Clinical and translational results from the phase II ABACO trial evaluating the activity of cabozantinib in pretreated patients with metastatic colorectal cancer.

Background: Angiogenesis is a key mechanism in metastatic colorectal cancer (mCRC). Novel agents targeting this pathway, like cabozantinib, are of great therapeutic need. Patients and methods: We conducted an open-label, single-arm phase II trial to assess the antitumor activity of cabozantinib in patients with pretreated mCRC who had progressed following at least two prior lines of therapy. The primary endpoint was the progression-free survival (PFS) rate at 16 weeks, whereas secondary endpoints included median PFS, overall survival (OS), response rate, disease control rate, and safety. DNA- and RNA-based translational analyses were carried out on biological samples. Results: From October 2019 to January 2023, 33 patients were treated with oral cabozantinib, 60 mg daily. The primary endpoint was met: 11/33 assessable patients (33%) were progression-free at 16 weeks. Median PFS was 2.27 months [95% confidence interval (CI) 1.71-3.65 months], median OS was 6.25 months (95% CI 3.81-10.26 months). Disease control rate was 45.5%. Cabozantinib was generally fairly tolerated. Exploratory analyses investigating the effect of clinical disease features on PFS showed no significant correlation. Comprehensive genomic profiling on 30 patients (tissues and plasma) suggested that absence of Conclusion: Within the limitations of a single-arm phase II trial, cabozantinib demonstrates both safety and antitumor activity in mCRC. The observed correlation between specific molecular features, such as EMT activation and angiogenesis, and cabozantinib activity is hypothesis-generating and warrants further investigation.