Dual Inhibition Proves Effective for BRAF-Mutated Colorectal Tumors


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In patients with metastatic colorectal cancer who have mutations in BRAF V600, the addition of the BRAF inhibitor vemurafenib (Zelboraf) to cetuximab ­(Erbitux) and irinotecan significantly improved progression-free survival, results of the phase II Southwest Oncology Group (SWOG) 1406 trial have shown.1


The duration of response was higher with the addition of vemurafenib, whereas the two responders in the control arm have a very short duration of response. I think this is the path forward.
— Scott Kopetz, MD

Median progression-free survival was doubled with the addition of the BRAF inhibitor, and response rates quadrupled, indicating that simultaneous inhibition of BRAF and the epidermal growth factor receptor (EGFR) is effective in tumors with mutations in BRAF V600, said lead author Scott Kopetz, MD, of The University of Texas MD Anderson Cancer Center, Houston, who reported the results at the 2017 Gastrointestinal Cancers Symposium.

“BRAF V600 mutations are present in about 7% of all metastatic colorectal cancer tumors. They are associated with an aggressive biology and don’t respond well to standard chemotherapy; therefore, overall survival is short in these patients,” Dr. Kopetz noted.

BRAF-mutated patients are being failed by our current standard-of-care therapies, whether it’s fluorouracil, irinotecan, EGFR inhibitors, or oxaliplatin,” he added. “Novel therapies such as this [experimental] regimen are needed for this rare and aggressive subset of colorectal cancer.”

Scientific Rationale for Triplet

“The BRAF V600 mutation results in constitutive activation of the MAP kinase pathway. Based on important preclinical work, it’s been recognized that when you inhibit the mutated protein, using a BRAF inhibitor, this transiently reduces MAP kinase signaling, but as a result there is feedback activation of EGFR. What was not active protein signaling through the EGFR pathway now becomes active, and this can reactivate the MAP kinase pathway. It’s the dual inhibition, then, of EGFR and BRAF that can shut down this signaling,” Dr. Kopetz explained.

Targeted Therapy for BRAF-Mutated Colorectal Cancer

  • The phase II SWOG 1406 trial evaluated the addition of the BRAF inhibitor vemurafenib to a regimen of cetuximab plus irinotecan in patients with BRAF-mutated metastatic colorectal cancer.
  • The trial met its primary endpoint, improving median progression-free survival from 2.0 months with cetuximab/irinotecan to 4.4 months with the addition of vemurafenib (HR = 0.42, P = .0002).

In murine models of BRAF V600 tumors and in a prior phase IB study, the combination of irinotecan, cetuximab, and vemurafenib showed encouraging antitumor activity, but as a single agent, vemurafenib has shown limited activity, as have cetuximab-based regimens. “This is what set the stage for this study,” he noted.

SWOG 1406 Details

Over 250 institutions were involved in SWOG 1406, but only 106 patients with mutations in BRAF V600 and extended RAS wild-type metastatic colorectal cancer were enrolled. About 50% of patients had received 1 prior regimen, and 40% had received prior irinotecan. Prior treatment with an anti-­EGFR agent was not allowed.

Dr. Kopetz commented that enrollment in SWOG 1406 exceeded the original target, showing that in a cooperative group setting, “rapid enrollment of a biomarker-enriched trial is possible.”

The patients were randomized to receive irinotecan (180 mg/m2 intravenously [IV] every 14 days) and cetuximab (500 mg/m2 IV every 14 days) with or without vemurafenib (960 mg orally twice daily). Crossover from the control arm to the experimental arm was allowed after documented disease progression. The primary endpoint was investigator-assessed progression-free survival.

Outcomes and Toxicity

Median progression-free survival was 4.4 months with the triplet, vs 2.0 months with cetuximab plus irinotecan (hazard ratio [HR] = 0.42, P = .0002). The response rate was 16% vs 4%, and the disease control rate was 67% vs 22% (P = .001).

“The duration of response was higher with the addition of vemurafenib, whereas the two responders in the control arm have a very short duration of response,” revealed Dr. Kopetz.

Grade 3/4 adverse events were significantly higher in the experimental arm and included neutropenia (28% vs 7%), anemia (13% vs 0%), and nausea (15% vs 0%). Arthralgias (a known side effect of vemurafenib) were numerically increased. There was no increase in skin toxicity or fatigue with the addition of vemurafenib. Treatment discontinuation due to adverse events occurred in 18% of the experimental arm and 8% of the control arm.

“Adverse event rates may be attributed to increased duration of exposure and are similar to what’s seen in prior second-line studies of cetuximab and irinotecan,” he added.

Almost 50% of patients in the control arm crossed over at the time of disease progression. Overall survival and efficacy at crossover data remain immature.

Moving Forward

Dr. Kopetz said it is difficult to “tease out” the benefit of EGFR inhibition alone in patients with BRAF mutations, but based on the synergy now observed clinically with dual inhibition, “I think this is the path forward,” he commented. This triplet is but one of several strategies being evaluated in BRAF-mutated patients, he indicated, such as adding a MEK inhibitor into the mix to “deepen the inhibition of the MAP kinase pathway.”

Subgroup analyses will assess the role of irinotecan in this regimen (ie, determine whether prior irinotecan impacts the clinical benefit) and will evaluate outcomes by microsatellite instability (MSI) status, “recognizing that 25% of the BRAF-mutated population in the metastatic setting has MSI-high tumors,” he said.

“Also, as a first for the cooperative group, we have established patient-derived xenografts from baseline biopsies, for future pharmacodynamics studies,” noted Dr. Kopetz. ■

Disclosure: Dr. Kopetz disclosed financial relationships with MolecularMatch, Amgen, Array BioPharma, Bayer, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Merrimack, Oculose, Roche, Sanofi, Sirtex Medical, and Taiho Pharmaceutical.

Reference

1. Kopetz S, McDonough SL, Morris VK, et al: Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). 2017 Gastrointestinal Cancers Symposium. Abstract 520. Presented January 21, 2017.


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