Se-Hoon Lee

BACKGROUND: (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: -mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. RESULTS: -related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. CONCLUSIONS: -mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

BACKGROUND: (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC) was significantly improved with amivantamab-lazertinib as compared with osimertinib. Results of the protocol-specified final overall survival analysis in this trial have not been reported. METHODS: -mutated (exon 19 deletion or L858R substitution), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib, osimertinib, or lazertinib. Overall survival (assessed in an analysis of the time from randomization to death from any cause) in the amivantamab-lazertinib group as compared with the osimertinib group was a key secondary end point. Additional end points included safety. RESULTS: A total of 429 participants each were assigned to receive amivantamab-lazertinib or osimertinib. Over a median follow-up of 37.8 months, amivantamab-lazertinib led to significantly longer overall survival than osimertinib (hazard ratio for death, 0.75; 95% confidence interval, 0.61 to 0.92; P = 0.005); 3-year overall survival was 60% and 51%, respectively. At the clinical cutoff date, 38% of participants in the amivantamab-lazertinib group and 28% in the osimertinib group were still receiving the assigned treatment. Adverse events of grade 3 or higher were more common with amivantamab-lazertinib (in 80% of participants) than with osimertinib (in 52%), particularly skin-related events, venous thromboembolism, and infusion-related events; these findings were consistent with the established safety profile of each treatment. No new safety signals were observed with additional follow-up. CONCLUSIONS: -mutated advanced NSCLC than osimertinib but was associated with an increased risk of adverse events of grade 3 or higher. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

<h2>Abstract</h2><h3>Introduction</h3> The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in <i>ALK</i>-positive or <i>ALK</i>-negative advanced NSCLC, respectively. <h3>Methods</h3> Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1. <h3>Results</h3> In the avelumab plus lorlatinib group (<i>ALK</i>-positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group (<i>ALK</i>-negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%–70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%–57%) with avelumab plus crizotinib (all partial responses). <h3>Conclusions</h3> Avelumab plus lorlatinib treatment in <i>ALK</i>-positive NSCLC was feasible, but avelumab plus crizotinib treatment in <i>ALK</i>-negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group. <h3>ClinicalTrials.gov identifier</h3> NCT02584634