Impact of select actionable genomic alterations on efficacy of neoadjuvant immunotherapy in resectable non-small cell lung cancer.

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

TLDR

  • Patients with actionable genomic alterations (AGAs) have a higher risk of treatment failure and diminished pathological regression after neoadjuvant immune checkpoint inhibitors (ICIs) compared to patients without AGAs.

Abstract

Neoadjuvant 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. Tumor 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). With 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, 2, 1, and 1mutations, 2 anaplastic lymphoma kinaseand 1fusions. 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. Patients with NSCLC harboring select AGAs, includingandalterations, 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.

Overview

  • This study explored the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant immune checkpoint inhibitors (ICIs) in patients with resectable non-small cell lung cancer (NSCLC).
  • The study aimed to investigate treatment failure (TF) rates and characteristics in patients with resectable NSCLC treated with neoadjuvant ICIs, focusing on the role of AGAs in treatment outcomes.
  • The study used data from a previously reported phase-2 randomized study (NCT03158129) to analyze the relationship between AGAs and TF in patients with resectable NSCLC.

Comparative Analysis & Findings

  • The study found that patients with AGAs had a higher risk of treatment failure (HR: 5.51, 95% CI: 1.68 to 18.1) and a shorter median time to treatment failure (24.7 months) compared to patients without AGAs.
  • The study also found that patients with AGAs had diminished pathological regression after neoadjuvant ICIs, with a median percentage of residual viable tumor of 72.5%.
  • In contrast, patients without AGAs and non-profiled squamous cell carcinomas (non-AGAs+NP SCC) had a lower risk of treatment failure and a longer median time to treatment failure, with a median percentage of residual viable tumor of 33.0%.

Implications and Future Directions

  • The study suggests that tumor molecular testing prior to initiation of neoadjuvant ICI therapy is important in patients with resectable NSCLC to determine the most effective treatment approach.
  • Future studies should investigate the use of targeted therapies in combination with ICIs to improve treatment outcomes in patients with AGAs.
  • The study underscores the need for further research on the optimal use of ICIs in patients with resectable NSCLC, including the identification of biomarkers for ICIs and the development of personalized treatment strategies.
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