Megan Othus

A phase II basket trial of dual anti‐CTLA‐4 and anti‐PD‐1 blockade in rare tumors (DART) SWOG S1609: durable responses and delayed pseudoprogression in small cell carcinoma of the ovary, hypercalcemic type cohort

Abstract Background The combined use of anti‐programmed cell death protein 1 ( PD‐1 )/anti‐cytotoxic T‐lymphocyte associated protein 4 ( CTLA‐4) checkpoint inhibitors has been effective in various cancer types. The Southwest Oncology Group (SWOG) Dual Anti‐ CTLA‐4 and Anti‐ PD‐1 Blockade in Rare Tumors (DART) S1609 study investigated ipilimumab and nivolumab in ultra‐rare cancers, including small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The purpose of the study was to evaluate the potential clinical benefit of ipilimumab and nivolumab in patients with SCCOHT. Methods DART was a prospective, open‐labeled, multicenter (>1,000 US sites), multi‐cohort phase II clinical trial of intravenous administration of ipilimumab (1 mg/kg, every 6 weeks) plus nivolumab (240 mg, every 2 weeks). The primary endpoint was overall response rate [ORR, confirmed complete response (CR) and partial response (PR)] per RECIST. Secondary endpoints included progression‐free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease ≥6 months), and toxicity. Immune responses were also evaluated. Results Six patients (median age, 30.5 years; median, 2 prior therapies; no prior immunotherapy exposure) with advanced/metastatic SCCOHT were evaluable. ORR and CBR were both 16.7% (1/6) with one patient having a confirmed CR lasting 46.2+ months. However, another patient had a confirmed immune CR (iCR) with immune PFS (iPFS) of 53+ months [ORR/iORR, 33.3% (2/6)]. Notably, the latter patient had a progressing lesion at 24 weeks after initial response, but with renewed regression with ongoing therapy, suggesting delayed pseudo‐progression. At 12‐months, 3 patients remained alive. Median PFS was 1.4 months (range, 0.9 months‐not reached); median OS was 14.2 months (2 months‐not reached). No adverse events caused treatment discontinuation. Conclusion Two of 6 patients (33.3%) with SCCOHT achieved durable CR/iCR and long‐term survival with ipilimumab plus nivolumab. Correlative studies to determine response and resistance markers are ongoing.

A Phase II Basket Trial of Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors SWOG S1609: Vulvar Cancers

Abstract Purpose: Dual PD-1/CTLA-4 inhibition shows promise in various malignancies. The SWOG S1609 Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART) trial presents initial results of ipilimumab/nivolumab in vulvar cancers. Patients and Methods: DART is a prospective/open-label/multicenter (1,016 US sites)/multicohort phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks). The primary endpoint was objective response rate [ORR; confirmed complete response and partial response (PR)] per RECISTv1.1, whereas progression-free survival (PFS), overall survival, clinical benefit rate (CBR; ORR plus stable disease ≥6 months), and toxicity were secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years; 0–6 prior therapies; no prior immunotherapy) were analyzed, all of whom had squamous cell carcinoma histology. The ORR was 18.8% (3/16), CBR was 25% (4/16), and CBR plus unconfirmed PR rate was 31% (5/16); the PFS was 34.1, 16.7. 15.5, 7.2, and 7.0 months for these five patients, respectively. The median PFS and overall survival were 2.2 and 7.6 months, respectively. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n = 4 each). Grade 3 to 4 adverse events occurred in 25% of patients (n = 4). There was one grade 1 to 2 adverse event (6.7%) that led to discontinuation and one (6.7%) grade 5 death adverse event. Conclusions: Ipilimumab plus nivolumab in vulvar cancers resulted in an objective response in 3 of 16 patients, all of whom had durable responses lasting over 1 year. Notably, two additional patients experienced durable stable disease and unconfirmed PR. Correlative studies to determine response and resistance markers are ongoing.

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.