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The combination of pembrolizumab and axitinib demonstrated comparable activity and safety vs sunitinib in Japanese patients vs the global population of patients with newly diagnosed metastatic renal cell carcinoma enrolled in the phase 3 KEYNOTE-426 trial.
The combination of pembrolizumab (Keytruda) and axitinib (Inlyta) demonstrated comparable activity and safety vs sunitinib (Sutent) in Japanese patients vs the global population of patients with newly diagnosed metastatic renal cell carcinoma (mRCC) enrolled in the phase 3 KEYNOTE-426 (NCT02853331) trial, according to findings from the study that were published in the International Journal of Clinical Oncology.
The results showed that the combination led to a similar improvement in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs sunitinib in Japanese patients vs patients in the ITT population.
In the Japanese population, the median OS was not reached in either arm (HR, 0.83; 95% CI, 0.39-1.76). The 12-month OS rate was 95% with the combination vs 90% with sunitinib. The 24-month OS rate was 79% vs 78%, respectively. Similarly, the median OS was not reached in the ITT population but did show a statistically significant improvement with the combination in both the primary and second interim analyses.
In the Japanese population, the median PFS was 20.6 months with the combination (95% CI, 12.5-23.5) vs 11.3 months (95% CI, 8.2-18.0) with sunitinib (HR, 0.61; 95% CI, 0.37-1.01). The 12-month PFS rates were 72% vs 48%, respectively.
“The results reported here provide long-term safety and efficacy data among the Japanese patient subgroup derived from the extended follow-up analysis of KEYNOTE-426. The results of this long-term post-hoc subgroup analysis show that first-line pembrolizumab [and] axitinib when compared with sunitinib improves ORR and PFS in Japanese patients with advanced clear cell mRCC in a manner similar to that in the global study population,” wrote lead study author Satoshi Tamada, MD, of the Department of Urology at Osaka City University in Osaka, Japan, and coauthors in the study publication. In primary and updated analyses of the phase 3, open-label study, pembrolizumab plus axitinib led to an improvement in OS and PFS vs sunitinib in patients with newly diagnosed mRCC, leading to the regimen’s approval as first-line therapy in this population in the United States, the European Union, Japan, and other countries/regions.
In the study, patients with clear cell mRCC were randomized to receive 200 mg of intravenous pembrolizumab every 3 weeks plus 5 mg of oral axitinib twice daily or 50 mg of oral sunitinib once daily for 4 weeks on and 2 weeks off for 35 cycles until progressive disease, unacceptable toxicity, or study withdrawal.
OS and PFS as assessed by blinded independent central review served as coprimary end points. ORR and safety were included as secondary end points.
Because the study also accrued patients from 25 sites in Japan, investigators conducted a post-hoc subgroup analysis to better understand the activity of the combination in this population.
The Japanese subgroup consisted of 94 patients (pembrolizumab/axitinib, n = 44; sunitinib, n = 50) and comprised 11% of the ITT population.
Baseline characteristics revealed that the Japanese subgroup consisted of older patients, more patients with favorable International Metastatic RCC Database Consortium risk, and more patients with Karnofsky Performance Scale scores of 90/100 vs 70/80 compared with patients in the ITT population.
The median time from randomization to data cutoff on January 6, 2020, was 29.5 months (range, 24.6-37.3).
At data cutoff, 75% patients in the combination arm vs 86% of patients in the sunitinib arm who received at least 1 dose of the study drug had discontinued treatment. Most discontinuations in both arms were due to disease progression (pembrolizumab/axitinib, 39%; sunitinib, 49%) or adverse effects (AEs; pembrolizumab/axitinib, 25%; sunitinib, 27%).
Seventy-three percent of patients in the combination arm received subsequent therapy vs 93% of patients in the sunitinib arm; 21% vs 60% of patients received at least 2 subsequent lines of therapy, respectively.
The most commonly used subsequent therapies in the combination arm were pazopanib (Votrient; 27%), axitinib (18%), and sunitinib (15%). In the sunitinib arm, the most commonly used subsequent therapies were nivolumab (Opdivo; 67%), axitinib, (43%), and pazopanib (14%). A VEGF/VEGFR inhibitor was used in 55% vs 62% of patients, respectively.
Additional results from the subgroup analysis showed that the ORR was 70% (95% CI, 55%-83%) with the combination vs 52% with sunitinib (95% CI, 37%-66%). The complete response rates were 14% vs 6%, respectively.
The duration of response among responders was 16.6 months (range, 4.2 to 29.1+) in the combination arm vs 9.9 months (range, 2.8+ to 25.2+) in the sunitinib arm. Twenty patients (70%) were in response for at least 12 months in the combination arm vs 9 (45%) patients in the sunitinib arm.
In terms of safety, all Japanese patients experienced a treatment-related AE (TRAE). Grade 3/4 TRAEs were reported in 70% of patients in the combination arm vs 78% of patients in the sunitinib arm.
Two deaths were reported in each arm not owing to a TRAE, and no deaths from TRAEs were reported.
The most common TRAEs in both arms were palmar plantar erythrodysesthesia syndrome and hypertension. AEs of interest occurred in 28 (64%) patients in the combination arm vs 26 (53%) patients in the sunitinib arm, the most common of which were hypothyroidism and hyperthyroidism in both arms.
Grade 3/4 AEs of interest occurred in 8 (18%) patients in the combination arm vs none in the sunitinib arm. Nine (20%) patients in the combination arm received high-dose corticosteroids (≥ 40 mg/day prednisone or equivalent for ≥ 1 day) to treat AEs of special interest.
TRAEs that led to the discontinuation of pembrolizumab, axitinib, pembrolizumab/axitinib, or sunitinib occurred in 32%, 34%, 14%, and 20% of patients, respectively.
“This analysis verifies the efficacy and safety of pembrolizumab [and] axitinib for the treatment of mRCC among Japanese patients,” concluded the study authors.