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 TP53 mutations and tumor mutational burden (TMB) ≥4 mutations/Mb positively correlated with response (PFS >16 weeks). Additionally, for a subset of 18 (54.5%) patients, RNA sequencing from archival formalin-fixed paraffin-embedded samples was carried out. Molecular subtypes 4 (CMS4) was the most represented transcriptional subtype (10/18 cases). To verify if other transcriptional features were associated with treatment benefit, for each sample we computed gene set variation analysis. For epithelial-mesenchymal transition (EMT) and angiogenesis gene sets, we identified a trend toward higher scores in tumors from patients with longer PFS. 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.
Falco et al. (Mon,) studied this question.