Phase 1b study of crizotinib in combination with pembrolizumab in patients (pts) with untreated ALK-positive (+) advanced non-small cell lung cancer (NSCLC)

Abstract

Background: 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. Trial design: 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.