Crizotinib in children and adolescents with advanced ROS1, MET, or ALK-rearranged cancer: Results of the AcSé phase II trial.

Abstract

11509 Background: Alterations of crizotinib (crz) molecular targets ALK, MET, ROS1 are found in a wide range of adult and pediatric (ped) cancers. Crz is approved for the treatment of adult patients (pts) with ALK+ advanced NSCLC but not developed and licenced in Europe for children. To avoid off-label use and allow for a nationwide safe access to crz for pts with ALK, MET or ROS1+ tumor, the French National Cancer Institute (INCa) launched the AcSé program, funding both access to tumor molecular diagnosis and an exploratory multi tumor phase II trial. We report the results of 11 ped cases out of 159 pts. Methods: Molecular diagnosis was performed in 28 regional INCa molecular genetic centers by break-apart FISH assays or sequencing. Rearrangements identified through pangenomic tumor profiling were eligible as well. Pts with ROS1, ALK or MET+ in treatment failure received crz 280 mg/m2 BID (except Anaplastic Large Cell Lymphoma [ALCL] pts who received crz 165 mg/m2BID) in capsules or oral solution. Responses were assessed every-8 weeks using RECIST v1.1. Results: From Aug. 2013 to Aug. 2015, 107 ped tumors were analyzed. Altered targets were found in 18 tumors (see table). 11 pts were enrolled, median age 9 yrs (range 3–16), 64% boys. 7 pts were still on treatment at the cut-off date, 2 for >12 months; 4 have stopped crz (2 PD, 1 doctor’s decision, 1 patient’s decision). Among the 8 evaluable pts (3 assessments pending), best responses were 1 CR (ALCL ALK trans), 3 PR (ALCL ALK trans, IMT ROS1 trans, meningioma ROS1 trans), 1 SD (mesothelioma ALK trans), and 3 PD (2 Nb ALK mut, glioma MET trans). Crz was well tolerated with 4 grade ≥3 AEs (QTc prolongation, nausea, loss of appetite, anemia). Mainly AEs were grade 1, were elevated transaminases (60% of pts), vomiting (50%), visual disorders (40%), fatigue (40%). Conclusions: Alterations of all crz targets were found in ped tumors and children can benefit from crz therapy. Clinical trial information: NCT02034981. Neuroblastoma (Nb) N=49 Rhabdomyosarcoma N=10 Inflammatory Myofibroblastic Tumor (IMT) N=3 Malignant Glioma N=14 Other cancers N=29 Miscellaneous with pangenomic profiling N=2 ALK Mutated 5 ALK Amplified (Amp) (>6 copies) 2 0 ALK Translocated (Trans) 1* 0 1 3 ROS1 Trans 1 1 MET Amp (>6 copies) 1 1 1 MET Trans 1 *: + ALK mutated.