The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was superior to sunitinib (Sutent) monotherapy as first-line treatment of advanced or metastatic renal cell carcinoma.
Bernard Escudier, MD
Frontline treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) reduced the risk of death by 32% compared with sunitinib (Sutent) for patients with metastatic renal cell carcinoma (mRCC), according to findings from the CheckMate 214 study presented at the 2017 ESMO Congress.
In the randomized trial, the median overall survival (OS) was not reached with the combination versus 32.9 months with sunitinib (HR, 0.68; 99.8% CI, 0.49-0.95; P = .0003). In those specifically with intermediate- and poor-risk RCC, who constituted about 75% of the intent-to-treat (ITT) population, median OS was not reached in the nivolumab and ipilimumab arm and was 26.0 months in the sunitinib arm, a 37% reduction in the risk of death (HR, 0.63; 99.8% CI, 0.44-0.89; P <.0001). There was not a benefit for the combination versus sunitinib in those with favorable risk.
“These results support the use of nivolumab and ipilimumab as a new first-line standard of care option for patients with advanced RCC,” said Bernard Escudier, MD, from Institut Gustave Roussy, Villejuif, France. "These results for the combination of nivolumab and ipilimumab are very encouraging in patients with first-line mRCC who have a very poor prognosis."
Based on the improvement in OS, Bristol-Myers Squibb, the company developing the combination, announced that the trial had been stopped to allow patients to cross over from the sunitinib arm. The company plans to submit the findings to regulatory authorities for potential approval.
CheckMate-214 included patients with advanced or metastatic clear cell RCC who were treatment-naïve. Patients were randomized 1:1 to nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg, every 3 weeks for 4 doses, followed by nivolumab, 3 mg/kg every 2 weeks; or to receive oral sunitinib, 50 mg a day for 4 weeks in 6-week cycles. Patients were stratified by risk group and region, and treatment was continued until disease progression or unacceptable toxicity.
In the 1096 patients in the ITT population, 23% were considered favorable risk, 61% as intermediate risk, and 17% as poor risk in each arm. As well, about one fourth in the ITT population had PD-L1 expression ≥1%. Among the 847 patients in the intermediate- or poor-risk groups, 79% were classified as intermediate risk (IMDC 1-2) and 21% as poor risk (IMDC 3-6) in each treatment arm. About one-fourth of the patients in each arm had PD-L1 expression ≥1%.
The most common sites of metastasis were the lung (approximately 70%), lymph nodes (approximately 50%), liver (approximately 20%), and bone (approximately 20%). Coprimary endpoints were ORR per independent radiology review committee (IRCC), progression-free survival (PFS; per IRRC), and OS.
Across the full ITT, the median PFS was not improved, which had been announced prior to the ESMO meeting (12.4 vs 12.3 months; HR, 0.98; 99.1% CI, 0.79-1.23; P = 0.8498). PFS in the intermediate- and poor-risk group was 11.6 months with the combination versus 8.4 months with sunitinib (HR, 0.82; 99.1% CI, 0.64-1.05; P = 0.0331). A P value of .009 was required for significance.
Across the full study, the confirmed ORR was 39% and 32% (P = 0.0191) in the nivolumab/ipilimumab group and sunitinib group, respectively. The confirmed ORR in the intermediate/poor risk patients was 42% in patients assigned to nivolumab plus ipilimumab compared with 27% in those assigned to sunitinib (P <.0001). Nine percent of patients in the nivolumab/ipilimumab group had a complete response (CR) and 32% had a partial response, compared with 1% CR and 25%, 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).
Favorable risk patients, in contrast, had a significantly higher confirmed ORR with sunitinib versus the combination arm (52% vs 29%, P =.0002), as well as a significantly longer PFS (25.1 vs 15.3 months; P <.0001).
In those with PD-L1 expression ≥1%, the Median PFS was significantly longer with the immunotherapy combination than with sunitinib (22.9 vs 5.9 months; HR, 0.48; P = .0003). Those with PD-L1 expression <1% did not benefit from the combination (HR, 1.00; P = 0.9670).
“In exploratory analysis, PD-L1 expression was quite an important factor, demonstrating a higher response rate and improved PFS with nivolumab/ipilimumab versus sunitinib,” said Escudier.
Among all treated patients, with a median follow-up of 25.2 months, 77% of patients assigned to nivolumab plus ipilimumab and 82% assigned to sunitinib discontinued treatment. The main reason for discontinuation in each group was disease progression (42% in the combination immunotherapy group and 55% 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 ipilimumab doses received was 4. Seventy-four percent of patients received all 4 doses of ipilimumab.
Adverse events (AEs) leading to discontinuation occurred in 22% of patients in the combination immunotherapy group compared with 12% in the sunitinib group. The most common grade 3/4 AEs in the combination group were fatigue (4%) and diarrhea (4%). In the sunitinib group, the most common grade 3/4 AEs were hypertension (16%), fatigue (9%), and Palmar-plantar erythrodysesthesia syndrome (9%). There were 7 treatment-related deaths in the combination group and 4 in the sunitinib group.
"The safety profile of nivolumab and ipilimumab was manageable and consistent with previous studies," said Escudier. "More high-grade treatment-related adverse events were observed with sunitinib and patients reported better symptom control with nivolumab and ipilimumab versus sunitinib."
Invited discussant Manuela Schmidinger, MD, medical oncologist at the University of Vienna, Austria, said that quality of response to nivolumab and ipilimumab “is highlighted by the rate of complete remission, the duration of response, and the translation into OS benefit,” while noting that sunitinib had never been defeated before in a head-to-head comparison in the setting of advanced or metastatic clear cell RCC. While nivolumab and ipilimumab as a first-line treatment could be a new standard of care in this patient population, with massive impact, “it’s not the final picture yet.”
Once the biology of a patient’s individual tumor can be properly addressed, the best treatment among various first-line options can be selected, she said. It’s possible that nivolumab and ipilimumab may be the better choice in favorable risk patients with high PD-L1 expression based on the exploratory analysis, but considering that most patients in the study were PD-L1-negative, its role as a predictive marker remains unclear. Further, patients with bone metastases may benefit preferentially from cabozantinib, given that it targets the bone microenvironment.
Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA5.