Biomarker-driven access to crizotinib in ALK, MET or ROS1 positive (+) malignancies in adults and children: The French national AcSé program (2018)

Background: Crizotinib (czb) was registered for ALK+ NSCLC in 2013 and recently for ROS1+ stage IV NSCLC. Czb targets (ALK, MET, ROS1) are also altered (translocation [tlc], amplification [amp], mutation [mut]) in a wide range of malignancies (malg.) in adults and children. To generate high evidenced-based knowledge and to prevent off-label use, the French National Cancer Institute (INCa) launched the AcSé Program: equal access to tumor molecular diagnosis including an exploratory phase II trial. Methods: Biomarker testing was proposed to patients (pts) ≥ 1 year old (yo) with an advanced disease among more than 15 malg. known to harbor a czb target alteration. If not eligible for any other trial, pts may enter one of the 22 cohorts defined by the type of tumor and target. Tumor response was evaluated every 2 months (mo) using RECIST v1.1. The primary endpoint is the objective response rate (ORR) at 2 mo [complete + partial response]. A two-stage Simon design is applied to each cohort. Results: From 08/2013 to 03/2018, 13179 pts from 186 centers have entered the biomarker program. Tumor alterations found in pts were: ALK tlc, mut, amp in 14/2070, 8/313, 10/1858; MET amp (≥6 copies/diploid genome) in 395/7932 [251/4171 NSCLC, 60/1232 glioblastomas, 28/939 colon, 35/570 esogastric, 7/640 ovarian cancers]; MET mut in 102/2836; ROS1 tlc in 82/4755 [NSCLC, cholangiocarcinoma, inflammatory myofibroblastic tumor (IMT)]. Overall, 237 pts (median age, 57 [1–92]) received czb (adult 250 mg bid; child 280 mg/m² bid).Table: 434PPositive cohortsPts analyzedCR/PR at 2 moORR % [IC95%]ALCL ALK tlc241254 [34-75]NSCLC MET amp ROS1 tlc MET mut25 37 28*including 4 pts wIth MET mut on other exon than exon 147 20 5**pts with MET mut exon 14 195 grade ≥3 adverse events (AEs) or SAE were reported in 83/237 pts. Grade ≥3 AEs were: ALT increased (6%), neutropenia (5%) and lymphopenia (5%).28 [10 - 46] 54 [38 - 70] 18 [4 -32]Esogastric MET amp9333 [7-70]IMT ALK tlc / ROS1 tlc8338 [9-76]* including 4 pts wIth MET mut on other exon than exon 14** pts with MET mut exon 14 195 grade ≥3 adverse events (AEs) or SAE were reported in 83/237 pts. Grade ≥3 AEs were: ALT increased (6%), neutropenia (5%) and lymphopenia (5%). Open table in a new tab Conclusions: Czb displayed a wide antitumor activity in several MET, ALK and ROS1+ malg. Equal and safe access across France to molecular testing and targeted therapies outside their approved indication is feasible. Clinical trial identification: NCT02034981. Legal entity responsible for the study: UNICANCER. Funding: ARC Foundation Inca Pfizer. Disclosure: G. Vassal: Travel, accomodations, expenses: BMS. J-Y. Blay: Advisory Board: Roche, Lilly, Ignyta, Deciphera, Novartis, Bayer, BMS; Corporate-sponsored research: Roche, Lilly, Ignyta, Deciphera, Novartis, Bayer, Novartis, GSK, AstraZeneca, MSD; Other substantive relationships: Surveillance committee of Innate Pharma. M. Perol: Advisory board: Pfizer. P. Brice: Advisory board: Takeda France; Corporate-sponsored research: Takeda Millenium, BMS, MSD. D. Moro-Sibilot: Speaker or advisory board: Eli Lilly, MSD, Roche, Novartis, BMS, Astra Zeneca, Takeda, Boehringer Ingelheim. All other authors have declared no conflicts of interest.