(P 166) SARC038: A PHASE 2 STUDY OF REGORAFENIB IN COMBINATION WITH NIVOLUMAB IN PATIENTS WITH REFRACTORY OR RECURRENT OSTEOSARCOMA

Objective: Combination VEGF targeted agents and checkpoint inhibitors have shown benefit in a variety of cancer types. Regorafenib, a multi-tyrosine kinase inhibitor, has shown benefit in patients with refractory/recurrent osteosarcoma in two randomized placebo-controlled trials, REGOBONE and SARC024. We hypothesized that the addition of nivolumab, a PD-1 inhibitor, to regorafenib will improve the progression-free survival (PFS) rate of patients with refractory/recurrent osteosarcoma compared to a similar patient population who received regorafenib alone.

Methods: SARC038 is a single-arm, historically-controlled phase 2 study utilizing a Simon’s 2-stage design. Patients ≥5 years of age with recurrent or refractory osteosarcoma, RECIST measurable disease after at least one line of prior systemic therapy and no prior exposure to VEGF targeted agents or checkpoint inhibitors were eligible. Treatment included nivolumab 480 mg IV (3 mg/kg days 1 and 15, if < 18 years of age) on day 1 and regorafenib 80-120 mg PO (60-72 mg/m2/dose, if < 18 years of age) days 1-21 in 28-day cycles. The primary endpoint was PFS rate at 4 months as determined by iRECIST. If 11 or more patients of the initial 20 patients were progression-free at 4 months, the trial would proceed to the second stage to enroll an additional 23 patients. The trial was designed to have a one-sided 0.1 level of significance and 80% power to detect a 4-month PFS rate of 0.65 compared to an historical control value of 0.48 (based on patients treated with regorafenib alone). Secondary endpoints included objective response rate (ORR) and PFS using RECIST and iRECIST, overall survival and adverse events.

Results: Between June 2021 and January 2023, 23 patients [12 female, median age of 22 (range, 9-73 years)] were enrolled. A median of 4 cycles (range, 1-25) of therapy were administered as of May 12, 2023. All patients were evaluable for toxicity and 20 were evaluable for the primary endpoint. Eight of 20 were progression free for at least 4 months, resulting in a 4-month PFS of 46.3% (95% CI: 28.3-75.8%), which did not meet criteria to proceed to stage 2. With a median follow up time of 5.4 months (range, 0.5-22.0), the median PFS was 3.6 months (95% CI: 1.8-NA). One-year survival was 55.1% (95% CI: 30.6-99.4%). Twenty patients were evaluable for ORR, one had a partial response. Eighteen treatment-related adverse events of grade ≥3 occurred in 12 (52.2%) of the patients, with rash (including hand-foot skin reaction) being the most common (N = 6). Thrombocytopenia and leucopenia were observed in 2 patients each and anemia, lymphopenia, elevated AST, back pain, diarrhea, oral mucositis and wound dehiscence were observed in one patient each. The severity and frequency of rash prompted an amendment to use an alternative dosing schedule of regorafenib, starting at a lower dose and escalating to higher dose if well tolerated for one week.

Conclusion: Overall, the combination of regorafenib and nivolumab was generally well tolerated; however, rash was a frequently observed adverse event requiring dose reduction of regorafenib. Although the study did not meet the protocol defined criteria for efficacy to proceed to the second stage, a subset of patients receiving the combination of nivolumab and regorafenib did benefit from the therapy. Analysis of clinical characteristics and biospecimens (blood, tumor tissue and stool) collected at baseline, during and at the time of progressive disease is ongoing to understand potential predictors of efficacy.