Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer

Abstract

Purpose: Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab.Experimental Design: We performed a phase IB/II study of 77 patients with previously treated mCRC. Primary objectives were to determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacodynamics, and efficacy. Using a 3 + 3 design, patients received FOLFOX6 with cetuximab and escalating doses of dasatinib (100, 150, 200 mg daily), followed by a 12-patient expansion cohort at 150 mg. Phase II studies evaluated FOLFOX plus dasatinib 100 mg in KRAS c12/13^mut patients or in combination with cetuximab if KRAS c12/13^WT FAK and paxillin were utilized as surrogate blood biomarkers of Src inhibition, and paired biopsies of liver metastases were obtained in patients in the expansion cohort.Results: In phase IB, the DLTs were grade 3/4 fatigue (20%) and neutropenia (23%). In phase II, grade 3/4 fatigue (23%) and pleural effusions (11%) were present. Response rates were 20% (6 of 30) in the phase IB escalation and expansion cohort and 13% (3 of 24) and 0% (0 of 23) in the KRAS c12/13^WT and mutant cohorts of phase II, respectively. Median progression-free survival was 4.6, 2.3, and 2.3 months, respectively. There was no evidence of Src inhibition based on surrogate blood biomarkers or paired tumor biopsies.Conclusions: The combination of dasatinib plus FOLFOX with or without cetuximab showed only modest clinical activity in refractory colorectal cancer. This appears to be primarily due to a failure to fully inhibit Src at the achievable doses of dasatinib. The combination of dasatinib plus FOLFOX with or without cetuximab did not show meaningful clinical activity in refractory colorectal cancer due to failure to fully inhibit Src. Clin Cancer Res; 23(15); 4146-54. ©2017 AACR.

Figure 1

Clinical efficacy of the FOLFOX + cetuximab + dasatinib treatment. A) Waterfall plot of best response for the regimen in the Phase IB study demonstrates 6 patients with a RECIST response. An additional 7 patients had tumor regression that did not meet RECIST criteria for response. Patients with progressive disease noted by new lesions are listed as +30% growth. B) Waterfall plot of patients in the Phase II study treated with dasatinib, FOLFOX, with or without cetuximab, measuring the maximum change from baseline in the sum of the longest diameter for target lesions.

Figure 2

A) Progression free survival of patients treated on the FOLFOX, cetuximab and dasatinib study, with 95% confidence intervals shown. Median PFS was 4.6 months (95% confidence interval of 3.0 to 5.5 months). B) Time to treatment failure on study drugs. All censored patients in both treatment arms were assumed to have had an event at the date of censoring. C) The ratio of time to treatment failure on study regimen to time to treatment failure on prior regimen, assessed logarithmically in all patients. D) Kaplan-Meier curve of overall survival calculated as time from trial initiation to time of death, stratified by tumor KRAS mutational status.

Figure 3

Quantification of pPaxillin [Y118] from PBMCs of patients treated on the FOLFOX + cetuximab + dasatinib clinical trial. Samples were collected at baseline and after 3 weeks of therapy (at day 8 of cycle 2). A) pPaxillin [Y118] was increased after 3 weeks on treatment. # paired t-test for fold change by densitometry. B) No difference is seen in the induction of pPaxillin by cohort. C) There is no correlation between change in pPaxillin and response to therapy, nor time to progression (TTP) (Figure D). Short and long TTP was defined as less than 4 months and greater than or equal to 4 months, respectively (approximately the median TTP).

Figure 4

In patients with evaluable paired biopsies in the expansion cohort semi-quantitative grading of total Src and phospho-Src [Y418] staining was performed. Each line represents an individual patient. There was a statistically significant increase in total Src staining after 3 weeks of treatment (P = 0.049). There was no change in phospho-Src staining (P = 0.3).