for results in 2017 or early 2018.There is a strong rationale for combining immunomodulatory drugs with VEGF inhibitors. The combination that shows the most promise so far is atezolizumab (Tecentriq) and bevacizumab (Avastin). Atezolizumab is a PD-L1 inhibitor. There was a very small study that was done on a small cohort of patients with kidney cancer as part of a larger trial on multiple tumor types. This showed the combination to be very well tolerated, and early results were favorable for kidney cancer.

There was also a large randomized phase II trial that was done with atezolizumab and bevacizumab compared with sunitinib. The results of that have not been published or presented at a meeting, and we anticipate that they would be published next year at the ASCO Annual Meeting. However, they were compelling enough internally to justify a phase III trial. That study has now completed accrual, as well.

There were also data presented at the 2016 ESMO Congress with axitinib (Inlyta) and pembrolizumab (Keytruda) that showed a 70% response rate. That is being compared with sunitinib. There is a combination of lenvatinib (Lenvima) and pembrolizumab that is being compared to sunitinib, too. There is another PD-L1 inhibitor, avelumab, which is being combined with axitinib and compared with sunitinib.