Abstract 1169: Increased immunotherapy sensitivity associated with damaging IFN-gamma pathway mutations in NSCLC
Authors: Azizi Alexander , Ravi Arvind , Vokes Natalie , Sammut Stephen-John , Gainor Justin , Getz Gad 
Published: March 2024

Abstract
Introduction: In vivo CRISPR screens across multiple murine models of malignancy revealed that loss of interferon gamma (IFN-γ)-mediated sensing predisposes to immune elimination. We assessed the association between damaging mutations in the IFN-γ pathway and clinical outcomes after immune checkpoint inhibition in the Stand Up to Cancer-Mark Foundation non-small cell lung cancer (NSCLC) cohort.
Methods: The sensitizing IFN-γ pathway genes were defined as IFNGR1, IFNGR2, JAK1, JAK2, STAT1, IRF1 & IRF9. Damaging mutations (including missense mutations) in any of these genes was considered as loss of pathway activity. We used the best observed response (measured by RECIST v1.1 criteria across time points) to define outcome. Complete and partial response were categorized as responses (R), while stable and progressive disease were categorized as non-responses (NR). The percentage change in target lesions (CTL) was also assessed. Response data was analyzed using additive logistic (LogR) and linear regression (LinR). Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox proportional-hazards models. Three predictor variable groups were established; the final models comprised IFN-γ pathway loss, tumor mutational burden (TMB), programmed death-ligand 1 (PD-L1) tumor proportion score (TPS), prior platinum chemotherapy, age, sex, histological subtype, initial tumor stage, and smoking pack years.
Results: 309 patients had evaluable whole-exome sequencing data, treatment with PD-(L)1 inhibitor regimens, and matched radiological responses (121 R [39%], 188 NR [61%]); 306 had matched OS data; 297 had matched PFS data; and 227 had matched CTL data. 27 (7%) patients had damaging mutations in the IFN-γ pathway [IFNGR1 (3); IFNGR2 (1); JAK1 (6); JAK2 (8); STAT1 (3); IRF1 (1); IRF9 (3); and JAK2 & IRF9 (1)]. Significant relationships were observed in univariable models between IFN-γ pathway loss and both response (LogR: OR 0.17, p=2 × 10−4*; LinR: OR 0.70, p=4.8 × 10−4*) and survival (PFS: HR 0.45, p=0.0067*; OS: HR 0.51, p=0.037*). IFN-γ pathway loss is significantly associated with TMB (p=9.7 × 10−8*, Wilcoxon signed rank test). Multivariable models incorporating TMB and PD-L1 TPS confirmed the significance of IFN-γ pathway loss in both response (LogR: OR 0.29, p=0.050*; LinR: OR 0.71, p=0.0052*) and survival (PFS: HR 0.37, p=0.036*; OS: HR 0.27, p=0.030*). These relationships persisted in the final multivariable models (LogR: OR 0.32, p=0.11; LinR: OR 0.69, p=0.012*; PFS: HR 0.39, p=0.068; OS: HR 0.15, p=0.0038*). Random gene sets, of similar total protein coding sequence length, significantly associated with TMB but not with multivariable models of response or survival.
Conclusion: In this NSCLC cohort, damaging IFN-γ pathway mutations associate with increased immunotherapy sensitivity, independently of TMB and other co-variates, as evidenced by multiple clinical outcomes.
Citation Format: Alexander Azizi, Arvind Ravi, Natalie Vokes, Stephen-John Sammut, Justin Gainor, Gad Getz. Increased immunotherapy sensitivity associated with damaging IFN-gamma pathway mutations in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1169.