Abstract B17: Activating mutations of phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene confer sensitivity to PD-L1 checkpoint inhibition in metastatic adenocarcinoma patients

Background: Immunotherapy has produced durable responses in advanced cancers with microsatellite instability (MSI). However, response rates remain low in many adenocarcinomas, and biomarkers predictive of response are urgently needed. Preliminary data suggest that PD-L1 checkpoint expression is increased in early-stage microsatellite stable colorectal cancers with PIK3CA mutations as compared to wild-type PIK3CA. Increased expression of PD-L1 has been reported to be associated with response to immunotherapy. The impact of activating PIK3CA mutations on response to anti-PD-L1 checkpoint inhibitors in metastatic adenocarcinomas remains unknown. The objective of our study is to evaluate the impact of activating PIK3CA mutations on treatment outcomes with anti-PD-L1 checkpoint inhibitors in metastatic adenocarcinomas without MSI. Methods: We retrospectively identified patients with metastatic adenocarcinoma treated with anti-PD-L1 antibody, either as monotherapy or in combination with anti-PD-1 antibody, in early-phase clinical trials at the MD Anderson Clinical Center for Targeted Therapy. Molecular profiling was performed on archived primary or metastatic tumor tissue using CLIA-certified targeted next-generation sequencing (FoundationOne or Oncomine), and results were annotated for functional significance by the MD Anderson Precision Oncology Decision Support Team. Fischer9s exact test was used for group comparisons. Median time to treatment failure (TTF) was estimated using the Kaplan and Meier method, and compared among groups by the log-rank test. Results: A total of 27 patients (female, 20; male, 7) with metastatic adenocarcinomas without MSI from 12 different sites (breast, colon and esophageal cancers being the most common cancer types with 7, 5 and 2 patients, respectively) were treated with anti-PD-L1 antibody. Activating PIK3CA mutations were present in 6 (22%) patients (E545K, 2; H1047R, 2; E542K, 1; co-occurring R88Q and K111N, 1). Patients with PIK3CA mutations had longer median TTF than patients with a wild-type PIK3CA (8.7 vs. 2.8 months, P=0.045). In addition, 3 of 6 (50%) patients with PIK3CA mutations had stable disease on treatment for > 6 months as compared to 1 of 21 (4.8%) patients with a wild-type PIK3CA (P=0.02). Conclusion: Our preliminary data suggest that activating PIK3CA mutations in patients with metastatic adenocarcinoma without MSI are associated with prolonged stable disease and longer TTF on treatment with PD-L1 checkpoint inhibitors. Future studies to validate our observations are warranted. Citation Format: Maliha Nusrat, David Hong, Sarina A. Piha-Paul, Vivek Subbiah, Jordi Rodon, Apostolia Tsimberidou, Abha Adat, Yan Wang, Michael Overman, Scott Kopetz, Funda Meric-Bernstam, Filip Janku. Activating mutations of phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene confer sensitivity to PD-L1 checkpoint inhibition in metastatic adenocarcinoma patients [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B17.