A new analysis reveals that high-risk endometrial cancer patients carrying inactivating PPP2R1A mutations demonstrate superior survival outcomes when treated with dual checkpoint inhibitor therapy, compared to those with wild-type PPP2R1A.
The retrospective study, presented at the 2025 SGO Winter Meeting, analyzed 101 patients with recurrent endometrial cancer who received combination therapy with lenvatinib and pembrolizumab. Among 24 patients with PPP2R1A mutations, median overall survival (OS) was not reached, while those with wild-type PPP2R1A (n=77) showed a median OS of 20.2 months (P = .05).
Mutation Status and Treatment Response
The survival advantage was even more pronounced in patients who also carried TP53 mutations. In this subgroup, PPP2R1A-mutated cases continued to show unreached median OS, compared to 15.8 months in PPP2R1A wild-type patients (P = .027).
"These findings suggest PPP2R1A mutation status could serve as a potential biomarker for immunotherapy response," noted Dr. Anne Knisely, a gynecologic oncology fellow at the University of Texas MD Anderson Cancer Center, who presented the findings.
Molecular Mechanisms and Therapeutic Implications
PPP2R1A encodes a crucial scaffold component of protein phosphatase-2A (PP2A), a ubiquitous enzyme involved in various cellular processes. Research has identified PP2A as a negative regulator of cytotoxic T-cell function, suggesting its inhibition could enhance anti-tumor immune responses.
Previous preclinical studies have demonstrated that combining PP2A inhibitors with PD-1 blockade produces synergistic effects and durable immune-mediated antitumor activity in multiple cancer models. This activity specifically depends on CD8 T cells, highlighting the importance of the immune component in the treatment response.
Future Research Directions
The findings have sparked interest in further investigation of PPP2R1A as a potential stratification marker for immunotherapy trials, particularly as treatment moves into frontline settings for endometrial cancer.
A phase 1/2 trial is currently underway at MD Anderson Cancer Center, evaluating the PP2A inhibitor LB-100 in combination with dostarlimab in recurrent ovarian clear cell carcinoma. The study aims to enroll 21 patients and will assess survival rates, immune-related adverse effects, and various response metrics.
"Understanding the functional relationship between PPP2R1A loss and enhanced antitumor immunity will be crucial for optimizing treatment strategies," Dr. Knisely emphasized. This research opens new avenues for personalizing immunotherapy approaches in gynecologic cancers based on molecular profiles.
