No abstract

Overall survival (OS) with the anaplastic lymphoma kinase (ALK) inhibitor (ALKi) crizotinib in a large population of unselected patients with ALK-positive non-smallcell lung cancer (NSCLC) is not documented. We sought to assess OS with crizotinib in unselected ALK-positive NSCLC patients and whether post-progression systemic treatments affect survival outcomes.ALK-positive NSCLC patients receiving crizotinib in French expanded access programs or as approved drug were enrolled. We collected clinical and survival data, RECIST-defined progressive disease (PD) and post-PD systemic treatment efficacy. We performed multivariable analysis of OS from crizotinib initiation and PD under crizotinib. Unselected ALK-positive NSCLC patients achieve good survival outcomes with crizotinib therapy. Next-generation ALKi may provide survival improvement after PD under crizotinib.

Introduction: This randomized phase II trial aimed at evaluating the engineered programmed cell death ligand 1 (PD-L1) antibody atezolizumab in SCLC progressing after first-line platinum-etoposide chemotherapy. Methods: Patients were randomized 2:1 to atezolizumab (1200 mg intravenously every 3 weeks) until progression or unacceptable toxicity, or conventional chemotherapy (up to 6 cycles of topotecan or re-induction of initial chemotherapy). Patients were not selected based on PD-L1 tissue expression. The primary endpoint was objective response rate at 6 weeks. A two-stage design with 2:1 randomization and O'Brien-Fleming stopping rules was used. The null hypothesis was rejected if more than 12 of 45 patients were responders. Results: Overall, 73 patients were randomized (atezolizumab n ¼ 49; chemotherapy n ¼ 24). At 6 weeks, 1 of 43 eligible atezolizumab patients achieved an objective response (2.3%, 95% confidence interval [CI]: 0.0-6.8), whereas 8 others had stable disease (20.9% disease control rate; 95% CI: 8.8-33.1). Among eligible chemotherapy patients (n ¼ 20), 10% achieved an objective response (65% disease control rate). Median progression-free survival was 1.4 months (95% CI: 1.2-1.5) with atezolizumab and 4.3 months (95% CI: 1.5-5.9) with chemotherapy. Overall survival did not significantly differ between groups. Median overall survival was 9.5 months versus 8.7 months for the atezolizumab and the chemotherapy group, respectively (adjusted hazard ratio atezolizumab : 0.84, 95% CI: 0.45-1.58; p ¼ 0.60). Two atezolizumab patients (4.2%) experienced grade 3 fatigue, and two others grade 1 dysthyroidism. Among 53 evaluable specimens, only 1 (2%) had positive immunohistochemical PD-L1 staining (SP142 clone). Conclusions: Atezolizumab monotherapy in relapsed SCLC failed to show significant efficacy. No unexpected safety concerns were observed.

The discrepancies observed between the IHC and FISH data revealed unexpected biological events, rather than technical issues, which potentially can have a strong impact on the therapeutic strategy with crizotinib.

EGFR expression is not stable during metastatic progression in a significant proportion of NSCLC. These findings have to be considered in future prospective studies.

Background: BRAF mutations occurring in 1%e5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. Patients and methods: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after 1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was 30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). Results: Of the 118 patients enrolled, 101 presented with a BRAF V600 mutation and 17 with BRAF nonV600 mutations; the median follow-up was 23.9 months. In the BRAF nonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAF V600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%e54.8%]. The ORR had a 99.9% probability of being 30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8e6.8), and OS was 10 months (95% CI 6.8e15.7). The vemurafenib safety profile was consistent with previous publications. Conclusion:Routine biomarker screening of NSCLC should include BRAF V600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAF V600 -mutated NSCLC but not those with BRAF nonV600 mutations. Trial registration: ClinicalTrials.gov identifier: NCT02304809.

The presence of SMM suggests an aggressive disease. Selection of patients for a local treatment is an important factor that determines survival. The ideal patient had a unique metachronous metastasic deposit that can be treated by surgery.

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.