SWOG/NCI Phase II Dual Anti-CTLA-4/PD-1 Blockade in Rare Tumors: Nonepithelial Ovarian Cancer

Abstract

Purpose: The role of dual checkpoint inhibition (ipilimumab at 1 mg/kg intravenously every 6 weeks and nivolumab at 240 mg intravenously every 2 weeks) in advanced rare/ultrarare nonepithelial ovarian cancers is yet to be explored.

Patients and methods: Dual anti-CTLA-4 and anti-PD-1 blockade in rare tumor is a prospective, multicenter (1,016 US sites), multicohort, single-arm phase II trial conducted through the Early Therapeutics and Rare Cancer SWOG/NCI Committee, assessing ipilimumab (anti-CTLA-4; 1 mg/kg every 6 weeks) and nivolumab (anti-PD-1; 240 mg every 2 weeks) in adults with advanced nonepithelial ovarian cancers who lack beneficial standard therapy. The primary outcome was overall response rate [ORR; complete response (CR)/partial response (PR)]; secondary outcomes were progression-free survival (PFS), overall survival, clinical benefit rate [stable disease (SD) ≥6 months plus ORR], and toxicity.

Results: Seventeen patients (median age: 64; number of prior therapies ranged from 0 to 8 with no immunotherapy exposure; eight granulosa, six carcinosarcomas, one Sertoli-Leydig, one yolk sac, and one Wolffian) were evaluated. In granulosa cell tumors, ORR was 25% (n = 2/8; one CR and one PR) and clinical benefit rate was 50% (n = 4/8); PFS was 58.3 (CR), 50.7+ (PR), 30.4 (SD), and 8.7 (SD) months. Median PFS was 3.5 months [95% confidence interval, 1.7-11.2 months]; median overall survival was 42.5 months (95% confidence interval, 10.1 months-not reached). One Sertoli-Leydig cell tumor showed a 22% regression (PFS, 11.2 months). Carcinosarcomas had no response. Three participants (18%) discontinued treatment due to grade 3 to grade 4 adverse events.

Conclusions: Ipilimumab-nivolumab shows activity in treatment-refractory granulosa cell tumors, with 25% (n = 2/8) of patients experiencing either CR or PR lasting more than 4 years.

Figure 1.. RECIST v1.1 Waterfall plot indicating maximum change in baseline tumor measurement following protocol therapy in (A) all histologies, (B) carcinosarcomas only, (C) granulosa cell tumors only.

Bars below the line indicate regressing disease; above the line, enlarging disease. Crosshatch indicates participants did not have tumor measurements available due to: stopping protocol therapy due to new lesions at first assessment (n=2), progression of non-measurable disease (n=1), or symptomatic deterioration (n=1). *One patient with a granulosa cell tumor had a response considered a CR with a −79% regression because of a lymph node measuring less than 1.0 cm. Abbreviation: CR, complete response; RECIST, response evaluation criteria in solid tumors.

Figure 2.. RECIST v1.1 Swimmer’s plot of progression-free survival following protocol therapy in (A) all histologies, (B) carcinosarcomas only, (C) granulosa cell tumors only.

Bars indicate PFS per individual patient. Circles indicate CR (n=1), triangles indicate PR (n=1), and squares indicate SD (n=6). Abbreviations: CR, complete response; PFS, progression-free survival; PR, partial response; RECIST, response evaluation criteria in solid tumors; SD, stable disease.

Figure 3.. RECIST v1.1 (A) progression-free and (B) overall survival of all 17 patients with non-epithelial ovarian cancers following protocol therapy.

Median progression-free survival was 3.5 months (95% CI 1.7–11.2 months). Median overall survival was 42.5 months (10.1-not reached). Abbreviation: CI, confidence interval; RECIST, response evaluation criteria in solid tumors.