LAUSR

Purpose: RET fusions drive oncogenesis in 1-2% of non-small cell lung cancer (NSCLC) and are sensitive to the selective RET inhibitors selpercatinib and pralsetinib. They have also emerged as mechanisms of acquired resistance to other targeted therapies. The genomic landscape of RET fusions and the impact of co-occurring genomic alterations on the efficacy of selective RET inhibitors is yet to be fully described. Methods: A total of 678 RET fusion-positive samples were analyzed from three cohorts: Guardant360® circulating tumor DNA (ctDNA) (n=467), tissue and/or plasma from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE) non-squamous NSCLC cohort (n=161), and the MD Anderson Cancer Center (MDACC) cohort of patients treated with selpercatinib or pralsetinib (n=50). Molecular characteristics were compared across all three cohorts and to the entire non-RET non-squamous NSCLC AACR Project GENIE cohort (n=17770). Fisher’s exact test was used to evaluate the difference in response rate between patient groups, and Cox proportional hazard models were used to calculate hazard ratios for time-to-event endpoints for patients in the MDACC clinical cohort (n=51, 50 patients with RET fusion, 1 patient with RET point mutation). Results: The most common fusion partner in all cohorts was KIF5B (ctDNA: 73%; GENIE: 69%; MDACC: 71%), followed by CCDC6 (19%; 17%; 18%) and NCOA4 (5%; 1%; 7%). Across all cohorts, co-mutations in TP53 were most common (60%; 34%; 40%) and EGFR, CDKN2A/B, MET, and ATM consistently co-occurred across all cohorts. EGFR co-occurred more frequently with non-KIF5B fusion partners (chi-square p < 0.006). MYC and CCND1 amplifications were enriched in all three cohorts compared to the non-RET cohort. In the MDACC clinical cohort (n=51), the majority were female, never-smokers, with adenocarcinoma histology. The median follow-up time was 28.3 months (95% CI: 15.2 ~ 35 months). Overall response rate (ORR) was 74.4% (95% CI: 58.8 ~ 86.5%), where patients with TP53 mutation had numerically lower ORR compared to patients without TP53 mutation (58.5% vs. 87.5%; p = 0.0632). Median progression-free survival (PFS) time was 16.5 months (95% CI: 13.5 ~ 27.4 months) and KIF5B fusions trended towards worse PFS outcome compared to non-KIF5B fusions (HR: 2.24; 95% CI: 0.88 ~ 5.67; p = 0.0896). TP53 alterations were associated with a significantly worse overall survival (OS) (HR: 2.93; 95% CI: 1.08 ~ 7.95; p = 0.0346). Conclusion: In the largest RET fusion-positive NSCLC cohort to date, RET fusions frequently co-occurred with other genomic alterations, most commonly in TP53. TP53 alterations are associated with a significant reduction in overall survival in patients treated with the selective RET inhibitors. Additional analysis is underway. Citation Format: Tuqa Al Khalaf, Simon Heeke, Lei Feng, Leylah M. Drusbosky, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, Jack Lee, Jianjun Zhang, Don Gibbons, Ara Vaporciyan, Vincent Lam, Vivek Subbiah, John Heymach, Yasir Elamin. The genomic landscape of RET fusions in non-small cell lung cancer and the impact of co-occurring genomic alterations on the efficacy of selective RET inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4264.