Cabozantinib/Temozolomide Shows Benefit for Leiomyosarcoma

The combination of cabozantinib with temozolomide led to significant clinical benefit in patients with leiomyosarcoma, according to results published in Lancet Oncology.¹

In a single-arm multicenter lead-in phase 2 study (NCT04200443), 74% of the 42 patients treated in the leiomyosarcoma cohort had no progression at 12 weeks, meeting the primary end point, and treatment was generally tolerable.

“These findings support the combination as a potential treatment option for patients with advanced leiomyosarcoma and provide a strong rationale for further study aimed at improving outcomes in this difficult-to-treat cancer,” stated Seth Pollack, MD, the Steven T. Rosen, MD, Professor of Cancer Biology, in a news release from Northwestern University’s Feinberg School of Medicine.² 

Leiomyosarcomas, a subtype of soft tissue sarcoma appearing in the smooth muscle tissue, are difficult to treat. Previous research suggested that there is a synergistic effect inhibiting tumor growth combining antiangiogenic agents which starve the tumor of its blood supply with traditional chemotherapy. This study specifically targeted the VEGF and MET pathways with cabozantinib, a multikinase inhibitor.

Study Design and Patient Profiles

The trial, conducted across 5 academic Sarcoma Centers of Excellence, enrolled 72 patients divided into 2 cohorts. Cohort 1 enrolled patients with uterine and non-uterine leiomyosarcoma and cohort 2enrolled patients with other types of soft tissue sarcomas.¹ The primary end point was progression-free survival (PFS) at 12 weeks in cohort 1. Secondary end points included overall response rate, median PFS, overall survival, and safety.

Participants received a daily dose of 40 mg oral cabozantinib and a 5-day course of temozolomide within a 28-day cycle. To ensure safety, the temozolomide dose was escalated from 150 mg/m² to 200 mg/m² in the second cycle only if the patient's blood counts remained stable.

Promising Results for Leiomyosarcoma

Between Jan 17, 2020, and Feb 6, 2023, 96 patients were assessed for eligibility and 72 were enrolled, 42 in cohort 1 and 30 in cohort 2. Thirty-one of 42 patients in cohort 1 had no progression at 12 weeks and were still receiving treatment. The Kaplan-Meier estimated PFS rate was 79.4%, due to censoring and not requiring patients to be receiving treatment at 12 weeks.

At a median follow-up of 18 months, 20 patients (48%) had died in cohort 1 and 23 (77%) had died in cohort 2 due to disease progression.

Safety and Tolerability

Adverse events were common, with 99% of patients experiencing at least one treatment-related adverse event. The most frequent severe (grade 3–4) issues included Platelet count decrease in 30% of patients, neutrophil count decrease in 18% of patients, hypertension in 10% of patients, and diarrhea in 8% of patients.

Importantly, the study reported notreatment-related deaths, and the safety profile was consistent with what is already known about these individual drugs, suggesting that the combination is manageable in a clinical setting.

Conclusions

The trial concludes that the combination of cabozantinib and temozolomide could potentially be a "viable treatment option" for patients with advanced leiomyosarcoma.

Pollack and other researchers at Northwestern are also investigating single-agent zanzalitinib, which targets VEGF, MET, and the TAM family of kinases, in an ongoing trial (NCT06571734) in patients with advanced leiomyosarcoma. The primary end point of this study is to evaluate 6-month PFS.

“Together, these efforts reflect a broader strategy to expand and improve treatment options for patients with advanced leiomyosarcoma through thoughtfully designed clinical trials,” Pollack said.

REFERENCES

1. 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. 2026;27(2):223-232. doi:10.1016/S1470-2045(25)00654-0

2. Rohman M. Combination treatment may slow disease progression in advanced sarcoma. News release. Northwestern Medicine Feinberg School of Medicine. February 10, 2026. Accessed February 11, 2026. https://tinyurl.com/tw4aaw9d