PPP2R1A Mutations Associated With Prolonged OS in High-Risk Endometrial Cancer

Patients with high-risk endometrial cancer who displayed inactivating PPP2R1A mutations achieved longer overall survival (OS) following treatment with dual checkpoint inhibitors than those with wild-type PPP2R1A, according to data from the endometrial cancer cohort of a retrospective study presented during the 2025 SGO Winter Meeting.1

Among the 24 patients with PPP2R1A-mutated, high-risk endometrial cancer who received lenvatinib (Lenvima) plus pembrolizumab (Keytruda), the median OS as not reached (NR). Conversely, the median OS was 20.2 months in those with PPP2R1A wild-type disease (n = 77; P = .05). Notably, the median OS among patients who also displayed TP53 mutations was also NR in the PPP2R1A-mutated group vs 15.8 months in the PPP2R1A wild-type group (P = .027).

“Further preclinical studies are warranted to demonstrate a clear functional link between PPP2R1A loss and enhanced antitumor immunity,” presenting author Anne Knisely, MD, MPH, a third-year fellow in gynecologic oncology at the University of Texas MD Anderson Cancer Center, stated during the oral presentation.

Study Background and Overview

Previously reported research conducted by Knisely and her colleagues has shown that patients with recurrent clear cell ovarian cancer who display PPP2R1A mutations have worse OS outcomes on checkpoint inhibitor–based regimens than those harboring wild-type PPP2R1A, with a median OS of 28.0 months vs 9.0 months in these respective patient populations (log-rank 1-sided P = .038).

“PPP2R1A is a gene that encodes the most common scaffold component of a protein phosphatase, [protein phosphatase-2A (PP2A)], which is a ubiquitous serine/threonine phosphatase implicated in diverse cellular processes,” Knisely explained. “Multiple studies have demonstrated the potential role of PP2A as a negative regulator of cytotoxic T-cell effector function.”

Prior research has also established PP2As potential mediation of CTLA-4 inhibitory signaling through dephosphorylation of Akt in activated T cells, and its elevated activity in regulatory T cells compared with conventional T cells.2 Additionally, PP2A inhibition has been shown to reverse hyperkalemia-induced suppression of tumor-infiltrating lymphocytes in a pharmacologic screen, further highlighting its potential as an immunotherapeutic target.

Accordingly, findings from a preclinical study published in Nature Communications showed that the addition of a PP2A inhibitor, LB-100, to PD-1 blockade demonstrated synergy and resulted in durable immune-mediated antitumor activity in a murine CT26 colon cancer model. The combination also synergistically decreased tumor growth of B16 melanoma in another murine model.

“This effect is immunogenic and specifically dependent on CD8 T cells, as the benefit with combination therapy is no longer seen when CD8 T cells are depleted,” Knisely noted.

The current analysis includes data from the retrospective endometrial cancer cohort, which enrolled 167 patients with recurrent endometrial cancer who previously received lenvatinib plus pembrolizumab.1 Of these patients, 164 had microsatellite stable tumors and 101 had known PPP2R1A mutation status. Progression-free survival (PFS) and OS outcomes were assessed according to whether patients had PPP2R1A-mutated or wild-type endometrial cancer.

Patients in the final cohort (n = 101) were further categorized into 2 high-risk subgroups. The first comprised patients with high-grade histologies (n = 114), including serous, clear cell, carcinosarcoma, mesonephric-like adenocarcinoma, and mixed high-grade carcinoma. The second high-risk subgroup included patients with TP53 mutations. Notably, these subgroups were not mutually exclusive.

Next Steps for Researching PPP2R1A Mutations in Gynecologic Cancers

Based on these results, Knisely and colleagues asserted that continued mechanistic studies of PPP2R1A mutations and PP2A inhibition in preclinical models are warranted.

“...Now that we are giving immunotherapy more in the frontline setting in endometrial cancer, it may be worth investigating genomic profiles of patients in this population to see if this gene may be a biomarker of response and something that can be used for stratification in future trials,” Knisely concluded.

A phase 1/2 trial (NCT06065462) is currently underway to evaluate the safety and efficacy of PP2A inhibition with LB-100 plus dostarlimab-gxly (Jemperli) in recurrent ovarian clear cell carcinoma.3 The study, led by MD Anderson Cancer Center, has an estimated enrollment of 21 patients. Estimated OS rates at 6 and 12 months will serve as the study’s primary objective, with key secondary objectives including assessment of immune related adverse effects, objective response rate (ORR), time to initial response, PFS, and duration of response per modified RECIST 1.1 criteria.

References

1. Knisely A. Inactivating PPP2R1A mutations are associated with prolonged survival after lenvatinib and pembrolizumab treatment in recurrent, microsatellite stable (MSS) endometrial cancer. Presented at: SGO Winter Meeting; January 30-February 1, 2025; Whistler, British Colombia, Canada. Oral Abstract 1.
2. Ho WS, Wang H, Maggio D, et al. Pharmacologic inhibition of protein phosphatase-2A achieves durable immune-mediated antitumor activity when combined with PD-1 blockade. Nat Commun. 2018;9(1):2126. Published 2018 May 29. doi:10.1038/s41467-018-04425-z
3. Safety and efficacy of targeting PP2A in ovarian clear cell carcinoma using dostarlimab and LB-100. ClinicalTrials.gov. Updated August 28, 2024. Accessed January 31, 2025. https://clinicaltrials.gov/study/NCT06065462