Results of a phase II trial of nivolumab and ipilimumab in children and young adults with relapsed or refractory INI1-deficient cancers.

10029 Background: Several aggressive pediatric and young adult cancers are characterized by loss of INI1 expression, including malignant rhabdoid tumor, ATRT, epithelioid sarcoma and poorly differentiated chordoma. These cancers have a poor prognosis and limited effective treatments for relapsed or refractory disease. Prior data nominated immune checkpoint inhibition as a potential strategy for INI1-deficient tumors. Methods: In this phase II multicenter trial of nivolumab and ipilimumab, patients 6 months to 40 years with relapsed or refractory INI1-deficient cancers were enrolled in two strata: extracranial solid tumors (Stratum 1) and CNS tumors (Stratum 2). The primary endpoint was objective response ≥partial response (PR) by RECIST v1.1 (Stratum 1) or RANO (Stratum 2). Secondary endpoints included progression-free survival, overall survival and 12-month disease control rate. Patients received nivolumab 3mg/kg and ipilimumab 1mg/kg every 3 weeks for 4 cycles followed by nivolumab 3mg/kg every 2 weeks for up to 1 year. A Simon’s two-stage design targeted a response rate >25%, with each stratum assessed separately. Interim analysis at Stage 1 required ≥1 of 10 patients to have response ≥PR to proceed to Stage 2; at Stage 2, ≥3 of 20 patients with response ≥PR for evidence of efficacy. Evaluable patients received study treatment and were assessed for response or had progressive disease. Results: Thirty patients from six centers enrolled across both Strata from 8/2020 to 5/2025 and 27 were evaluable for the primary endpoint. Three inevaluable Stratum 1 patients were replaced per protocol. In Stratum 1, 1 patient (with poorly-differentiated chordoma) of 20 evaluable patients had ≥PR (ORR: 5%; 95% CI: 0.1-25%). In Stratum 1 (n=20), the 3-month EFS±SE and OS±SE were 20%±9% and 60%±11%, respectively, and the proportion of patients who were progression-free at 12-months was 5% (95%CI=0.1%-25%). Stratum 2 closed early with 7 patients enrolled, too few for Stage 1 interim analysis. No Stratum 2 patients had ≥PR [ORR: 0% (n=7)]. Patients received a median of 2 cycles of study treatment. The most common ≥ grade 3 treatment-related adverse events were decreased lymphocyte count (n=3), increased AST (n=3) anemia (n=2), and pneumonitis (n=2). Conclusions: The study did not meet the predetermined threshold for efficacy for Stratum 1. Immune checkpoint inhibitor therapy could warrant further exploration in poorly differentiated chordoma. Clinical trial information: NCT04416568 . Patient characteristics (n=27 evaluable patients). Median (Range) Age at enrollment (years) 7.1 (0.6-37.6) Lines of prior therapy 2 (1-7) n (%) Age group <18 yrs 24 (89%) ≥18 yrs 3 (11%) Sex Male 15 (56%) Female 12 (44%) Cancer diagnosis Stratum 1 20 (74%)