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Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours
Patrick Schöffski1, Michael Gordon2, David C Smith3
1Department of General Medical Oncology, Leuven Cancer Institute, University Hospital Leuven, Leuven, Belgium.
Background:
Cabozantinib is an inhibitor of tyrosine kinases, including MET, vascular endothelial growth factor receptor, AXL and RET. This multi-cohort phase II randomised discontinuation trial explored anticancer activity of cabozantinib in nine tumour types.
Patients And Methods:
Cabozantinib was administered (100 mg, once daily) to patients with advanced, recurrent or metastatic cancers. Those with stable disease at week 12 were randomised 1:1 to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) in the randomised phase.
Results:
A total of 526 patients were enrolled. The highest ORR was observed in ovarian cancer (OC) (21.7%); the largest PFS benefit was observed in castration-resistant prostate cancer (CRPC) (median 5.5 versus 1.4 months for placebo; hazard ratio 0.14, 95% confidence interval: 0.04, 0.52). Disease control rates were >40% for CRPC, OC, melanoma, metastatic breast cancer (MBC), hepatocellular carcinoma (HCC) and non-small cell lung cancer. Median duration of response ranged from 3.3 (MBC) to 11.2 months (OC). Encouraging efficacy results and symptomatic improvements prompted early suspension of the randomised stage and conversion to open-label non-randomised expansion cohorts. Dose reductions to manage adverse events (AEs) occurred in 48.7% of patients. The most frequent grade III-IV AEs were fatigue (12.4%), diarrhoea (10.5%), hypertension (10.5%) and palmar-plantar erythrodysesthesia syndrome (8.7%).
Conclusions:
Clinical antitumour activity of cabozantinib was observed in a subset of tumour types: CRPC and OC were evaluated further in expansion cohorts. Phase III programs were initiated in CRPC and HCC. Interpretation of efficacy outcomes was limited by early termination of the randomised portion of the trial.
Trial Registration Number:
NCT00940225.
Insights
Cabozantinib showed anticancer activity in advanced cancers, particularly ovarian and castration-resistant prostate cancers. Further trials are ongoing due to promising results, despite early trial termination.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Cabozantinib is a multi-tyrosine kinase inhibitor targeting MET, VEGFR, AXL, and RET.
- Exploration of cabozantinib's anticancer potential across diverse tumor types.
Purpose of the Study:
- To evaluate the efficacy of cabozantinib in patients with advanced, recurrent, or metastatic cancers.
- To assess objective response rate (ORR) and progression-free survival (PFS) in a randomized discontinuation trial.
Main Methods:
- Phase II randomized discontinuation trial involving 526 patients across nine tumor types.
- Cabozantinib (100 mg daily) administered; patients with stable disease at week 12 randomized to cabozantinib or placebo.
- Primary endpoints: ORR at week 12 and PFS during the randomized phase.
Main Results:
- Highest ORR in ovarian cancer (21.7%). Significant PFS benefit in castration-resistant prostate cancer (CRPC) (median 5.5 vs. 1.4 months).
- Disease control rates exceeded 40% in CRPC, ovarian cancer, melanoma, metastatic breast cancer, hepatocellular carcinoma, and non-small cell lung cancer.
- Median duration of response varied from 3.3 to 11.2 months. Common Grade III-IV AEs included fatigue, diarrhea, and hypertension.
Conclusions:
- Cabozantinib demonstrated clinical antitumour activity in specific cancer types, notably CRPC and ovarian cancer.
- Early trial termination due to promising results led to expansion cohorts and initiation of Phase III trials in CRPC and HCC.
- Interpretation of efficacy was impacted by the early termination of the randomized phase.
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