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Joyce F. Liu, MD, MPH
Joyce F. Liu, MD, MPH
Posted: Friday, August 8, 2025
In a study published in Nature, researchers investigated immune checkpoint blockade (ICB) therapy in patients with ovarian clear cell carcinoma, a cancer type that poses considerable clinical challenges with few effective therapies. Overall and progression-free survival outcomes were significantly improved in patients with PPP2R1A-mutated tumors. Parallel preclinical investigations revealed that targeting PPP2R1A in in vitro and in vivo models was associated with improved survival in treatment settings with several forms of immunotherapy, including chimeric antigen receptor T-cell therapy and ICB. The findings were validated in additional ICB-treated patient cohorts across multiple cancer types.
Study Details
The research was conducted through two different clinical trials of 34 patients with recurrent, platinum-resistant ovarian clear cell carcinoma. Patients were treated with anti–CTLA-4 and anti–PD-1/PD-L1 antibodies administered in combination or sequentially. In the first trial (NCT03026062, n = 33), patients were given sequential therapy consisting of tremelimumab at 3 mg/kg every 4 weeks for up to four doses, followed by durvalumab at 1.5 g every 4 weeks for up to nine doses after progression; or combination therapy consisting of tremelimumab at 1 mg/kg plus durvalumab at 1.5 g every 4 weeks for up to four doses followed by durvalumab monotherapy at 1.5 g for up to nine doses or until progression. In the second trial (NCT01928394, n = 1), the patient was given ipilimumab at 1 mg per kg every 6 weeks plus nivolumab at 3 mg/kg every 2 weeks until progression.
Key Results
Next-generation sequencing revealed that 11 of the 34 patients (32.4%) had somatic mutations in the PPP2R1A gene. Among these patients, a significantly longer overall survival was observed compared with those without such a mutation (median overall survival 66.9 vs 9.2 months; hazard ratio = 0.40; 95% confidence interval = 0.15–1.08; P = .031). Progression-free survival was also longer among patients with a PPP2R1A mutation (3 vs 1.8 months; P = .034). An examination of the clinical course and responses in our cohort of patients with PPP2R1A mutations provided a key insight that the observed survival benefit was associated with delayed responses that sometimes followed a period of initial progression or stable disease. All of the patients in the study were enrolled on clinical trials that allowed for a continuation of immunotherapy beyond apparent disease progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1, which may have contributed to durable disease control in patients with PPP2R1A-mutated tumors.
Higher rates of grade ≥ 3 immune-related adverse events were noted in PPP2R1A mutation carriers (45.5% vs 13.0% for noncarriers; P = .079), which is consistent with previous studies demonstrating a positive correlation between immune-related adverse events and favorable outcomes in patients treated with ICB.
The authors concluded: “The results from these studies suggest that therapeutic targeting of PPP2R1A may represent an effective strategy to improve patient outcomes after ICB or other forms of immunotherapy, although additional mechanistic and therapeutic insights are needed.”
Disclosure: For full disclosures of the study authors, visit www.nature.com.
