Cabozantinib-Temozolomide Combination Shows Promise in Advanced Leiomyosarcoma with 74% Disease Control Rate
核心洞察
A phase II study of 72 patients demonstrated that the combination of cabozantinib and temozolomide achieved a 79.4% progression-free survival rate at 12 weeks in patients with unresectable or metastatic leiomyosarcoma (搜索).
The dual-targeting approach yielded a median progression-free survival of 6.3 months and median overall survival of 19.2 months in the leiomyosarcoma (搜索) cohort.
Treatment was well-tolerated with manageable toxicity profiles, with the most common grade 3-4 adverse events being platelet count decrease (30%) and neutrophil count decrease (18%).
A novel combination therapy targeting dual pathways has demonstrated meaningful clinical benefit in patients with advanced leiomyosarcoma (搜索), according to results from a multicenter phase II study published in The Lancet Oncology. The combination of cabozantinib and temozolomide achieved a 79.4% progression-free survival rate at 12 weeks in patients with unresectable or metastatic leiomyosarcoma.
Study Design and Patient Population
The U.S. multicenter study enrolled 72 patients between January 2020 and February 2023, including 42 patients with unresectable or metastatic leiomyosarcoma (搜索) in the primary cohort and 30 patients with other soft-tissue sarcomas in an exploratory cohort. Patients received cabozantinib at 40 mg once-daily and temozolomide at 150 mg/m² on days 1 to 5 of a 28-day cycle for the first cycle. Starting from cycle two, temozolomide was increased to 200 mg/m² on days 1 to 5 of each 28-day cycle if the absolute neutrophil count was more than 1.5 × 10⁹/L and the platelet count was more than 100.0 × 10⁹/L.
Efficacy Results
In the leiomyosarcoma (搜索) cohort, 31 of 42 patients (74%) achieved progression-free survival at 12 weeks while still receiving treatment. The Kaplan-Meier estimate of progression-free survival at 12 weeks was 79.4% (95% confidence interval = 68.6%–86.8%), accounting for censoring and without requiring patients to be receiving treatment at 12 weeks.
Median progression-free survival reached 6.3 months (95% CI = 4.6–7.0 months) in the leiomyosarcoma (搜索) cohort, compared to 3.0 months (95% CI = 1.4–4.6 months) in the exploratory cohort of other soft-tissue sarcomas. Post hoc analysis revealed median overall survival of 19.2 months (95% CI = 11.4 months to not reached) in the leiomyosarcoma cohort and 7.7 months (95% CI = 4.8–10.9 months) in the exploratory cohort. The 24-month overall survival rates were 36.4% and 16.8%, respectively.
Safety Profile
The combination therapy demonstrated a manageable safety profile with no treatment-related deaths reported. The most common grade 3 to 4 treatment-related adverse events among all patients included platelet count decrease (30%), neutrophil count decrease (18%), hypertension (10%), and diarrhea (8%). The investigators noted that treatment was tolerable and did not reveal any new safety signals.
Dual-Pathway Targeting Strategy
The study investigated dual targeting of vascular endothelial growth factor (VEGF (搜索)) and mesenchymal epithelial transition factor receptor (MET) pathways with cabozantinib, a multi-kinase inhibitor, combined with temozolomide chemotherapy. This approach represents a novel strategy combining VEGF/MET signaling inhibition with DNA damage mechanisms for treating leiomyosarcoma (搜索).
According to Maria Babak, Head of The Babak Lab (搜索) and Assistant Professor at City University of Hong Kong, the results are "exciting to see the phase II results for the cabozantinib–temozolomide combination, which achieved a 74% 12-week PFS rate in advanced leiomyosarcoma (搜索)."
Clinical Implications
The investigators concluded that "cabozantinib with temozolomide showed a meaningful clinical benefit and could potentially be a viable treatment option for patients with unresectable or metastatic leiomyosarcoma (搜索)." The combination achieved an overall response rate of 17% in the leiomyosarcoma cohort, with researchers noting that the therapy "shows clinically meaningful disease control in advanced leiomyosarcoma and warrants further testing in randomized trials."
Mark Agulnik, MD, of Division of Medical Oncology, Keck School of Medicine, University of Southern California, Los Angeles, served as the corresponding author for the study.