ImmunoSarc2: A Spanish Sarcoma Group (GEIS) phase Ib trial of doxorubicin and dacarbazine plus nivolumab in first line treatment of advanced leiomyosarcoma

11502 Background: The immunogenic death caused by certain chemotherapy agents consists of molecular changes in tumor dying cells that stimulate immunogenicity and enhance antitumor effects. Doxorubicin is one validated drug related to immunogenic death, mainly through calreticulin membrane translocation that elicits immunogenic signals as phagocytosis by dendritic cells. Doxorubicin+pembrolizumab was explored in a phase I/II trial treating patients with metastatic/unresectable sarcomas, achieving 22% PR, 59% SD, and 19% PD, with mPFS of 8.1 months superior to historical controls. We hypothesized that the addition of an anti-PD1 (nivolumab) would increase the antitumor activity of commonly used upfront polychemotherapy in leiomyosarcoma (LMS) of doxorubicin plus dacarbazine. We present here the phase Ib, cohort 7b of ImmunoSarc2 trial. Methods: Adult patients (pts), with ECOG 0-1, naïve of previous anthracycline-containing treatments and with centrally confirmed diagnosis of advanced/metastatic leiomyosarcoma (LMS) were eligible. Initial dose level 0 (L0) was defined as doxorubicin (DOX) 75 mg/m2/d 20 min on D1 followed by dacarbazine (DAC) 400 mg/m2/d 60 min on D1 and 2, plus nivolumab (NIV) 360 mg on D2 after DAC Q3W with GCSF support. This combo would be given up to 6 courses of 21-day cycles, followed by 1-year NIV maintenance. A -1 dose level (L-1) was defined with the same regimen but with NIV 240 mg. A classic 3+3 phase 1 design was used to determine the MTD based on DLTs (main endpoint) observed during the first 21-day cycle. The cohort was foreseen to be extended with the RP2D up to 20 evaluable patients. Secondary endpoints included ORR and safety profile among others. Results: Between January 2022 and February 2023, 20 pts (M/F 6/14), ECOG 0/1 (15/5), with median age 54 years (31-72) were enrolled. All patients were treated with the initial L0 scheme and no DLTs were observed being L0 the RP2D. Grade 3-4 toxicities were neutropenia (20%), anemia (10%), febrile neutropenia, asthenia, and GGT increased (5% each). Four pts are not evaluable for efficacy (1 due to uncompliant dosing and 3 for not reaching the first tumor assessment yet). Of 16 efficacy-evaluable pts, RECIST ORR according to local clinical site assessment was 9 PR (56.2 %), 6 SD (37.5%), and 1 PD (6.3%) (2 SD cases had tumor size reductions > 20%). Five pts ended treatment due to progression (4 radiological, 1 clinical) and 15 pts remain under the trial therapy. mPFS for evaluable patients was 8.67 months (95% CI: 7.96-9.37) with a median follow-up of 8 months (2-12). Conclusions: DOX 75 mg/m2/d on D1 followed by DAC 400 mg/m2/d on D1 and 2, plus NIV 360 mg on D2 after DAC Q3W, followed by 1-year NIV maintenance is a feasible and well-tolerated scheme. Clinical activity is encouraging improving historical efficacy outcomes in first line of advanced LMS, which deserves further testing in phase II trials. Clinical trial information: NCT03277924 .