A phase II study investigating cabozantinib in patients with refractory metastatic colorectal cancer (AGICC 17CRC01).

Abstract

103 Background: Therapeutic resistance to antiangiogenics in metastatic colorectal cancer (mCRC) inevitably develops via multiple mechanisms including upregulation of the MET kinase pathway. Cabozantinib, an oral multityrosine kinase inhibitor targeting MET, AXL, and VEGFR, demonstrated significant anti-tumor activity in CRC xenograft and cell line models. Methods: A single-arm, two-stage phase II study was conducted at 7 AGICC centers nationwide. 44 patients (pts) with mCRC who had progressed on or were intolerant of standard of care agents were treated with cabozantinib 60 mg daily in q3 wk cycles. The primary endpoint was 12-wk PFS rate. Based on the control arm of phase III CORRECT study, the Kaplan-Meier 12-wk PFS rate estimate was 13% and served as the null hypothesis. This study was powered at 0.906 to detect the alternative hypothesis of 12-wk PFS rate of 33% with a type I error rate of 0.044. Secondary endpoints were safety, RR, OS, and retrospective analysis of PFS and RR based on RAS, BRAF, and PIK3CA mutation status. Results: 44 pts were enrolled and 34 pts were response-evaluable as having undergone at least the first 6-wk restaging scan. 10 pts discontinued treatment prior to the first 6-wk scan due to clinical disease progression. Median number of cycles was 4 and median follow-up was 2.5 months. As of data-cutoff 8/23/2019, 55 Grade 3/4 AEs were reported with the most common being hypertension, fatigue, diarrhea, pain, HFS, nausea, vomiting, and proteinuria. 32 SAEs occurred in 18 pts. 5 Grade 5 AEs were reported: disease progression (3), disseminated intravascular coagulopathy, and bowel perforation. 15 pts (34%) achieved ≥ 12-wk PFS and 8 patients remain on treatment. Best response was 1 PR and 31 SD with a DCR at 6 wks of 72.7%. Of the pts who achieved ≥ 12-wk PFS, 12 had left-sided primary tumors, 5 had a RAS mutation, 1 had a PIK3CA mutation, and all pts were BRAF WT and MSI stable. Conclusions: Cabozantinib was deemed safe and demonstrates encouraging efficacy in a heavily pretreated mCRC pt population. These results support further investigation of cabozantinib in mCRC. Clinical trial information: NCT03542877.

Cabozantinib for the treatment of solid tumors: a systematic review

“…In all, 18 phase II studies and one phase I study evaluated patients with various types of tumor. [79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96] In all but one of these studies, 79 the cabozantinib dose was 60 mg. In one study in 50 patients with relapsed or refractory metastatic urothelial carcinoma (mUC), the primary endpoint, ORR (95% CI), was 19% (9-34%).…”

“…One study, in 44 patients with metastatic colorectal cancer, had 12-week PFS rate as the primary endpoint, which was 34%. 92 A retrospective analysis of phase II data measured OS in 108 patients with recurrent glioblastoma, in whom antiangiogenic therapy had not previously failed. After treatment with cabozantinib 100 mg or 140 mg QD, median OS was 11.0 months.…”

Lost in translation: Revisiting the use of tyrosine kinase inhibitors in colorectal cancer

“…Despite encouraging activity of cediranib in a phase I clinical study, it was not further investigated for patients with CRC [25]. Cabozantinib treatment was found to be safe and demonstrated encouraging efficacy as 34% of the heavily pre-treated patients with CRC achieved ≥12 weeks PFS in an ongoing phase II clinical study [26]. Another multi-kinase inhibitor, lenvatinib did not demonstrate cytotoxic but rather cytostatic effect in vitro and gave variable results in vivo [27,28].…”

Tackling Refractory Metastatic Colorectal Cancer: Future Perspectives

“…Apatinib is a highly selective oral inhibitor of VEGFR2 [ 109 ], with a putative activity as a multidrug resistance reverser as well [ 110 ]. A single-arm phase II trial of this compound in Chinese chemorefractory mCRC patients reported a DCR of 69% and a median OS of 9.1 months, with hypertension (13%), hand-foot syndrome (10%), and thrombocytopenia (10%) being the most frequent grade ≥3 AEs.…”