Abstract 799: CDKN2A mutation predicts immunotherapy resistance in stage III/IV NSCLC

Purpose: Immune checkpoint blockade (ICB) has improved outcomes for patients with non-small cell lung cancer (NSCLC). However, most patients experience disease progression. There is limited data regarding molecular predictors of progression, particularly in those patients predicted to respond most favorably. We used a next-generation sequencing (NGS) platform to identify genomic aberrations associated with clinical outcomes following ICB in NSCLC. Methods: We retrospectively reviewed stage III/IV NSCLC patients who received radiotherapy (RT) in our department and underwent NGS with OncoPlus, a 1212-gene hybrid capture genomic sequencing assay. We characterized tumor mutations and insertions/deletions for patients who received ICB as well as other systemic therapies and investigated their associations with clinical outcome. Results: 149 patients with stage III/IV NSCLC received RT from 2011-2019 and underwent OncoPlus. Median age was 65, median ECOG was 1, and 125 had a smoking history. 87% had adenocarcinoma. AJCC 8th edition staging: IIIA (n=24), IIIB (n=14), IIIC (n=3), IVA (n=16), and IVB (n=92). 79% had PD-L1 staining: 0% in 45 patients (38%), 1-49% in 34 (29%), and ≥50% in 38 (32%). All received RT to a median of 2 lesions (range 1-15); 48% received palliative RT and 52% received ≥1 course of definitive RT (conventional or ablative). The majority received systemic therapy: 68% (n=102) received chemotherapy, 55% (n=82) received ICB, and 30% (n=44) received targeted therapies. Median follow-up was 18 months (range 1-95); most experienced isolated distant failure (n=64, 43%) or regional/distant failure (n=35, 23%) following their first RT course. The most frequent pathogenic mutations/indels were TP53 (68%, n=101), KRAS (31%, n=45), CDKN2A (27%, n=40), STK11 (26%, n=39), EGFR (19%, n=28), and TP53/KRAS co-mutation (17%, n=26). We found CDKN2A mutation (25%)/deletion (75%) was associated with inferior median recurrence-free survival (RFS; 3 vs. 6 mo., p=0.013) and more markedly median OS (13 vs. 38 mo., p=0.015) compared to wild-type tumors. On multivariate Cox proportional hazards analysis including stage, ECOG, PD-L1 %, TMB, type of RT, and # of RT sites, CDKN2A loss was independently associated with 2.5-fold risk of progression (p=0.018) and 3.3-fold risk of death (p=0.05). In high TMB (top 25th%; n=21) or high PD-L1 (>50%; n=30) NSCLCs, CDKN2A loss was negatively associated with RFS (TMB p=0.005; PD-L1 p=0.034) and in the high PD-L1 cohort with a trend towards inferior OS (p=0.08). Conclusions: In a large cohort of stage III/IV NSCLC patients treated with systemic therapy and RT, NGS identified CDKN2A mutation/deletion as a predictor of ICB resistance and poor outcome. In the context of recent evidence for sensitivity to CDK4/6 inhibition of CDKN2A-deficient tumors, our findings raise the possibility of utilizing currently available targeted agents in the treatment of CDKN2A-deficient NSCLC patients progressing on ICB. Citation Format: Stanley I. Gutiontov, Sean Pitroda. CDKN2A mutation predicts immunotherapy resistance in stage III/IV NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 799.