Phase II Trial of LP-300 in Combination With Carboplatin and Pemetrexed in Never Smoker Patients With Relapsed Advanced Primary Adenocarcinoma of the Lung After Treatment With Tyrosine Kinase Inhibitors

Introduction: Most patients with non-small cell lung cancer (NSCLC) who have never smoked possess tumors bearing tyrosine kinase oncogenes. While such tumors may exhibit robust responses to front-line tyrosine inhibitors (TKIs), disease progression is inevitable. Subsequent available therapies confer limited benefit, thus developing effective treatments for these patients remains a critical need. LP-300 is a novel compound that enhances chemotherapy sensitivity and inhibits the activity of tyrosine kinase oncogenes. Retrospective subset analyses of prior phase III studies found females and never-smokers, groups likely to have oncogene-driven tumors, obtained a considerable survival advantage with LP-300 combined with platinum-based chemotherapy as compared to chemotherapy alone. Prospective validation of these findings in patients with oncogene-driven NSCLC is needed. Methods: The HARMONIC clinical trial, which is currently in progress, is a global, randomized, phase II study (NCT05456256) evaluating the 3-drug regimen of LP-300 with pemetrexed and carboplatin versus pemetrexed and carboplatin alone in 90 patients with advanced primary lung adenocarcinoma bearing tyrosine kinase oncogenes. Patient randomization is stratified by gender and favors the LP-300 containing arm (2-1). Patients must have tumors bearing tyrosine kinase actionable alterations (i.e. EGFR, ALK, ROS1, MET, RET, BRAF, or NTRK) and have prior TKI progression or intolerance. Primary endpoints are progression-free survival (PFS) and overall survival (OS). Secondary endpoints include objective response rate, duration of objective response, clinical benefit rate, and incidence of adverse events. Conclusion: This phase II trial is accruing patients at sites in the U.S, Japan, and Taiwan. Patient accrual is expected to be completed in the Fall of 2026.