Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial

Abstract

Background: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC).Patients and methods: Advanced NSCLC patients with c-MET 6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance.Results: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET 6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET 6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET 6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported.Conclusions: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET 6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified.

<p>Incidence of <em>ROS1</em>-Rearranged Non-Small-Cell Lung Carcinoma in India and Efficacy of Crizotinib in Lung Adenocarcinoma Patients</p>

“…[32][33][34] Updated results of the AcSé phase II trial showed a higher best ORR of 69.4% during treatment in 37 patients of an ROS1-translocation cohort. 35 Similarly, the METROS phase II trial also showed a very high ORR of 65% and median PFS of 22.8 (95% CI 15.2--30.3 months with crizotinib therapy among 26 patients with ROS1-rearranged pretreated NSCLC. 36 Two studies from India have reported a good response to crizotinib therapy.…”

Predictive molecular pathology in non–small cell lung cancer in France: The past, the present and the perspectives

“…6,21,22 The program accès sécurisé à des thérapies ciblées innovantes (AcSé) was established by the INCa to develop clinical trials with different targeted therapies for cancer patients showing specific genomic alterations, notably on MET, RET, HER2, or BRAF. [23][24][25][26] These genomic alterations could be investigated not only in advanced NSCLC, but also in a number of other solid tumors. The patients presenting a specific molecular alteration could be included in a clinical trial.…”

<p>Targeting the MET-Signaling Pathway in Non-Small–Cell Lung Cancer: Evidence to Date</p>

“…87 The AcSé phase II trials on 25 crizotinib-treated patients with MET amplification (GCN>6), the ORR was 16%, and the respective median PFS and OS were 3.2 (95% CI: 1.9-3.7) months and 7.7 (95% CI: 4.6-15.7) months. 88 Tivantinib also yielded disappointing results for patients with MET amplification (defined as GCN>4): median PFS last 3.6 months for those given the erlotinib-tivantinib combination, as for those taking erlotinib alone. 83 Other molecules, like tepotinib or capmatinib, are being tested to treat this anomaly.…”

“…No difference between MET-amplified and METex14-mutated patients was found for any clinical endpoint. 87 In the AcSé crizotinib study, 88 In light of the outcomes of the Profile-1001 study, in 2018, the FDA granted, crizotinib (Xalkori) a breakthroughtherapy designation for the treatment of patients with NSCLC harboring METex14 alterations that progressed after receiving platinum-based chemotherapy.…”