Abstract
Axitinib plus pembrolizumab has a 73% response rate in previously untreated advanced renal cell carcinoma.
Major finding: Axitinib plus pembrolizumab has a 73% response rate in previously untreated advanced renal cell carcinoma.
Clinical relevance: The selective VEGFR inhibitor axitinib has less toxicity than multitargeted inhibitors with anti–PD-1.
Impact: Axitinib may allow for dual targeting of VEGFR and PD-1 for enhanced efficacy in renal cell carcinoma.
VEGFR inhibitors have proven beneficial in patients with advanced renal cell carcinoma, but many patients eventually develop drug resistance. Immune checkpoint blockade with anti–PD-1 or anti–PD-L1 antibodies has demonstrated antitumor activity in patients with advanced renal cell carcinoma who have progressed after therapies targeting the VEGF pathway. However, combined inhibition has proven too toxic, due in part to off-targeted effects of multitargeted tyrosine kinase inhibitors (TKI). Axitinib is a potent, selective VEGFR1–3 inhibitor that has clinical activity in metastatic renal cell carcinoma, prompting Atkins and colleagues to hypothesize that axitinib plus the anti–PD-1 antibody pembrolizumab might be better tolerated than combinations with less-selective TKIs targeting VEGFR. The safety and efficacy of combination therapy with axitinib plus pembrolizumab was evaluated in an open-label phase Ib trial of 52 patients with previously untreated advanced renal cell carcinoma; 11 patients were enrolled in the dose-finding phase, and 41 patients were enrolled in the dose-expansion phase. The primary endpoint was dose-limiting toxicity during the dose-finding phase to estimate the maximum tolerated and recommended phase II dose, and secondary endpoints included adverse events and antitumor activity. In the dose-finding phase, three dose-limiting toxicities occurred, and the maximum tolerated dose was estimated to be 5 mg axitinib twice daily plus 2 mg/kg pembrolizumab every 3 weeks. Overall, treatment with axitinib plus pembrolizumab was tolerable, although grade 3–4 treatment-related adverse events occurred in 65% (34 of 52) of patients. Objective responses were observed in 38 of 52 patients (73%), including 4 complete and 34 partial responses, and the median progression-free survival was 20.9 months. In addition to suggesting that selective VEGFR inhibition may result in reduced toxicity in combination therapies compared with multitargeted TKIs, these findings reveal that axitinib plus pembrolizumab is tolerable and has antitumor activity in patients with renal cell carcinoma.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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