Phase I/II study of cabozantinib alone or in combination with panitumumab in patients with <i>MET</i> -amplified metastatic colorectal cancer.

146 Background: Despite the introduction of anti-EGFR therapies, resistance remains a significant challenge in metastatic colorectal cancer (mCRC). MET amplification is a recognized resistance mechanism. Cabozantinib, a multi-kinase inhibitor targeting MET, has shown promise in overcoming resistance to anti-EGFR therapy. This study aimed to evaluate the efficacy and safety of cabozantinib alone (Cabo) or in combination with panitumumab (Cabo+Pmab) in patients with MET-amplified mCRC. Patients and Methods: The study population included patients with RAS and BRAF wild-type mCRC who had progressed on anti-EGFR therapy and subsequently confirmed MET amplification by circulating tumor DNA. The phase I part aimed to establish the recommended cabozantinib dose in combination with panitumumab by assessing dose-limiting toxicity (DLT) within the first four weeks. The primary endpoint of phase II part was objective response rate (ORR) in patients receiving the study treatment as third-line therapy or later. In phase II part, patients were randomized to Cabo or Cabo+Pmab group. Based on a threshold ORR of 1.6% response rate and an expected efficacy of 30%, the planned sample size was 14 patients with one-sided alpha of 1.25% and power of 80% in each arm, Cabo and Cabo+Pmab. A tumor response of at least 3 out of 14 patients would warrant further investigation of these treatments. Results: A total of 35 patients were enrolled (6 in phase I and 29 in phase II, 28 for the primary analysis; 13 in Cabo and 15 in Cabo+Pmab). In phase I, no DLTs were observed. This allowed researchers to set the maximum tolerated dose and recommend a dosage of 60 mg/day of cabozantinib in combination with panitumumab for phase II. Of 28 pts for the primary analysis, ORR was 7.7% (1/13; 95%CI 0.2-36%) in Cabo group and 0% (0/15; 95%CI 0-21.8%) in Cabo+Pmab group, median progression-free survival was 3.1 months in both groups, and cumulative proportion of pts with grade ≥3 treatment-related adverse events was 38.5% (including hypertension [23.1%]) in Cabo and 60% (including hypomagnesaemia [20%]) in Cabo+Pmab group. Conclusions: The combination of cabozantinib 60 mg plus panitumumab had manageable safety profile. However, this treatment did not demonstrate significant clinical benefit in patients with MET-amplified mCRC. Further investigation is warranted to explore alternative therapeutic strategies for this patient population. Clinical trial information: jRCT1080224637 .