Exploring molecular resistance mechanisms in therapy naïve NSCLC patients: A retrospective 2 year Indian study.

e15074 Background: We hereby present the meta analysis from molecular profiling of NSCLC patients treated at our centre over the past 2 years. NSCLC accounts for 10.4% (n = 1768) of newly detected solid cancers at our centre. 20–30% patients exhibit lack of durable response to respective 1 st line therapeutic regimes. This study aims to understand genomic factors contributing towards therapeutic resistance and necessitating combinatorial regimes. Methods: We analyzed CGP results of 242 treatment naïve lung cancer patients across 2 years & studied co-occurring mutations pertaining to downstream pathways including tyrosine kinase pathway, mTOR/AKT/PI3kinase pathway, CDK4/6 pathway, RAS/RAF/MEK/ERK pathway and others, to further understand the impact of such genomic alterations on 1 st line therapy. In this study we included only newly diagnosed cases of NSCLC who were previously untreated (therapy naïve). Results: We observed that 47.5% (115/242) were EGFR-mut while 52.5% (127/242) were EGFR-wt. From the EGFR-mut cohort 48% (55/115) revealed presence of singular alterations that were sensitive to 1 st line EGFR TKIs while 52% (60/115) had accompanying secondary genomic alterations. From the EGFR-wt cohort 22% (27/127) did not reveal any other somatic alteration while 78% (100/127) contained other therapeutically relevant mutations. Secondary genomic alterations observed in EGFR-mut cases were further subdivided into two categories: a. Mutations involving a singular oncogenic driver pathway [80% (48/60)] and, b. Mutations involving multiple oncogenic driver pathways [20% (12/60)]. Secondary genomic alterations observed in EGFR wild type cases were subdivided into three categories: a. druggable - harbouring singular non-EGFR gene alterations (eg. ALK etc) 21% (21/100), b. co-occurring mutations involving multiple non-EGFR oncogenic driver pathways 16% (16/100) (eg. ALK fusions co-occurring with KRAS mutation) and, c. Genomic alterations devoid of approved 1 st line target therapy i.e those who were treated with chemotherapeutic regimes 64% (64/100) (eg. KRAS G12D). Across the board, patients with somatic mutations in TP53 at baseline performed relatively poorer in both target therapy and chemotherapy arms. Conclusions: 28% (68/242) patients harboured resistance imparting genomic alterations at baseline. This analysis reveals the staggering prevalence of resistance causing genomic alterations in NSCLC patients at baseline & co-relates with PFS of 1 years or less on 1 st line therapy. We hypothesize that combinatorial therapeutic approaches like those of combining EGFR TKIs with chemotherapy, CDK4/6i, mTORi, MEKi and other agents will make significant impact in PFS and OS. Also comprehensive somatic NGS profiling must necessarily be included in pre-therapeutic workup of all NSCLC patients so as to ensure better response and survival.