First-Line Chemoimmunotherapy and Chemotherapy Outcomes in Patients With RET Fusion-Positive Lung Cancer in LIBRETTO-431

INTRODUCTION: Single-agent checkpoint inhibitor therapy achieves suboptimal outcomes in patients with advanced RET fusion-positive lung cancer. Prospective data on the role of adding checkpoint inhibitor therapy to platinum doublet chemotherapy have not previously been available. METHODS: In the registrational, phase 3 LIBRETTO-431 study, patients with RET fusion-positive lung cancer were randomized to receive selpercatinib or platinum-doublet chemotherapy (pemetrexed and carboplatin or cisplatin) with or without pembrolizumab. An analysis of outcomes, including progression-free survival (PFS) and overall survival (OS) in patients treated with chemoimmunotherapy and chemotherapy alone, was performed. RESULTS: Eighty-three patients received chemoimmunotherapy, and 19 patients received chemotherapy alone. No significant differences in smoking history (p = 0.10), programmed death-ligand 1 status (p = 0.3), or baseline brain metastases (p = 0.8) were identified between the two groups. The median PFS by blinded independent central review was 11.2 months (95% confidence interval: 10.9-16.8) in chemoimmunotherapy-treated patients and not reached (95% confidence interval: 4.9-not reached) in chemotherapy-treated patients. PFS by blinded independent central review was not significantly different (p = 0.8) between chemoimmunotherapy- and chemotherapy-treated patients. The median OS was not reached for either group. OS did not significantly differ (p > 0.9) between chemoimmunotherapy- and chemotherapy-treated patients. CONCLUSIONS: In patients with advanced RET fusion-positive lung cancer treated in this global, multicenter trial, outcomes with first-line chemoimmunotherapy and chemotherapy were not significantly different in this secondary analysis. Using chemotherapy alone is a reasonable strategy for these oncogene-driven tumors. Based on the overall findings from LIBRETTO-431, selective RET inhibitors remain the preferred first-line therapy for patients with RET fusion-positive non-small cell lung cancer.