The Food and Drug Administration (FDA) approved the immunotherapy combination of Yervoy (ipilimumab) plus Opdivo (nivolumab) to treat patients with intermediate- or poor-risk advanced renal cell carcinoma in the frontline setting.
The approval was based off results from the ongoing, randomized phase 3 CheckMate-214 trial, where patients were randomized to receive either Yervoy plus Opdivo or Sutent (sunitinib). The combination decreased the risk of death by 37 percent compared to Sutent.
“This is a major milestone for patients battling advanced kidney cancer. The combination of nivolumab and ipilimumab provided a clear clinically relevant advantage in terms of prolonging the lives of RCC patients over sunitinib, a standard during the past ten-plus years,” Toni K. Choueiri, M.D., Director, Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute said in an interview with CURE.
“The new combination should be a new standard moving forward in advanced RCC of intermediate and poor risk per the IMDC criteria.”
In the randomized trial, the median overall survival (OS) was not reached with the combination, but it was 32.9 months with Sutent. In those specifically with intermediate- and poor-risk RCC, who constituted about 75 percent of the intent-to-treat (ITT) population, median OS was not reached in the Opdivo plus Yervoy arm, and was 26 months in the Sutent arm, a 37 percent reduction in the risk of death. There was not a benefit for the combination versus Sutent in those with favorable risk.
Across the full ITT, the median PFS was not improved (12.4 vs 12.3 months). However, PFS in the intermediate- and poor-risk group was 11.6 months with the combination versus 8.4 months with Sutent.
The combination had higher overall response rates (ORR) – 39 percent and 32 percent in the Opdivo/Yervoy and Sutent groups, respectively. The confirmed ORR in the intermediate/poor risk patients was 42 percent in patients assigned to Opdivo/Yervoy compared with 27 percent in those assigned to Sutent. Nine percent of patients in the combination group had a complete response (CR) and 32 percent had a partial response, compared with 1 percent CR and 25 percent, respectively, in the sunitinib group. The median duration of response was significantly superior with nivolumab/ipilimumab compared with sunitinib (not reached vs 18.2 months).
Patients with favorable risk, in contrast, had a significantly higher confirmed ORR with Sutent versus the combination arm (52 percent vs 29 percent), as well as a significantly longer PFS (25.1 vs 15.3 months).
In those with PD-L1 expression, which the combination targets, higher than 1 percent, the median PFS was significantly longer with the immunotherapy combination than with Sutent (22.9 vs 5.9 months). Those with PD-L1 expression less than 1 percent did not benefit from the combination.
Among all treated patients, with a median follow-up of 25.2 months, 77 percent of patients assigned to Opdivo/Yervoy and 82 percent assigned to Sutent discontinued treatment. The main reason for discontinuation in each group was disease progression (42 percent in the combination immunotherapy group and 55 percent in the sunitinib group). The median duration of therapy was 7.9 and 7.8 months, respectively. In the immunotherapy arm, the median number of nivolumab doses received was 14 and the median number of Yervoy doses received was four. Seventy-four percent of patients received all 4 doses of Yervoy.
Side effects that led to discontinuation occurred in 22 percent of patients in the combination immunotherapy group compared with 12 percent in the Sutent group. The most common grade 3 or 4 AEs in the combination group were fatigue (4 percent) and diarrhea (4 percent). In the Sutent group, the most common grade 3/4 AEs were high blood pressure (16 percent), fatigue (9 percent), and Palmar-plantar erythrodysesthesia syndrome (9 percent). There were seven treatment-related deaths in the combination group and 4 in the sunitinib group.
Despite this great advancement, there is still work that needs to be done, says Choueiri.
“Future efforts should focus on biomarkers of response to the combination, novel strategies building on nivolumab plus ipilimumab and managing and preventing immune-related adverse events,” he said. “So much to hope for and it is humbling to see all these advances happening in RCC.”