Monga V; Okuno S; Van Tine B; Pollack SM; Weiss M; Hirbe A; Viveiros P; Schulte B; Attia S; Siontis B; Milhem MM; Charlson JA; Robinson S; Okunowo O; Frankel P; Woo D; Yoon J; Agulnik M · 2026 · The Lancet. Oncology
Paper
BACKGROUND: The prognosis for patients with unresectable or metastatic soft tissue sarcomas remains poor. Evidence shows that a combination of antiangiogenic agents and chemotherapy inhibit tumour growth. We aimed to investigate the dual targeting of VEGF and MET pathways with cabozantinib and temozolomide in patients with unresectable or metastatic leiomyosarcoma and other soft tissue sarcomas. METHODS: This multicentre, single-arm, lead-in phase 2 trial was conducted at five academic Sarcoma Centers of Excellence of the Midwest Sarcoma Trials Partnership in the USA. Eligible patients were aged 18 years or older, had histologically-confirmed unresectable or metastatic uterine and non-uterine leiomyosarcoma (cohort 1) and other soft tissue sarcomas (cohort 2; exploratory), an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, up to five previous chemotherapy regimens, adequate organ and bone marrow function, and measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1). Patients received oral cabozantinib 40 mg (as a starting dose) once per day and temozolomide 150 mg/m 2 on days 1-5 of a 28-day cycle for cycle one. Starting from cycle two, temozolomide was escalated to 200 mg/m 2 on days 1-5 of each cycle, if the absolute neutrophil count was more than 1·5 × 10 9 /L and platelet count was more than 100·0 × 10 9 /L, and treatment continued until disease progression or unacceptable drug-related adverse events. The primary endpoint in cohort 1 was progression-free survival at 12 weeks, assessed in the intention-to-treat population (defined as all enrolled patients). This study is registered with ClinicalTrials.gov, NCT04200443 (completed accrual). FINDINGS: Between Jan 17, 2020, and Feb 6, 2023, 96 patients were assessed for eligibility, 24 were ineligible, and 72 were enrolled. The median age at enrolment was 59 years (IQR 52-66) in cohort 1 (n=42) and 63 years (50-69) in cohort 2 (n=30), with a median follow-up of 18·0 months (17·5-20·7). 42 (58%) of 72 patients were female and 30 (42%) were male. In cohort 1, progression-free survival at 12 weeks was reached by 31 (74%) of 42 patients who were still receiving cabozantinib and temozolomide. The Kaplan-Meier estimate of progression-free survival was higher due to censoring and not requiring patients to be receiving treatment at 12 weeks (79·4% [95% CI 68·6-86·8]). 20 (48%) patients in cohort 1 and 23 (77%) in cohort 2 had died due to disease progression at the end of the study. 71 (99%) of 72 patients had grade 1 or higher treatment-related adverse events. The most common grade 3-4 adverse events attributed to either one or both drugs were platelet count decrease (22 [30%]), neutrophil count decrease (13 [18%]), hypertension (seven [10%]), and diarrhoea (six [8%]). There were no treatment-related deaths. INTERPRETATION: Cabozantinib with temozolomide showed a meaningful clinical benefit and could potentially be a viable treatment option for patients with unresectable or metastatic leiomyosarcoma. Treatment was tolerable and did not reveal any new safety signals. FUNDING: Exelixis.
Analysis
This phase 2 trial investigated the efficacy of cabozantinib and temozolomide in patients with unresectable or metastatic leiomyosarcoma and other soft tissue sarcomas, showing promising progression-free survival.
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