Combo reduced disease progression, offered durable survival benefit in patients with advanced disease

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,” wrote lead author Thomas Powles, MD, MBBS, MRCP, of Barts Cancer Institute and Queen Mary University of London, London, UK, and fellow researchers.

“Based on these results, the combination of pembrolizumab plus axitinib is considered a new standard of care for the first-line treatment of advanced renal cell carcinoma. Because durable response is a hallmark of anti-PD-1 therapy, it is important to understand the benefit of pembrolizumab plus axitinib with longer follow-up,” they added.

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.

After a median follow-up of 30.6 months, Powles et al observed a continued clinical benefit in the following primary endpoints in patients treated with pembrolizumab plus axitinib compared with sunitinib:

  • Overall survival: median not reached versus 35.7 months, respectively (95% CI: 33.3-not reached; HR: 0.68; 95% CI: 0.55-0.85; P=0.0003).
  • Progression-free survival: median: 14.5 months (95% CI: 12.7-18.9) versus 11.1 months (95% CI: 9.1-12.5); HR 0.71; 95% CI: 0.60-0.84; P ˂ 0.0001).

In addition, a full 60% of patients treated with the combination of pembrolizumab plus axitinib achieved a confirmed objective response, as compared with 40% of patients treated with sunitinib (P < 0.0001). Complete responses were seen in 9% versus 3%, respectively.

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% versus 3%, respectively), and diarrhea (11% versus 5%).

There were no new treatment-related deaths since the first interim analysis.

In their accompanying editorial, Giuseppe Procopio, MD, and colleagues from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, stressed the importance of immunotherapy in the treatment of RCC.

They hail results from this latest analysis of the KEYNOTE-426 study from Powles and colleagues as a “milestone,” especially for the robustness of data showing enhanced overall survival, progression-free survival, and objective response rates.

“[D]ata from the KEYNOTE-426 study must be read and interpreted together with the existing published literature, and in particular with the CheckMate 214 trial (nivolumab plus ipilimumab versus sunitinib), the JAVELIN Renal 101 trial (avelumab plus axitinib versus sunitinib), and the IMmotion151 trial (atezolizumab plus bevacizumab versus sunitinib). Given the impossibility of making direct comparisons between the different combinations, clinical experience and confidence with one combination over another is the best way for oncologists to choose between these therapeutic options according to evidence-based recommendations,” they concluded.

Study limitations include the possible effects of the well-publicized interim results of KEYNOTE-426, inadequate powering for subgroup analysis, limited depth of response analysis, and the unavailability of data to estimate the durability of benefit after treatment cessation.

  1. In the latest analysis of data from the KEYNOTE-426 trial, researchers found that with extended follow-up, pembrolizumab plus axitinib continued to show a survival benefit compared with sunitinib.

  2. Specifically, the combination of pembrolizumab, an anti-PD-1 antibody, plus axitinib, a VEGFR inhibitor, showed significantly improved overall survival, progression-free survival, and confirmed objective responses compared with sunitinib.

E.C. Meszaros, Contributing Writer, BreakingMED™

KEYNOTE-426 was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

Powles has received research funding from AstraZeneca, Roche, Bristol-Myers Squibb, Exelixis, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; honoraria from Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; and travel accommodation from Roche, Pfizer, Merck Sharp & Dohme, AstraZeneca, and Ipsen.

Procopio has received honoraria or education grants for consultation, advisory board attendance, and providing lectures from AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Ipsen, Merck, Merck Sharp & Dohme, Pfizer, and Novartis, outside of the submitted work.

Cat ID: 835

Topic ID: 78,835,730,835,127,192,925