ImmunoSarc2 (Cohort 7a): A Spanish Sarcoma Group (GEIS) phase Ib trial of epirubicin and ifosfamide plus nivolumab in first line of advanced undifferentiated pleomorphic sarcoma (UPS).

Abstract

11514 Background: It was hypothesized that anthracycline-based chemotherapy plus anti-PD1 (nivolumab) could enhance the activity of upfront chemotherapy in advanced UPS, based on a double-hit in the immunogenic cell death circuit. This peculiar tumor cell death eventually activates an adaptive immune response through particular molecular changes in dying tumor cells and microenvironment, triggered by specific drugs such as anthracyclines. We previously reported a phase Ib trial in leiomyosarcoma patients with the combination of doxorubicin, dacarbazine, and nivolumab, obtaining 56.5% of ORR. We present here the phase Ib, cohort 7a, of the ImmunoSarc2 trial. Methods: Adult patients (pts), with ECOG 0-1, naïve of previous anthracycline-containing treatments, and with a centrally confirmed diagnosis of advanced/metastatic UPS were eligible. Initial dose level 0 (L0) was defined as epirubicin 60 mg/m 2 /d 20 min on D1 and D2 followed by ifosfamide 3 g/m 2 /d 3-h on D1-3, plus nivolumab (NIV) 360 mg on D3 after chemotherapy. Cycles were given Q3W with GCSF and MESNA 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 to include up to a maximum of 20 evaluable patients. Secondary endpoints included ORR and safety profile among others. Results: Between January 2022 and June 2024, 16 patients M/F (9/7), ECOG 0/1 (15/1), with median age 56 years (29-77) 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 62.5%, febrile neutropenia 18.8%, anemia 31.3%, and thrombocytopenia 25%. A patient died following a subarachnoid hemorrhage in the context of grade 4 thrombocytopenia and an accidental fall. Of 16 patients, RECIST ORR according to local clinical site assessment was 68.8% distributed as 1 CR (6%), 10 PR (63 %), 4 SD (25%), and 1 PD (6%). With a median follow-up of 16.3 months (95% CI, 7.2-25.4), the median of PFS was 9.9 months (95% CI 7-12.7), while the median OS was not reached, and the 1-year OS rate was 81% (95% CI 62-100). Conclusions: Epirubicin 60 mg/m 2 /d d1-2 plus Ifosfamide 3 g/m 2 /d d1-3 plus NIV 360 mg on d3 Q3W, followed by 1 year of NIV is a feasible and manageable scheme that exhibits relevant activity as an upfront line in advanced UPS patients. A phase II/III trial is designed aiming to confirm the advantage of chemo-immunotherapy over chemotherapy alone in this context. Clinical trial information: NCT03277924 .