Induction immune-checkpoint inhibitors for resectable oncogene-mutant NSCLC: A multicenter pooled analysis

Abstract

Despite limited efficacy of immunotherapy for advanced non-small-cell lung cancer (NSCLC) with driver mutations, whether neoadjuvant immunotherapy could be clinically valuable in those patients warrants further investigation. We utilized 40 oncogene-mutant NSCLC treated with induction immunotherapy from a large consecutive multicenter cohort. Overall response rate was 62.5% while 2 patients had disease progression. Of 39 patients that received surgery, R0 resection rate was 97.4%. The major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. Pre-treatment PD-L1 expression was not a predictive biomarker in these patients. Median disease-free survival for all oncogenic mutation and EGFR mutation was 28.5 months. Indirect comparison through integrating CTONG1103 cohort showed neoadjuvant immunotherapy plus chemotherapy yielded the most superior efficacy among erlotinib and chemotherapy for resectable EGFR-mutant NSCLC. No MPR patients were identified with neoadjuvant immunotherapy plus chemotherapy for uncommon EGFR insertion or point mutations. Our results indicated the potential clinical feasibility of neoadjuvant immunotherapy for resectable localized oncogene-mutant NSCLC especially for EGFR-mutant NSCLC.

Conflict of interest statement

W.-Z.Z. received speech honoraria from AstraZeneca, Roche, Eli Lilly, and Pfizer. Y.-L.W. received research funding from Roche and speech honoraria from AstraZeneca, Roche, Eli Lilly, Pfizer and Sanofi, and he was a research consultant for AstraZeneca. L.W. and D.S.Y. received speech honoraria from AstraZeneca and Roche. L.-L.Y., Q.-X.O., and Y.S. are employees of Nanjing Geneseeq Technology Inc. The remaining authors declare no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1. Overview of clinicopathological characteristics and clinical outcome of oncogene-mutant NSCLC treated with neoadjuvant immunotherapy.

a Overview of clinicopathological charteristics and clinical outcome of oncogene-mutant NSCLC treated with neoadjuvant immunotherapy. Clinicopathological charateristics including smoking status, therpeutic regimens, PD-L1 expression, treatment duration and preoperative radiologic response (according to Response Evaluation Criteria in Solid Tumors [RECIST]) were annotated for each patients. The horizontal dash line indicates the threshold for a major pathological response (90% regression). Pathological regression was presented in colored bar plot regarding different oncogene mutation. b Correlation between radiological shrinkage and pathological regression. Spearman correlation was used to measure the relevance. c Association between PD-L1 expression and MPR status. Centre line represents the median value of PD-L1 expression. Error bars represent the upper and lower quartiles of PD-L1 expression and whiskers defines the minimal and maximun value. PD Progression disease, SD Stable disease, PR Partial response, MPR Major pathological response, pCR Pathological complete response. d Disease-free survival (DFS) of all patients, EGFR-mutant patients and KRAS-mutant patients treated with neoadjuvant immunotherapy through Kaplan-Meier survival analysis.

Fig. 2. Efficacy of neoadjuvant treatments for EGFR-mutant NSCLC.

Comparison of different treatment modalities for resectable EGFR-mutant NSCLC in regard to radiological response and pathological assessment by integrating chemotherapy and EGFR-TKI cohorts from CTONG1103 study. ADC Adenocarcinoma, SQC Squamous cell carcinoma, SD Stable disease, PR Partial response, PD Progression disease, CR Compelete response, MPR Major pathological response, pCR P athological complete response.

Fig. 3. Overview of infiltrating immune contexture and genomic profile of resected PL and DLNs after neoadjuvant immunotherapy.

a Non-supervised clustering of infiltrating immune microenviornment among PL and DLNs through ImmuCellAI. Pie chart indicates the proportion of samples which are antipated as responsive to immunotherapy. R Responder, NR Non-responder. b Comparison of specific immune cell subtypes among different patients. Kruskal-Wallis test was used to testify the difference among patients. Centre dots represent the median value of specific immune cell infiltration. Error bars represent the upper and lower quartiles and whiskers defines the range within 1.5IQR. c Radiological evaluation before and after neoadjuvant immunotherapy for PT4. d Genomic evolutionary trajectory between PL and DLNs of PT4. e Indel- and SNV-induced neoantigens burden among PL and DLNs through NeoPredPipe.

Fig. 4. Immune phenotypes and enriched functional pathway among PLs and DLNs.

a Expression profile of functional genesets including antigen presenting cell abundece, T/NK cell abundence, IFN activity and T cell exhasution were presented through z-score. b Radar plots of comprehensive immune phenotypes including PD-L1 expression in PL, T-cell inflamed GEP and suppressor cell score in PL and DLNs were scaled into 0–100%. T_PD-L1 represents expression of PD-L1 in tumor; T_GEP represents gene-expression profile of infiltrating lymphocytes in tumor; T_SC represents suppressor cell in tumor; LN_GEP represents gene-expression profile of infiltrating lymphocytes in draining lymph nodes; LN_SC represents suppressor cell in draining lymph nodes. c Gene set enrichment analysis (GSEA) of PL and DLNs upon responders and non-responders.