A Phase II Study Investigating Cabozantinib in Patients with Refractory Metastatic Colorectal Cancer (AGICC 17CRC01)
Aaron J Scott1, Atrayee Basu Mallick2, Efrat Dotan3
1Division of Hematology and Oncology, University of Arizona Cancer Center, Tucson, Arizona.
Purpose:
Multi-tyrosine kinase inhibitors (TKI) have shown clinical activity in patients with metastatic colorectal cancer. Cabozantinib, a multi-TKI, exhibited potent antitumor activity superior to regorafenib in preclinical colorectal cancer patient-derived tumor xenograft models. This phase II study aimed to investigate cabozantinib, a multi-TKI, in patients with refractory, metastatic colorectal cancer (mCRC).
Experimental Design:
A nonrandomized, two-stage, phase II clinical trial evaluating 12-week progression-free survival (PFS) was conducted in eight cancer centers across the United States between May 2018 and July 2020.
Results:
A total of 44 patients were enrolled between May 2018 and May 2019, 40 of which were response evaluable. Of the total 769 reported adverse events (AE), 93 (12%) were ≥ grade 3. Five grade 5 AEs were reported of which four were unrelated to study drug and one was reported as possibly related due to bowel perforation. Eighteen patients (45%) achieved 12-week PFS with stable disease or better (confidence interval, 0.29-0.62; P < 0.001). One patient (3%) had a partial response, and 27 other patients achieved stable disease as best response per RECISTv1.1. Median PFS was 3.0 months, and median overall survival was 8.3 months. Of the 18 patients who achieved 12-week PFS, 12 had left-sided primary tumors, 11 were RAS wild type, 11 were PIK3CA wild type, and 6 had previous regorafenib therapy. The 12-week PFS rate was higher in RAS wild-type tumors compared with RAS mutant tumors (0.61 vs. 0.32; P = 0.11).
Conclusions:
This phase II study demonstrated clinical activity of cabozantinib in heavily pretreated, patients with refractory mCRC, and supports further investigation.
Significance:
Targeting angiogenesis through VEGF axis blockade provides incremental survival benefit in patients with mCRC. The hepatocyte growth factor/MET signal transduction pathway has been observed as a mechanism for acquired resistance. Dual inhibition of VEGF plus MET is an attractive therapeutic strategy. This phase II trial demonstrated clinical activity with cabozantinib, a multi-TKI targeting VEGFR2 and MET, in patients with refractory, mCRC.
Insights
Cabozantinib showed clinical activity in patients with refractory metastatic colorectal cancer (mCRC). This multi-tyrosine kinase inhibitor (TKI) achieved a 45% 12-week progression-free survival rate in heavily pretreated individuals.
Area of Science:
- Oncology
- Pharmacology
Background:
- Multi-tyrosine kinase inhibitors (TKIs) demonstrate clinical efficacy in metastatic colorectal cancer (mCRC).
- Cabozantinib, a multi-TKI, showed superior preclinical antitumor activity compared to regorafenib in colorectal cancer models.
- The hepatocyte growth factor/MET pathway is implicated in acquired resistance to anti-angiogenic therapies.
Purpose of the Study:
- To evaluate the clinical activity of cabozantinib in patients with refractory metastatic colorectal cancer (mCRC).
- To assess the 12-week progression-free survival (PFS) rate of cabozantinib in heavily pretreated mCRC patients.
Main Methods:
- A nonrandomized, two-stage, phase II clinical trial was conducted across eight US cancer centers.
- The study enrolled 44 patients with refractory mCRC between May 2018 and May 2019.
- The primary endpoint was 12-week PFS, with safety and overall survival also assessed.
Main Results:
- Eighteen of 40 response-evaluable patients (45%) achieved 12-week PFS (stable disease or better).
- Median PFS was 3.0 months, and median overall survival was 8.3 months.
- Common adverse events included grade ≥3 events in 12% of cases; one possible drug-related grade 5 adverse event (bowel perforation) was reported.
Conclusions:
- Cabozantinib demonstrated clinical activity in heavily pretreated patients with refractory mCRC.
- The findings support further investigation of cabozantinib in this patient population.
- Dual inhibition of VEGF and MET pathways represents a promising therapeutic strategy for mCRC.
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