Impact of Select Actionable Genomic Alterations on Efficacy of Neoadjuvant Immunotherapy in Resectable Non-small Cell Lung Cancer

Authors

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

Publication Date

10-23-2024

Journal

The Journal for ImmunoTherapy of Cancer

Abstract

Background: 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.

Methods: 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).

Results: 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 (EGFR), 2 KRAS, 1 ERBB2, and 1 BRAF mutations, 2 anaplastic lymphoma kinase (ALK) and 1 RET fusions. 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.

Conclusions: Patients with NSCLC harboring select AGAs, including EGFR and ALK alterations, 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.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Male, Female, Neoadjuvant Therapy, Middle Aged, Aged, Immunotherapy, Immune Checkpoint Inhibitors, Genomics, Immunotherapy, Lung Cancer, Nivolumab, Ipilimumab, Recurrence

Comments

Associated Data

PMID: 39448200