Phase Ib/II study of ibrutinib (ibr) in combination with cetuximab (cetux) in patients (pts) with previously treated metastatic colorectal cancer (mCRC)

Abstract

Background: Third- or later-line treatments for mCRC have low response rates (1e 37%) and limited PFS (1.4e5.6 mo) and OS (6.1e14.0 mo) (Arnold Ann Oncol 2018). Ibr is a once-daily Bruton’s tyrosine kinase (BTK) inhibitor approved for the treatment of various B-cell malignancies. Ibr also inhibits other kinases, including ETK, ITK, and EGFR tyrosine kinase (Wang Clin Cancer Res 2018; Dubovsky Blood 2013; Gao J Natl Cancer Inst 2014), and may provide complementary activity with cetux. Dual targeting of EGFR may improve OS in mCRC (Weickhardt J Clin Oncol 2012). This cohort of the phase Ib/II study (NCT02599324) evaluated efficacy and safety of ibr + cetux in pts with mCRC. Methods: Eligible pts had KRAS or NRAS wild type mCRC previously treated with 2e4 regimens and were cetux-naive. Pts received oral ibr once daily at 560 mg (starting dose) or 840 mg (recommended phase II dose) plus IV cetux (400 mg/m2 initial dosethen 250 mg/m2 weekly) in 21-d cycles until unacceptable toxicity or progression. Efficacy (overall response rate [ORR], PFS, duration of response [DOR], disease control rate [DCR], and OS) and safety are reported. Results: 58 pts received ibr + cetux (ibr 560 mg, n¼8; ibr 840 mg, n¼50). Median age was 62 y; 38%, 40%, and 22% of pts had received 2, 3, and 4 prior regimens for mCRC, respectively. Median follow-up was 20.9 mo. ORR was 16% (Table). Median PFS was 4.8 mo (range 3.9e5.6). Median treatment duration was 3.2 mo for ibr and 3.0 mo for cetux. Grade 3 adverse events (AEs) occurred in 41 pts (71%); the only grade 3 AE occurring in 10% of pts was dermatitis acneiform (15 pts [26%]). Two pts (3%) had AEs leading to death; neither were related to study drug. Two pts (3%) had major hemorrhage and 53 pts (91%) had rash of any grade (grade 3 in 17 pts [29%]). Conclusions: Ibr + cetux was moderately active in heavily pretreated, refractory, cetux-naive pts with mCRC. There were no new safety signals and the safety profile was consistent with those of the individual drugs.