Clinical outcomes and immune phenotypes associated with co-occurring mutations in non-small cell lung cancer.

Background: mutation in non-small cell lung cancer (NSCLC) is associated with worse survival as well as primary resistance to PD-1/PD-L1 targeting immunotherapy. We hypothesize that co-occurring mutations and tumor mutation burden (TMB) may impact response to therapy and prognosis.

Methods: Forty-one patients with -mutated NSCLC seen in our Thoracic oncology clinic with available next-generation sequencing tumor data were included in the analysis. Data from the Cancer Genome Atlas (TCGA) was used for survival and immune gene expression analysis. Overall and progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared using a log-rank test.

Results: In the 41 patients included, common co-occurring alterations with were (54%), (44%), (37%) and (27%). Overall 17 patients received locoregional therapy with surgery or radiation with median OS of 8.6 years and there was no significant difference in clinical outcomes with and TP53 co-occurring mutations. Response to both chemotherapy and immunotherapy was poor across all co-occurring mutations. However, co-mutation was associated with improved clinical benefit with immunotherapy. Patients with higher TMB had longer PFS with immunotherapy. In TCGA survival analysis, tumors with mutation with or without co-mutation were associated with worse survival (P<0.05) but tumors with co-mutation did not have worst survival compared to wild type tumors. Moreover, co-occurring mutations had significant effect on intratumoral immune status with both alone and co-mutated tumors showing more enrichment for wound healing immune subtype while co-mutated tumors showed more enrichment for IFN-g immune subtype.

Conclusions: Our retrospective analysis in patients with -mutated NSCLC found that both TMB and co-occurring mutations may be predictors for response to immunotherapy with worse outcomes in patients with low TMB or co-mutation and improved outcomes with co-mutation. Patients with -mutated NSCLC also demonstrate chemotherapy resistance but have similar outcomes with localized treatment compared to wild type tumors. Moreover, co-mutations with or significantly alter tumor immune landscape of -mutated tumors and therefore response to immunotherapy.