Pembrolizumab plus axitinib is superior to sunitinib for the treatment of patients with treatment-naïve, advanced renal cell carcinoma (RCC), according to the most recent exploratory analysis of data from the KEYNOTE-426 study. The phase III KEYNOTE-426 study is an ongoing, randomized, open-label trial in 861 adults with treatment-naïve, advanced RCC from 129 sites in 16 countries. Patients were randomized to treatment with intravenous pembrolizumab (200 mg every 3 weeks for up to 35 cycles) plus axitinib (5 mg orally twice daily) or sunitinib monotherapy (50 mg orally once daily for 4 weeks per 6-week cycle).

Initial results showed that the combination of pembrolizumab—an anti-PD-1 antibody—plus axitinib—VEGFR inhibitor—was superior in efficacy to sunitinib monotherapy in patients with advanced RCC who were treatment-naïve.

“Immunotherapy-based drug combinations have transformed the treatment landscape of advanced renal cell carcinoma. In treatment-naive patients with advanced renal cell carcinoma, compared with sunitinib, the combination of pembrolizumab, an anti-PD-1 antibody, plus axitinib, a VEGFR inhibitor, showed significant improvements in overall survival, progression-free survival, and the proportion of patients who had a confirmed objective response at a median follow-up of 14.2 months,” says Thomas Dr. Powles, MD, MBBS, MRCP, of Barts Cancer Institute and Queen Mary University of London, London, UK, and fellow researchers.

Dr. Powles and colleagues have now published results from their recent exploratory analysis of KEYNOTE-426, with extended follow-up, in The Lancet Oncology. For this latest analysis, they assessed the long-term efficacy and safety of pembrolizumab plus axitinib compared with monotherapy with sunitinib in patients with advanced RCC.

In a plenary abstract presentation in the Poster Highlights Session: Renal Cell Cancer – Clinical Trial Updates session at ASCO GU 2021, Elizabeth Plimack, MD, MS, professor in the Department of Hematology/Oncology and chief of the Division of Genitourinary Medical Oncology at Fox Chase Cancer Center and colleagues provide an update on the KEYNOTE-426 study examining outcomes for patients who received pembrolizumab and axitinib and have completed 2 years of follow-up.

The primary end points were overall survival (OS) and progression-free survival (PFS), with key secondary end points of objective response rate (ORR) and safety. According to protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent. Pembrolizumab was stopped for all patients at 2 years. Axitinib could be continued until progression or toxicity. In this presentation, the authors report an exploratory subgroup analysis of KEYNOTE-426 describing outcomes of patients who completed 2 years of pembrolizumab.

Among 432 patients who were treated with pembrolizumab and axitinib, 29.9% completed 2 years of study therapy. The authors further limited their analysis to 103 patients who didn’t discontinue axitinib due to progressive disease. The median age was 61 (36-82) years, and 73.8% were male.

The majority of patients in this subset had International mRCC Database Consortium intermediate/poor risk disease (n=67) while 36 had favorable risk disease. The median follow-up duration from randomization to data cut-off was 30.1 months. Among patients who completed 2 years of study therapy, neither median OS or median PFS were reached as of 3 years.

Approximately, 85.4% of patients who completed 2 years of therapy per protocol had objective response, of which 16 patients had complete response. On multivariable analysis, patients younger than 65 years (OR 1.76, 95% CI 1.07-2.90), those with performance status of 90/100 (OR 2.10, 95% CI 1.03-4.24), those with favorable (OR 4.99, 95% CI 1.63-15.27) and intermediate (OR 4.90, 95% CI 1.67-14.41) risk disease, and those with sarcomatoid features (OR 2.19, 95% CI 1.08-4.43) were more likely to complete two years of therapy.

The most frequent treatment-related adverse events of grade 3 or worse included hypertension, seen in 22% of patients treated with pembrolizumab plus axitinib compared with 20% of patients treated with sunitinib, increases in alanine aminotransferase (13% vs 3%, respectively), and diarrhea (11% vs 5%).

The authors conclude that this exploratory analysis demonstrates that a significant proportion of patients in the pembrolizumab and axitinib arm are able to complete 2 years of pembrolizumab with ongoing clinical benefit.

Reference: Plimack, ER, et al. Outcomes for patients in the pembrolizumab+axitinib arm with advanced renal cell carcinoma (RCC) who completed two years of treatment in the phase III KEYNOTE-426 study. Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021) 327-327.