SAN FRANCISCO (FRONTLINE MEDICAL NEWS) – The immune checkpoint inhibitor nivolumab has a consistent survival benefit over everolimus among diverse patients with previously treated advanced clear-cell renal cell carcinoma, finds a subgroup analysis of the CheckMate 025 trial reported at the 2016 Genitourinary Cancers Symposium.

Patients in the open-label phase III trial had received one or two prior anti-angiogenic therapies, usually one of the tyrosine kinase inhibitors that target signaling through the vascular endothelial growth factor receptor.

In all, 821 patients were randomized to nivolumab (Opdivo), an antibody to the cell surface receptor programmed death 1 (PD-1), or everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin that is considered a standard of care in this setting.

Previously reported results showed that the trial met its primary endpoint, with an overall survival favoring nivolumab among the entire trial population (hazard ratio, 0.73; P = .0018) ( N Engl J Med. 2015;373:1803-13 ), ultimately resulting in FDA approval of the drug. Nivolumab also yielded a better response rate, fewer grade 3 and 4 adverse events, and improved quality of life.

Findings of the new subgroup analysis showed that compared with everolimus, nivolumab was associated with a roughly 20%-50% reduced risk of death across patients stratified by disease characteristics and prior therapies, reported lead author Dr. Robert J. Motzer of Memorial Sloan Kettering Cancer Center, New York.

“Consistent with the benefit observed in the overall population of CheckMate 025, nivolumab demonstrated an overall survival and objective response benefit across all key subgroups we examined … Nivolumab is a new standard of care for patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy, and we think it’s a good choice as a second-line agent,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In the same session, investigators reported findings of a subgroup analysis of the METEOR trial, which compared cabozantinib (Cometriq), an oral multitargeted tyrosine kinase inhibitor, with everolimus in a similar patient population. Those data were much the same, showing a consistent progression-free survival benefit of cabozantinib across subgroups.

Weighing results of the two trials, session chair Dr. Toni K. Choueiri, director of the Kidney Cancer Center at the Dana-Farber Cancer Institute, Boston, asked, “For patients who progress on a first-line VEGFR TKI, let’s say sunitinib, is your agent of choice nivolumab or cabozantinib?”

“My treatment of choice in that patient would be nivolumab, [because of] the survival benefit, the tolerability, the durability of responses that we see when the responses do occur,” Dr. Motzer replied. “I also am attracted by a change in mechanism. A change in mechanism of action to a different type of drug is what I prefer.”

This choice would remain the same even if the METEOR trial eventually shows an overall survival benefit of cabozantinib, he added.

“Obviously, we have a number of different options here. I don’t think that there is any one right answer … Neither of these drugs has been compared to the other. Neither of them has been compared to axitinib. So it’s really an individual decision. It’s going to be a patient’s decision. It’s going to be a physician’s decision,” he said. “Hopefully, as we get more experience, more data, more trials, we’ll have more evidence to base our decision on.”

A session attendee asked, “Where do we go from here? What will the approval of cabozantinib and the use of cabozantinib mean for the development of the combination of everolimus and lenvatinib, which we’ve been working on?”

“We have a number of drugs that are coming into the armamentarium that are hopefully going to get approved. Nivolumab has been approved. Cabozantinib I anticipate will be approved. I don’t know about lenvatinib –we’ll have to see,” Dr. Motzer said, adding that axitinib is also in the mix.

“We would need some comparative trials. For lenvatinib, what we’d like to see is that going into the first-line setting perhaps combined with a checkpoint inhibitor. We are currently doing a study at our center with lenvatinib and pembrolizumab. I think that will be a great combination,” he added. “So you’re right, it’s a time where suddenly this year, we may have three new drugs for kidney cancer, and we need to sort that out. We have lots of good options for our patients now.”

Results of the CheckMate 025 subgroup analysis showed a lower risk of death with nivolumab compared with everolimus among patients whether their Memorial Sloan Kettering Cancer Center (MSKCC) risk score was favorable (hazard ratio, 0.80), intermediate (hazard ratio, 0.81), or poor (hazard ratio, 0.48).

Benefit was consistent in patients with bone metastases (hazard ratio, 0.72) and liver metastases (hazard ratio, 0.81).

Nivolumab was likewise superior to everolimus in the roughly 60% of patients who had previously received sunitinib (hazard ratio, 0.81) and in the roughly 30% who had previously received pazopanib (hazard ratio, 0.60).

And benefit was essentially the same whether patients had been on first-line therapy for less than 6 months, a poor prognostic marker (hazard ratio, 0.76), or for longer than that (hazard ratio, 0.78).

There was also an overall survival advantage in favor of nivolumab when patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, number of sites of metastases, and number of prior anti-angiogenic therapies.

The previously published results showed an advantage in favor of nivolumab regardless of programmed death–ligand 1 (PD-L1) expression, Dr. Motzer noted.

The benefit in terms of overall response rate was also consistently in favor of nivolumab over everolimus across these diverse patient subgroups.

Dr. Motzer disclosed that he has a consulting or advisory role with Eisai, Novartis, and Pfizer; that he receives travel expenses from Bristol-Myers Squibb; and that his institution receives research funding from Bristol-Myers Squibb, Eisai, Genentech/Roche, GlaxoSmithKline, Novartis, and Pfizer. The trial was sponsored in part by Bristol-Myers Squibb in collaboration with Ono Pharmaceutical Co. Ltd.