Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial
Michael B Atkins, Elizabeth R Plimack, Igor Puzanov, Mayer N Fishman, David F McDermott, Daniel C Cho, Ulka Vaishampayan, Saby George, Thomas E Olencki, Jamal C Tarazi, Brad Rosbrook, Kathrine C Fernandez, Mariajose Lechuga, Toni K Choueiri, Michael B Atkins, Elizabeth R Plimack, Igor Puzanov, Mayer N Fishman, David F McDermott, Daniel C Cho, Ulka Vaishampayan, Saby George, Thomas E Olencki, Jamal C Tarazi, Brad Rosbrook, Kathrine C Fernandez, Mariajose Lechuga, Toni K Choueiri
Abstract
Background: Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma.
Methods: In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742.
Findings: Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response).
Interpretation: The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331).
Funding: Pfizer Inc.
Conflict of interest statement
Declaration of interests
JCT, BR, ML, and KCF are employees of and own stock in Pfizer.
MBA declares receiving fees for consulting from Bristol-Myers Squibb (BMS), Pfizer, Novartis, Genentech-Roche, Merck, and Eisai. ERP declares receiving fees for consulting from AstraZeneca, BMS, Clovis, Eli Lilly and Company, Exelexis, Genentech, Horizon Pharma, Inovio, Novartis, Pfizer, and Roche, and grant support to her institution has been received from AstraZeneca, BMS, Merck, Peloton, Pfizer, GlaxoSmithKline (GSK), Dendreon, Aveo, Acceleron, and Eli Lilly Inc. MNF has received research funding from BMS, Exelixis, Eisai, Genentech, Acceleron, Merck, Prometheus, Nektar, Alkermes, and Pfizer, and has served on speakers bureaus for Exelixis. DFM declares receiving fees for consulting from BMS, Pfizer, Novartis, Genentech-Roche, Merck, Eisai, Array BioPharm, Prometheus, and Exelixis. SG declares receiving fees for consulting and serving on advisory boards from Pfizer, Exelixis, BMS, Novartis, Bayer, Janssen, Corvus, and AstraZeneca, and institutional grant support from BMS, Novartis, Bayer, Pfizer, Merck, and Agensys. TKC declares receiving fees for consulting and for serving on advisory boards from GSK, Novartis, Pfizer, Merck, AstraZeneca, Bayer, Genentech, Exelixis, Eisai, Cerulean, Foundation Medicine Inc, Corvus, and Prometheus, and grant support through his institution from BMS, GSK, Novartis, Exelixis, Pfizer, Merck, Roche, AstraZeneca, TRACON Pharmaceuticals, and Peloton. DCC declares receiving fees for consulting from Pfizer, Genentech, Prometheus, BMS, and Exelixis. UV declares research support from Astellas, Novartis, and Exelixis and consulting fees from Pfizer, Bayer, and BMS. All other authors declare no competing interests.
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Source: PubMed