Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation

Abstract

In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAF^V600E metastatic colorectal cancer, further augmented by irinotecan. The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAF^V600E-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAF^V600E circulating cell-free DNA (cfDNA) trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression.

Significance: Vemurafenib, in combination with irinotecan and cetuximab, was well tolerated in patients with refractory, BRAF-mutated metastatic colorectal cancer, and both survival outcomes and response rates exceeded prior reports for vemurafenib and for irinotecan plus cetuximab in BRAF^V600E metastatic colorectal cancer. In vivo models demonstrated regressions with the triplet, in contrast with vemurafenib and cetuximab alone. cfDNA predicted radiographic response and identified mutations reactivating the MAPK pathway upon progression. Cancer Discov; 6(12); 1352-65. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1293.

Trial registration: ClinicalTrials.gov NCT01787500.

Figure 1

(A) Waterfall plot characterizing best response to treatment for each patient (B) Spider plot demonstrating response to treatment for each patient over time according to the dose level (C) Doses of treatment for each patient on study according to dose level (D) Kaplan-Meier plot for progression-free survival. Representative sequential imaging of a pretreatment abdominal tumor (E) with subsequent shrinkage upon treatment (F) are also shown.

Figure 2

(A) Changes in BRAF^V600E cfDNA allele fraction from baseline after one dose of treatment for 12 patients with serial samples available, classified according to radiographic responders (blue) or non-responders (black). (B) Percentage change in BRAF^V600E cfDNA fraction versus percent change in radiographic volume of target lesions at the time of first restaging (after 4 doses of treatment), according to radiographic responders (black) or non-responders (red). Representative trends in cfDNA fraction (black) and radiographic changes (red) for patients with radiographic response (C) and progression (D).

Figure 3

(A) Relative changes in mutant allele fractions for various oncogenes implicated in MAPK signaling (red) pre-treatment and post-progression, with superimposed BRAF^V600E cfDNA allele fraction (black). (B) Median nuclear: cytoplasmic ratios for ERK2 and FOXO3a as surrogate measures of MAPK and PI3K/Akt signaling for variants detected in plasma samples from patients at progression. Decreasing nuclear:cytoplasmic ratio for ERK2 and FOXO3a represents decreasing MAPK and increasing PI3K/Akt signaling, respectively.

Figure 4

Xenograft studies using two BRAF^V600E models of mCRC reveal reductions in mean tumor volumes (A, B) and in individual mice (C, D) treated with the triple combination of irinotecan plus vemurafenib and cetuximab relative to mice treated with irinotecan alone or the vemurafenib/cetuximab doublet.

Figure 5

In vitro analyses of two BRAF^V600E cell lines - RKO and B1003, respectively - demonstrated synergism (combination index [CI] < 1) when SN-38 (metabolite of irinotecan; A and B), BYL719 (PI3K inhibitor; C and D), and trametinib (MEK inhibitor; E and F) were all added to vemurafenib and cetuximab.