620P A phase II trial evaluating the activity of cabozantinib in pre-treated patients with metastatic colorectal cancer (mCRC): ABACO trial initial molecular data

Angiogenesis is a crucial mechanism in colorectal cancer (CRC) development and progression, and anti-angiogenic drugs are a mainstay of CRC systemic treatment. We conducted, according to Simon’s “minimax” two stage design, an open-label, single arm phase II trial to evaluate the antitumor activity of cabozantinib in pretreated metastatic CRC (mCRC) patients (pts), that progressed after at least 2 lines of prior therapy for metastatic disease. The primary endpoint was the Progression Free Survival (PFS) rate at 16 weeks; secondary endpoints include PFS, Overall Survival (OS), Response Rate (RR), Disease Control Rate, safety. Here we present the initial exploratory biomarkers analysis. From October 2019 to January 2023 a total of 33 (19 male and 14 female) pts, median age of 58 years (30-79), were treated with cabozantinib 60 mg/daily per os. A comprehensive genomic profiling by next generation sequencing (NGS) was performed with FoundationOne CDx and FoundationOne Liquid CDx (324 genes) on tumor tissue (20/33) and plasma circulating tumor DNA (ctDNA) (15/33) both in 8/33 pts. 11 out of 33 patients were free of progression at 16 weeks and were considered responders and among these the NGS analysis was available at the time of abstract submission in 10 pts. No specific genetic feature was identified in responders, only 1 patient had AXL amplification (that represents a potential target of cabozantinib). Of note MET amplification found in 2/25 pts did not correlate with response to cabozantinib. In not responding pts SMAD4 mutation as well as genetic alteration defying a “BRCAness" phenotype were most reported. RNASeq analysis is currently ongoing in 26/33 (78.8%) patient samples. The ABACO study showed clinical activity of cabozantinib in a subset of refractory mCRC, to the date of the analysis no predictive markers were identified so far. Further analysis are ongoing.