Impact of select actionable genomic alterations on efficacy of neoadjuvant immunotherapy in resectable non-small cell lung cancer
Authors: Zhou Nicolas , Leung Cheuk H , William William N , Weissferdt Annikka , Pataer Apar , Godoy Myrna C B , Carter Brett W , Fossella Frank V , Tsao Anne S , Blumenschein George R , Le Xiuning , Zhang Jianjun , Skoulidis Ferdinandos , Kurie Jonathan M , Altan Mehmet , Lu Charles , Glisson Bonnie S , Byers Lauren A , Elamin Yasir Y , Mehran Reza J , Rice David C , Walsh Garrett L , Hofstetter Wayne L , Roth Jack A , Tran Hai T , Wu Jia , Solis Soto Luisa M , Kadara Humam , Swisher Stephen G , Vaporciyan Ara A , Gibbons Don L , Lin Heather Y , Lee J Jack , Heymach John V , Negrao Marcelo V , Sepesi Boris , Cascone Tina 
Published: October 2024

BackgroundNeoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant ICIs remains unclear. We report the influence of AGAs on treatment failure (TF) in patients with resectable NSCLC treated with neoadjuvant ICIs.MethodsTumor molecular profiles were obtained from patients with stage I–IIIA resectable NSCLC (American Joint Committee on Cancer seventh edition) treated with either neoadjuvant nivolumab (N, n=23) or nivolumab+ipilimumab (NI, n=21) followed by surgery in a previously reported phase-2 randomized study (NCT03158129). TF was defined as any progression of primary lung cancer after neoadjuvant ICI therapy in patients without surgery, radiographic and/or biopsy-proven primary lung cancer recurrence after surgery, or death from possibly treatment-related complications or from primary lung cancer since randomization. Tumors with AGAs (n=12) were compared with tumors without AGAs and non-profiled squamous cell carcinomas (non-AGAs+NP SCC, n=20).ResultsWith a median follow-up of 60.2 months, the overall TF rate was 34.1% (15/44). Tumor molecular profiling was retrospectively obtained in 47.7% (21/44) of patients and select AGAs were identified in 12 patients: 5 epidermal growth factor receptor(EGFR), 2KRAS, 1ERBB2, and 1BRAFmutations, 2 anaplastic lymphoma kinase(ALK)and 1RETfusions. The median time to TF in patients with AGAs was 24.7 months (95% CI: 12.6 to 40.4), compared with not reached (95% CI: not evaluable (NE)–NE) in the non-AGAs+NP SCC group. The TF risk was higher in AGAs (HR: 5.51, 95% CI: 1.68 to 18.1), and lower in former/current smokers (HR: 0.24, 95% CI: 0.08 to 0.75). The odds of major pathological response were 4.71 (95% CI: 0.49 to 45.2) times higher in the non-AGAs+NP SCC group, and the median percentage of residual viable tumor was 72.5% in AGAs compared with 33.0% in non-AGS+NP SCC tumors.ConclusionsPatients with NSCLC harboring select AGAs, includingEGFRandALKalterations, have a higher risk for TF, shorter median time to TF, and diminished pathological regression after neoadjuvant ICIs. The suboptimal efficacy of neoadjuvant chemotherapy-sparing, ICI-based regimens in this patient subset underscores the importance of tumor molecular testing prior to initiation of neoadjuvant ICI therapy in patients with resectable NSCLC.