American Association for Cancer Research

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Supplementary Figure 1 from A Phase II Study Investigating Cabozantinib in Patients with Refractory Metastatic Colorectal Cancer (AGICC 17CRC01)

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posted on 2023-04-04, 01:45 authored by Aaron J. Scott, Atrayee Basu Mallick, Efrat Dotan, Steven J. Cohen, Philip J. Gold, Howard S. Hochster, Somasundaram Subramaniam, Afsaneh Barzi, George S. Watts, Patrick J. Blatchford, Wells A. Messersmith

KM curves for PIK3CA mutant subjects.



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). 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. 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). This phase II study demonstrated clinical activity of cabozantinib in heavily pretreated, patients with refractory mCRC, and supports further investigation. 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.