Two-Drug Cocktail Active against RCC

The combination of an immune checkpoint inhibitor and a molecularly targeted drug outperforms the standard of care in advanced renal cell carcinoma (RCC), according to the first phase III trial to report positive results from such a combination for the disease. The findings, presented at the European Society for Medical Oncology 2018 Congress in Munich, Germany, show that avelumab (Bavencio; EMD Serono) plus axitinib (Inlyta; Pfizer) works better than sunitinib (Sutent; Pfizer).

Targeted therapies, such as the multikinase angiogenesis inhibitor sunitinib, have been mainstays of RCC treatment for more than a decade. More recently, immune checkpoint inhibitors have become treatment options. This year, for instance, the FDA approved the combination of nivolumab (Opdivo; Bristol-Myers Squibb) and ipilimumab (Yervoy; Bristol-Myers Squibb) for certain patients with RCC. Trials have now begun evaluating combinations of immunotherapies and targeted drugs.

One of those studies is the phase III JAVELIN Renal 101 trial, which enrolled 886 patients with advanced, previously untreated RCC. Researchers randomly assigned 444 patients to receive sunitinib and 442 patients to receive avelumab, a PD-L1 inhibitor, and axitinib, a VEGFR inhibitor. Both drugs are FDA approved—axitinib for RCC, and avelumab for Merkel cell carcinoma and urothelial carcinoma.

“There's a theoretical potential for synergy” between the two drugs, says study senior author Toni Choueiri, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA. VEGF can cause immunosuppression, so blocking its receptor with axitinib may increase the potency of avelumab.

At the conference, the study's lead author, Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, reported that progression-free survival (PFS) in patients who received the drug combination was 13.8 months, versus 8.4 months in patients who received sunitinib. Among the 560 patients who were PD-L1 positive, PFS was 13.8 months in the subset treated with avelumab and axitinib, compared with 7.2 months in the sunitinib group.

The objective response rate (ORR) was also higher in patients who received the two drugs than in those treated only with sunitinib, 51% versus 26%. In the PD-L1–positive patients, ORR was 55% in the group that received both drugs, compared with 26% in the sunitinib group. Final overall survival data are not yet available, but the results so far suggest that “we have another combination for the first line in renal cell carcinoma,” says Choueiri.

The incidence of side effects that were grade 3 or 4 was similar in the two groups—51% in the avelumab–axitinib group and 48% in the sunitinib group. However, 4% of patients who received the drug combination discontinued treatment because of side effects, whereas 8% of sunitinib patients did so.

“It's the first phase III trial that shows significant activity of immunotherapy and targeted therapy” in RCC, says Roberto Pili, MD, of the Indiana University School of Medicine in Indianapolis, who wasn't connected to the research. “The data confirm that combining the two approaches makes sense.”

Other studies have found high levels of toxicity from pairing checkpoint inhibitors with targeted drugs in RCC. In the phase I CheckMate 016 trial of nivolumab plus sunitinib, for example, 81.8% of patients who received both drugs developed grade 3 or 4 side effects (J Immunother Cancer 2018;6:109).

“The new findings suggest that the avelumab–axitinib combination may be less toxic,” Pili says. “Administering these drugs sequentially rather than concomitantly might reduce toxicity even further, but we still do not know whether it would be as effective,” he says. –Mitch Leslie

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