A phase II, multi-cohort study with pemetrexed plus cisplatin combination in patients with relapsed or refractory advanced soft tissue sarcoma: Leiomyosarcoma cohort (ALBATROSS-SARC-LMS01).

11559 Background: Given the promising results in previous single arm trial (NCT03809637), this histology-specific, multi-cohort, phase II trial was conducted to evaluate the efficacy and safety of pemetrexed plus cisplatin in patients with advanced and refractory soft tissue sarcoma (STS). Methods: In this trial (NCT04605770), we enrolled patients with metastatic and/or recurrent STS who had failed 1-2 prior cytotoxic regimens and maintained adequate performance status and organ function. The treatment regimen consisted of pemetrexed 500 mg/m² and cisplatin 75 mg/m² on day 1 of each 3-week cycle up to 6 cycles, followed by pemetrexed monotherapy. A total of 164 patients were planned for assignment into 4 histology- based cohorts (n=41 each) to account for a 10% drop-out rate: Cohort 1 (leiomyosarcoma, [LMS)), Cohort 2 (liposarcoma), Cohort 3 (vascular sarcoma), and Cohort 4 (other sarcomas). The primary endpoint was progression-free rate at 12 weeks (PFR12 weeks) utilizing a Simon’s two-stage design (P1=40%, P0=20%, α=β=0.1). In the first stage, 17 patients were accrued; if at least 4 successes were observed, the cohort was to be expanded to 37 evaluable patients. To account for a 10% drop-out rate, the final enrollment target was set at 41 patients per cohort. Results: As of October 2025, 74 (45.1%) patients were enrolled. Among those, cohort 1 (LMS) reached full enrolment with 40 patients (median age; 53 years, female; 87.5%, 75% had received 2 prior lines of chemotherapy). Among Of 39 evaluable patients, 7 (17.9%) achieved a confirmed partial response, and 22 (53.8%) had stable disease, resulting in a disease control rate (DCR) of 74.3%. The median progression free survival was 6.3 months (95% CI, 4.9-7.6) with 74.0% of PFR12 weeks. Notably, the observed DCR and PFR12 weeks compare favorably with historical data for other second/third-line regimens in LMS, such as gemcitabine plus docetaxel (typical DCR 50–60%; PFR12 weeks 40–50%). The median OS was 20.5 months (95% CI 14.3-26.7), with a median of 7 treatment cycles administered (range 1-31). Although treatment-related adverse events (TRAEs) occurred in the majority of patients, grade ≥3 TRAEs were observed in only 10 (25%) patients, mainly anemia (n=10, 25%), neutropenia (n=7, 17.5%), and nausea (n=3, 7.5%). One TREA (drug hypersensitivity) led to treatment discontinuation due to drug hypersensitivity. Conclusions: The combination of pemetrexed and cisplatin was well tolerated and demonstrated promising activity in patients with relapsed, advanced STS, particularly in LMS cohort. The efficacy observed exceeded historical outcomes for standard-of-care second-line therapies, warranting further investigation in future histology-specific studies. Clinical trial information: NCT03809637 .