Crizotinib is approved internationally for the treatment of ALK+ advanced NSCLC. However, disease progression ultimately occurs in the vast majority of pts, often due to the development of secondary crizotinib-resistant ALK mutations or signal transduction bypass pathways. The immune checkpoint programmed cell death 1 (PD-1) pathway can be exploited by tumors to limit T cell activity, allowing tumors to evade immune detection. ALK+ NSCLC is associated with high PD ligand 1 (PD-L1) expression, and data from a preclinical model has suggested that combining PD-1- and ALK-targeted therapies may be beneficial (Ota et al, Clin Cancer Res 2015; Voena et al, Cancer Immunol Res 2015). The anti–PD-1 antibody, pembrolizumab is approved in the US for the treatment of advanced PD-L1+ NSCLC after progression on a platinum-based chemotherapy and an approved tyrosine kinase inhibitor for those with an EGFR or ALK genomic aberration.
The primary objectives of this ongoing multicenter study (NCT02511184) are to determine the maximum tolerated dose (MTD) of crizotinib combined with pembrolizumab (dose-finding; part 1) and the recommended phase 2 dose (dose expansion; part 2), with secondary objectives to evaluate the safety profile and antitumor activity of the combination, the pharmacokinetics of both drugs, and PD-L1 expression as a predictor of antitumor activity. Part 1 uses a modified toxicity probability interval method to determine the MTD, with a starting crizotinib dose of 250 mg twice daily on a continuous schedule and intravenous pembrolizumab 200 mg on day 1 of each 21-day cycle. Seventy patients are expected to be enrolled, with 30 dose-limiting toxicity-evaluable patients expected in part 1, including a target of 10 treated at the MTD who will also contribute to the planned 50 required for part 2. Key eligibility criteria include ALK+ advanced NSCLC, no prior systemic therapy for metastatic disease, measurable disease (RECIST v1.1), available archival tumor tissue, and ECOG performance status 0/1 (part 1) or 0–2 (part 2). Pts with stable treated brain metastases are eligible. Enrollment in part 1 began in Oct 2015, with 5 pts currently enrolled.
Clinical trial identification
Clinical Trials Registration number: NCT02511184
Legal entity responsible for the study
Funding for this research was provided by Pfizer Inc. and Merck & Co., Inc.
F.R. Vizcarrondo: Research funds from Pfizer. N.A. Pennell: Consultant for AstraZeneca, Boehringer Ingelheim. H. West: Consultant/honoraria for Ariad, BMS, AstraZeneca, Genentech/Roche, Novartis, Pfizer, Merck. J. Tarazi, K. Wilner, W. Tan, Y. Liu: Pfizer employee. A. Polli, O. Valota: Pfizer employee, owns stocks. B. Piperdi: Employee of Merch & Co., Inc. K.L. Reckamp: Research support from Pfizer to institution. All other authors have declared no conflicts of interest.