Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406)

Abstract

Purpose: BRAF^V600E mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of BRAF^V600E by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab.

Methods: One hundred six patients with BRAF^V600E-mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily).

Results: Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, P = .001). The response rate was 17% versus 4% (P = .05), with a disease control rate of 65% versus 21% (P < .001). A decline in circulating tumor DNA BRAF^V600E variant allele frequency was seen in 87% versus 0% of patients (P < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype.

Conclusion: Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAF^V600E-mutated CRC.

Trial registration: ClinicalTrials.gov NCT02164916.

FIG 1.

(A) Progression-free survival, (B) overall survival, and (C) progression-free survival in the crossover arm.

FIG 2.

RECIST waterfall plots: (A) cetuximab + irinotecan arm, (B) vemurafenib + cetuximab + irinotecan arm, and (C) crossover arm. The bars on each plot represent the largest decrease under baseline of the sum of longest diameters of all target measurable lesions, or if no decrease was observed, smallest increase in the sum of longest diameters of target measurable lesions. The patient whose increase was greater than 100% over baseline has been truncated at 100% and is represented by a left-slanted bar pattern. Patients whose best response was progression due to new lesions, death (due to disease), or clear worsening of nonmeasurable disease are represented by a bar showing a 100% increase. Patients whose best response could not be determined because of symptomatic deterioration or early death (prior to any follow-up assessments and clearly not due to disease) are represented by a cross-hatched bar showing 100% increase. Patients whose best response could not be determined because of inadequate assessment are represented on the far-left side of the plot with a solid bar showing a 100% increase. Note: two cetuximab + irinotecan and four vemurafenib + cetuximab + irinotecan patients had nonmeasurable disease; six cetuximab + irinotecan arm and seven vemurafenib + cetuximab + irinotecan arm patients with measurable disease at baseline were not represented in these plots because of inadequate assessment during follow-up.

FIG 3.

ctDNA waterfall plots: (A) control arm and (B) experimental arm. This plot only includes patients with baseline and follow-up data where ctDNA alterations were detected (N = 34). Patients with > 100% increase were truncated at 100% (one in vemurafenib + cetuximab + irinotecan and nine in cetuximab + irinotecan cohort). Dark shading reflects patients with confirmed partial responses.

FIG A1.

CONSORT flow diagram. Six patients were deemed ineligible due to: inadequate hematologic function (2), not having BRAF^V600E mutation (3), and receiving chemotherapy within 14 days prior to randomization (1).

FIG A2.

Treatment arm comparisons of progression-free survival in patient subgroups. PIK3CA mutations were limited to known somatic variants.

FIG A3.

Patterns of ctDNA response and resistance in six patients who received vemurafenib + cetuximab + irinotecan. (A,B) Rapid restitution of existing clonal pattern with progression at 4 months. (C,D) Prolonged disease control, with rising BRAF^V600E allele frequency preceding radiologic progression by 2-4 months, (E) Rapid rebound in BRAF^V600E allele frequency followed by slow subsequent increases prior to radiographic progression, (F) Development of a large number of new variants at the time of progression in a patient with MSI-H. These patterns are reflective of the broader population.