Activity of crizotinib in relapsed MET amplified malignancies: Results of the french acsé program

Background: Crizotinib (crz) is registered only for the treatment of patients (pts) with ALK-translocated lung cancer. Crz is also a MET inhibitor. MET is amplified in several malignancies. Activity of crz in MET amplified (+) tumors was explored as part of the French National Cancer Institute (INCa) AcSé program, including both access to tumor molecular diagnosis and an exploratory multi-tumor 2-stage design phase II trial. We report here results in pts with MET + tumors. Methods: MET analysis on formalin-fixed, paraffin-embedded tumor samples was proposed in 170 investigating centers and performed in 28 regional INCa molecular genetic centers. MET+ was explored by FISH in tumor samples showing an IHC score of ≥2+. Pts with a tumor showing > 6 MET copies, whatever the MET/CEN7 ratio, were eligible, providing they were not eligible for any other academic or industry trial evaluating another MET inhibitor. Study treatment consisted in crz 250 mg BID. The objective response rate (ORR) and disease control rate (DCR) were assessed every 8 weeks, using RECIST v1.1. Results: From Aug. 2013 to Dec. 2014, MET was prospectively analyzed in the tumors of 3,044 pts, and amplification (median copy number=7) was found in 100/1,358 lung, 19/591 colon, 5/275 ovary, 13/218 glioblastoma, 10/180 gastric, 1/63 hepatocarcinoma, 1/50 kidney and 0/11 thyroid. 46 pts were enrolled in the trial. Median age: 59 yrs (range 30-92), 65% males and 95% metastatic disease at study entry. 23 pts were still on treatment at the cut-off date, 23 have stopped crz (18 PD, 2 adverse events, 1 death, 2 others reasons). Among the 30 pts evaluable for response at 8 weeks, we observed 4 PR and 8 SD, leading to DCR=40% [95% CI: 23-59]. At 6 months, DCR=15% achieved in 4/26 evaluable pts (3 lung, 1 gastric). Crz was well tolerated with only 8 grade ≥3 adverse events (AEs) or SAE. Most common AEs, mainly grade 1, were fatigue (64 % pts), anemia (53%), ALAT and ASAT increased (both 53%) and visual disorders (50%). Conclusions: Nationwide biomarker-driven access to crz for pts with MET+ malignancy is feasible. Crz showed responses in MET+ lung. No response was observed in MET+ colon cancer. (Table Presented).