Phase I/II Dose-Finding Study of Crizotinib (CRIZ) in Combination with Erlotinib (E) in Patients (PTS) with Advanced Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Background c-Met expression is common in NSCLC tumors and has been implicated in the development of resistance to EGFR inhibitors. Criz is an ALK and MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical studies, combining criz with an EGFR inhibitor enhanced anti-tumor activity in NSCLC cell lines that were sensitive or resistant to EGFR inhibition. The phase I portion of a phase I/II study (A8081002; NCT00965731) investigated the combination of E (EGFR TKI) and criz in pts with advanced NSCLC. Methods Pts had advanced NSCLC, 1 or 2 prior chemotherapy regimens, and no previous MET-directed therapy. Endpoints included maximum tolerated dose (MTD) determination, safety, and pharmacokinetics (PK). Pts received E 100 mg QD for ≥7 days before adding criz 150 or 200 mg BID (150 + 100 and 200 + 100, respectively). Results As of March 15th 2012, 27 pts had started therapy. Median (range) duration of combination therapy in 150 + 100 (n = 19) was 7 weeks (0.1–28.0); for 200 + 100 (n = 7) was 6.9 weeks (1.9–77.6). Five pts had dose-limiting toxicities (grade [G] 2 and unable to receive at least 80% of the planned dose or ≥G3), all of which resolved: 3 pts at 150 + 100, G2 vomiting, G2 esophagitis and dysphagia, G3 diarrhea and dehydration; and at 200 + 100, G3 dry eye (1 pt) and G3 esophagitis (1 pt). Most pts (96%) experienced treatment-related adverse events (TRAEs), mainly of G1 or 2 severity. Common TRAEs were diarrhea (73%), rash (62%) and fatigue (46%). Six pts discontinued therapy due to TRAEs (150 + 100: G3 diarrhea, G3 dehydration, and G1 hyponatremia in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n = 1 each; 200 + 100: G3 dry eyes, G1 esophagitis, n = 1 each). One partial response (200 + 100; duration 73 weeks) and 9 stable diseases (n = 7 150 + 100, n = 2 200 + 100; duration 8–62 weeks) were observed overall. Co-administration of both doses of criz with E increased E AUC by 1.8 fold; criz PK parameters appeared to be unaffected. Plasma exposure to E 100 mg QD with criz was comparable to 150 mg QD from historical data. Conclusions E plus criz at the MTD was well tolerated, with no unexpected AEs, and showed signs of activity in a pre-treated population. E 100 mg QD plus criz 150 mg BID was defined as MTD. Disclosure S.I. Ou: Advisory relationship with Pfizer and Genentech (both compensated). Received honoraria from Pfizer, Genentech and Lilly. Research funding from Pfizer. K. Eaton: Research funding from Pfizer. A. Argiris: Advisory relationship with Pfizer. Received honoraria from Pfizer. Research funding from Pfizer. G. Otterson: Received honoraria from Genentech and Abraxis/Celgene. Research funding from Genentech, Abraxis/Celgene, Pfizer, Tragara, Amgen, Pharmacyclics, OSI and GSK. F. Robert: Research funding to the University of Alabama at Birmingham. N. Brega: Employed by Pfizer as a Director. Hold Pfizer stock. T. Usari: Employed by Pfizer as a statistician. Holds Pfizer stock. W. Tan: Employed by Pfizer. Holds Pfizer stock. All other authors have declared no conflicts of interest.