Expert Discusses Immunotherapy Combos in Kidney Cancer

Immunotherapy combinations are showing potential for treating patients who have renal cell carcinoma (RCC), according to Robert J. Motzer, M.D., 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 Opdivo (nivolumab)—which was approved in November 2015 for second-line RCC—with Yervoy (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 Tecentriq (Tecentriq) and the VEGF inhibitor Avastin (bevacizumab).

What are the benefits of Opdivo as a treatment for patients with RCC?

In an interview with CURE, 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 Opdivo in RCC as a single agent.Opdivo was studied in a pivotal phase 3 trial compared with Afinitor (everolimus) in patients who had progressed on drugs such as Sutent (sunitinib) and Votrient (pazopanib). The primary endpoint of the trial was overall survival (OS) and that was reached, showing a benefit of OS for Opdivo compared with Afinitor. This trial established Opdivo 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 Opdivo compared with Afinitor. 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 Afinitor. 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 Opdivo to be used in combination in RCC?

The other notable aspect of that trial was the favorable safety profile for Opdivo; there were a few grade 3 or 4 adverse events. This was reflected by an improvement in quality of life for patients treated with Opdivo compared with Afinitor. 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 1b trial that showed promising activity for Yervoy in combination with Opdivo. We looked at different dose levels and one thing that really stood out was that there was a particular dosage and combination that was well tolerated and effective. That was the Opdivo at 3 mg/kg with Yervoy at 1 mg/kg. When we used the higher dose of Yervoy 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 3 tria l—CheckMate-214— that compared Sutent with Opdivo/Yervoy in first-There is a strong rationale for combining immunomodulatory drugs with VEGF inhibitors. The combination that shows the most promise so far is Tecentriq and Avastin. Tecentriq 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 2 trial that was done with Tecentriq and Avastin compared with Sutent. 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 2 trial. That study has now completed accrual, as well.

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