On 19 April 2019, the FDA approved the programmed death 1 (PD-1) inhibitor pembrolizumab (KEYTRUDA®, Merck) plus axitinib – a selective and potent receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 – as a first-line treatment for advanced renal cell carcinoma (RCC) patients.

KEYNOTE-426

The FDA approval followed the results of the randomised, multicentre, open-label KEYNOTE‑426 (NCT02853331) study in 861 advanced RCC patients with any PD-L1 expression status and who did not undergo prior systemic therapy for advanced or metastatic disease. Eligible patients received either pembrolizumab 200 mg intravenously in 3-week cycles plus axitinib 5 mg orally (p.o.) twice daily, or sunitinib 50 mg p.o. once daily for 4 weeks followed by 2 weeks off sunitinib treatment. All participants received study-treatment until confirmed progression disease or the occurrence of unacceptable toxicity. Pembrolizumab treatment was provided for up to 24 months. Major efficacy measures included the overall survival (OS) and progression-free survival (PFS) by blinded independent central review (RECIST 1.1.).

At a pre-specified interim analysis, the combination of the PD-1 and VEGFR inhibitors showed a statistically significant improvement in OS when compared to sunitinib (HR=0.53; 95% CI, 0.38-0.74; P<0.0001). Although the median OS was not reached in either arm, the 12-month OS-rate for pembrolizumab plus axitinib measured 90% compared to 78% with sunitinib. The PFS was also improved in patients receiving pembrolizumab plus axitinib vs those receiving sunitinib (HR=0.69; 95% CI, 0.57-0.84; P=0.0001), with a median PFS of 15.1 and 11.1 months for patients receiving the anti-PD-1 plus anti-VEGFR treatment combination vs. sunitinib, respectively.

Safety

Common adverse reactions in >20% of patients receiving pembrolizumab plus axitinib included diarrhoea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. Grade 3 and 4 hepatotoxicities occurred in 20% of patients receiving the combination and led to permanent discontinuation of treatment in 13% of patients.

Full prescribing information KEYTRUDA®.