First-Line Therapy for Metastatic RCC Remains Controversial Amid New Approvals

In April of this year, the US Food and Drug Administration (FDA) approved pembrolizumab plus axitinib as a first-line treatment for patients with advanced renal cell carcinoma (RCC). The approval, however, comes at a time of considerable progress in the first-line treatment of advanced RCC and means pembrolizumab plus axitinib may not necessarily be the new standard of care for this patient population.

The approval comes 1 year after the FDA approval of nivolumab plus ipilimumab for the same treatment line and very similar population of patients. In addition, the pivotal trials-that is, the phase III KEYNOTE 426 trial of pembrolizumab plus axitinib and the phase III CheckMate 214 trial of nivolumab plus ipilimumab-behind each approval used the same comparator arm: sunitinib, which was the standard of care at the time. Without a head-to-head trial, it’s unclear which combination treatment is better.

During an interview with Cancer Network, Kai Tsao, MD, medical director of the Ruttenberg Treatment Center at The Tisch Cancer Institute, offered perspective on which combination therapy could be used upfront among patients with advanced RCC. But first, he cautioned that given the dozens of factors that must be considered to arrive at a treatment decision, “there’s no one right answer.”

That said, Tsao noted that the approved indications are different. Pembrolizumab plus axitinib is indicated for favorable-, intermediate-, and poor-risk disease, whereas nivolumab plus ipilimumab is indicated for only intermediate- and poor-risk disease, not favorable-risk disease. He asserted that the standard of care should be pembrolizumab plus axitinib for favorable-risk disease because ipilimumab plus nivolumab did not show an overall survival (OS) benefit for favorable-risk disease in CheckMate 214.

For patients with intermediate- or poor-risk disease, however, the choice is less clear. Tsao said the choice is “controversial” because both combinations showed an OS benefit against sunitinib. In addition, the overall response rate was higher for pembrolizumab plus axitinib (59%) compared with ipilimumab plus nivolumab (42%), but ipilimumab plus nivolumab had a higher complete response rate (9% vs 5.8%). “In terms of efficacy, nobody really knows which one is better in the overall sense,” he said.

When considering tolerability, ipilimumab plus nivolumab appears to be better tolerated by patients compared with pembrolizumab plus axitinib. Grade 3 or 4 adverse events occurred in 46% of patients who received ipilimumab plus nivolumab, whereas 76% of patients who received pembrolizumab plus axitinib had a grade 3 or higher adverse event; this included 2.6% of patients who died.

“Whether one vs the other is better, we don’t know at this point,” summed up Tsao. He said that on the basis of tolerability and complete response rate, ipilimumab plus nivolumab is a combination that “a lot of us feel [is] a very good choice for the patients.” He added, “Although they both should be considered the standard of care.”

“The bar has been raised high now in 2019,” said Tsao. “Overall survival is the new gold standard for the first-line setting.”

Additional combinations are currently being evaluated in the same space, and one-avelumab plus axitinib-received FDA approval this week, on the basis of the phase III JAVELIN Renal 101 trial for first-line treatment of advanced RCC, but OS benefit has not yet been seen against the comparator arm sunitinib, only improvement in progression-free survival.