Abstract 3172: Evaluation of cytotoxic T cell infiltration and clinical benefit from PD-L1 checkpoint inhibition among PIK3CA mutant microsatellite stable (MSS) metastatic adenocarcinoma patients
Authors: Nusrat Maliha , Tapia Coya , Call S. Greg , Hong David S. , Piha-Paul Sarina A. , Subbiah Vivek , Rodon Jordi , Tsimberidou Apostolia M. , Adat Abha , Wang Yan , Meric-Bernstam Funda , Overman Michael J. , Kopetz Scott , Janku Filip 
Published: September 2020

Background: Immunotherapy has produced durable responses in advanced cancers with microsatellite instability. However, response rates remain very low for microsatellite stable (MSS) adenocarcinomas, and biomarkers predictive of response are urgently needed. PI3K pathway alterations are known to modulate anti-tumor immune microenvironment. We previously reported increased cytotoxic T cell infiltration and greater clinical benefit from immunotherapy among PIK3CA mutant MSS colorectal cancer patients as compared to PIK3CA wild-type patients. Here, we investigated the immune repertoire and treatment outcomes with anti-PD-L1 checkpoint inhibitors in PIK3CA mutant MSS metastatic adenocarcinoma patients.

Methods: We retrospectively identified metastatic adenocarcinoma patients 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 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). PIK3CA mutations were annotated for functional significance by the Precision Oncology Decision Support Team. Density of cytotoxic T cells was determined using immunohistochemistry (IHC) on biopsy or resection specimens. Microsatellite status was assessed using IHC or polymerase chain reaction. Median time to treatment failure (TTF) was estimated using Kaplan and Meier method. Groups were compared using Fischer's exact, Student's T test or Log-rank test, as appropriate.

Results: Twenty-seven patients with MSS metastatic adenocarcinoma (female, 20; male, 7) from 12 different sites were treated with anti-PD-L1 antibody. Breast, colon and esophageal cancers were the most common cancers with 7, 5 and 3 patients, respectively. Activating PIK3CA mutations were present in 7/27 (26%) patients (H1047R, 3; E545K, 2; E542K, 1; co-occuring R88Q and K111N, 1). Patients with activating PIK3CA mutations had trend towards longer median TTF as compared to PIK3CA wild-type patients (6.6 vs. 3.1 months, P=0.1). Similarly, 3/7 (42.9%) patients with activating PIK3CA mutations had stable disease (SD) &gt; 6 months as compared to 2/20 (10%) patients with wild type PIK3CA (P=0.09). CD8 densities were available for 8 patients (5 PIK3CA mutant, 3 PIK3CA wild). Among PIK3CA mutant patients, mean CD8 density was higher in patients who had SD &gt; 6 months as compared to those who did not (630.3 vs 305.1 cells/mm3; P=0.06).

Conclusion: Activating PIK3CA mutations are enriched among MSS metastatic adenocarcinoma patients with prolonged SD (&gt; 6 months) on anti-PD-L1 treatment. PIK3CA mutant patients with prolonged SD have higher CD8 densities, possibly due to high-affinity neopeptide-HLA interactions. Larger studies to validate our observations are warranted, including assessment of neopeptide load and HLA types, which may help identify an immunotherapy sensitive subset of PIK3CA mutant MSS adenocarcinoma.

Citation Format: Maliha Nusrat, Coya Tapia, S. Greg Call, David S. Hong, Sarina A. Piha-Paul, Vivek Subbiah, Jordi Rodon, Apostolia M. Tsimberidou, Abha Adat, Yan Wang, Funda Meric-Bernstam, Michael J. Overman, Scott Kopetz, Filip Janku. Evaluation of cytotoxic T cell infiltration and clinical benefit from PD-L1 checkpoint inhibition among PIK3CA mutant microsatellite stable (MSS) metastatic adenocarcinoma patients [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 3172.