Cabozantinib Plus Temozolomide Demonstrates Clinical Activity in Advanced Leiomyosarcoma

Clinical Summary: 

• Design/Population: This multicenter, single-arm, lead-in phase 2 trial evaluated cabozantinib plus temozolomide in patients with unresectable or metastatic leiomyosarcoma or other soft tissue sarcomas treated at 5 US academic sarcoma centers. The primary efficacy analysis focused on patients with uterine and nonuterine leiomyosarcoma.
• Key Outcomes: The combination demonstrated encouraging progression-free survival and durable disease control with a manageable safety profile. The most common grade 3/4 adverse events were hematologic toxicities, and no treatment-related deaths or new safety signals were observed.
• Clinical Relevance: These findings support further evaluation of cabozantinib plus temozolomide as a biologically rational treatment strategy for patients with advanced leiomyosarcoma who have limited options after first-line therapy.

Varun Monga, MBBS, University of California San Francisco, San Francisco, California, discusses results from a multicenter phase 2 study evaluating cabozantinib combined with temozolomide in patients with unresectable or metastatic leiomyosarcoma and other soft tissue sarcomas. The study investigated whether combining a multitargeted tyrosine kinase inhibitor with alkylating chemotherapy could improve disease control in a heavily pretreated population.

The combination demonstrated encouraging clinical activity with durable disease control in a subset of patients while maintaining a manageable safety profile. Although the study was not randomized, these findings provide support for further investigation of combination targeted therapy strategies in advanced leiomyosarcoma.

Transcript: 

Hi, I'm Varun Monga. I'm a medical oncologist at the University of California, San Francisco. I'm going to talk about our study using the combination of cabozantinib and temozolomide in patients with unresectable or metastatic leiomyosarcoma and other soft tissue sarcomas, a multicenter, single-arm, lead-in phase 2 trial.

Patients with advanced sarcoma have limited durable treatment options beyond first-line therapy.We designed this study to test whether combining a multitargeted TKI like cabozantinib with temozolomide could enhance tumor control through complementary mechanisms.

We observed a meaningful signal of activity with manageable toxicity, including durable disease control in a subset of patients. While this was not a randomized study and the sample size remains a limitation, the findings support further investigation of biologically rational combinations.I think the broader message is that thoughtful combination strategies may represent an important path forward in sarcoma.

In this study, we explored the combination of cabozantinib and temozolomide in a multicenter, single-arm, lead-in phase II trial conducted at five academic sarcoma centers of excellence in the United States. Eligible patients were age 18 or older. In cohort 1, patients had histologically confirmed unresectable or metastatic uterine or nonuterine leiomyosarcoma. Cohort 2 included other soft tissue sarcoma subtypes and was exploratory in nature. Patients had to have an ECOG performance status of 0 to 1, and up to 5 previous chemotherapy regimens were allowed before enrollment. Organ function had to meet protocol-defined criteria, and patients needed to have measurable disease according to RECIST 1.1.

Patients received oral cabozantinib 40 mg once daily as the starting dose. Oral temozolomide was given at 150 mg/m² on days 1 through 5 during cycle 1 and was escalated to 200 mg/m² on days 1 through 5 beginning in cycle 2, provided hematologic criteria were met. Treatment was given in 28-day cycles. The primary end point in cohort 1 was progression-free survival at 12 weeks, assessed in the intention-to-treat population. Patients were enrolled at the 5 participating sites between January 2020 and February 2023.

A total of 96 patients consented, and ultimately 72 patients were enrolled. The median age at enrollment was 59 years, with a median follow-up of 18 months.

The progression-free survival rate at 12 weeks in cohort 1 was 74%.The most common grade 3/4 adverse events attributable to one or both study drugs were thrombocytopenia, occurring in 30% of patients; neutropenia in 18%; hypertension in 10%; and diarrhea in 8%. There were no treatment-related deaths.

In summary, cabozantinib and temozolomide demonstrated meaningful clinical benefit and could potentially represent a viable treatment option for patients with unresectable or metastatic leiomyosarcoma.The treatment was tolerable and did not reveal any new safety signals.

Source: 

Monga V, Okuno S, Van Tine B, et al. Cabozantinib and temozolomide in patients with unresectable or metastatic leiomyosarcoma and other soft tissue sarcomas: A multicentre, single-arm, lead-in phase 2 trial. Lancet Oncol. Published online: January 16, 2026. doi:10.1016/S1470-2045(25)00654-0