Exploring the Role of Immunotherapy-Based Treatments for Advanced Non–Small-Cell Lung Cancer With Novel Driver Alterations

Impact of novel driver alterations on response to immunotherapy (IO) in advanced non-small-cell lung cancer (aNSCLC) is not well understood. In this study IO response of 84 aNSCLC patients harboring novel driver alterations (m-cohort) was analyzed and compared to a wild-type cohort. Overall, no detrimental effect was identified for IO based treatments for m-cohort. Adding chemotherapy could improve outcomes. Background: Immunotherapy (IO) single agent or combined with chemotherapy (CT-IO) is the standard treatment for advanced non-small-cell lung cancer (aNSCLC) without driver alterations. IO efficacy in patients with novel driver alterations is not well reported.Materials and Methods: Data of aNSCLC patients treated with IO or CT-IO in any line from January 2016 to September 2022 were retrospectively collected. Patients harbor ing novel dr iver alterations (mcohort), including MET exon 14 skipping, BRAF (V600E or atypical), RET rearrangements, HER2 point mutations/exon 20 insertions or uncommon EGFR mutations/EGFR exon 20 insertions, and wild type patients (wt-cohort) were eligible. Clinico-pathological data were extracted from Institutional databases and compared through chi square or Fisher's exact test. Survivals were estimated through Kaplan-Meier method and compared by log-rank test. Results: m-cohort and wt-cohort included 84 and 444 patients, respectively. Progression free survival (PFS) was 5.53 vs. 4.57 months ( P = .846) and overall survival (OS) was 25.1 vs. 9.37 months, ( P < .0001) for m-cohort compared to wt-cohort. Within the m-cohort, BRAF atypical mutations had the better outcomes (Overall Response Rate [ORR], PFS), targeted agents timing did not affect response to IO and CT-IO had better ORR and disease control rate (DCR) compared to IO single agent ( P = .0160 and P = .0152). In the PD-L1 >= 50% group, first line IO single agent resulted in inferior ORR ( P = .027) and PFS ( P = .022) in m-cohort compared to wt-cohort. Conclusion: IO based treatments seem not detrimental for patients harboring novel driver alteration. Adding CT could improve modest responses to IO alone. Confirmation on larger datasets is required.