Vemurafenib Plus Cetuximab/Irinotecan Improves PFS in BRAF-Mutant Metastatic CRC

Scott Kopetz, MD, PhD

The addition of vemurafenib (Zelboraf) to irinotecan (Onivyde) and cetuximab (Erbitux) led to a significant improvement in progression-free survival (PFS) versus irinotecan and cetuximab alone in patients with BRAF V600E–mutated metastatic colorectal cancer (CRC), according to the results of the SWOG S1406 study published in the Journal of Clinical Oncology.¹

Specifically, the triplet regimen reduced the risk of disease progression or death by 50% in this patient population (HR, 0.50; 95% CI, 0.32-0.76; P = .001). The median PFS was 4.2 months with the triplet versus 2.0 months with the doublet. Moreover, 80% of patients in the experimental arm had not progressed at week 9 compared with 39% of those in the control arm.

The triplet regimen also elicited a higher response rate compared with the doublet regimen, at 17% and 4%, respectively (P = .05). The disease control rates in the experimental and control arms were 65% and 21%, respectively.

Forty-two percent of the patients on the control arm (n = 21) crossed over to receive vemurafenib, irinotecan, and cetuximab following disease progression. No significant difference in overall survival (OS) benefit was observed between the 2 treatment arms (HR, 0.77; 95% CI, 0.50-1.18; P = .23). Following crossover, the median PFS was 5.4 months in the cohort, with a response rate of 19% and a disease control rate of 76%.

"That 1-2-3 action, that triple threat, shuts off a powerful growth pathway in these cancers," Scott Kopetz, MD, PhD, lead author of the study and a physician-scientist at the University of Texas MD Anderson Cancer Center, stated in a press release.² "In this trial, unlike in BEACON, we added chemotherapy and found that it makes for a more effective way to treat this aggressive form of CRC."

Preclinical and coclinical data have suggested that irinotecan may be able to augment the activity of BRAF and EGFR inhibitors, comparable to the clinical benefit observed in patients with KRAS wild-type tumors who were treated with an EGFR inhibitor plus irinotecan.

These early findings led to a phase 1b study of vemurafenib, cetuximab, and irinotecan, in which the triplet demonstrated a response rate of 35%, as well as a promising PFS benefit. Based on these early data, the SWOG 1406 trial was launched.

To be eligible for enrollment, patients needed to have been diagnosed with histologically or cytologically confirmed metastatic or locally advanced or unresectable, BRAF V600E adenocarcinoma of the colon or rectum; their tumors could not harbor NRAS or KRAS mutations.

Additionally, those with brain metastases permitted for inclusion if they had received acceptable treatment with radiotherapy or surgery and achieved stability at least 90 days prior to step 1 initial registration. Patients were able to undergo 1 to 2 prior lines of therapy with chemotherapy for metastatic disease prior to enrollment, but previous treatment with EGFR, BRAF, or MEK inhibitors was not permitted. A Zubrod performance status of 0-1 was also required for participation.

In the open-label phase 2 study, patients were randomized 1:1 to receive either the triplet or doublet regimen. Patients were stratified based on whether they had previously undergone treatment with irinotecan. Both cohorts were administered 180 mg/m2 of irinotecan and 500 mg/m2 of cetuximab intravenously every 2 weeks. Patients who received the triplet regimen also received a 960 mg dose of oral vemurafenib.

The primary end point of the study was PFS per local evaluation by the investigator. Key secondary outcomes of interest included toxicity, OS, overall response rate (ORR), as well as ORR and PFS in patients who crossed over from the doublet arm to the triplet arm after experiencing disease progression. Patients who enrolled on the study were observed for 3 years after randomization or until death, whichever occurred first.

The median age in the experimental and control cohorts was 59.7 years and 61.9 years, respectively. In the control arm, 38% of patients had previously undergone treatment with irinotecan and 52% had received prior adjuvant chemotherapy; these rates were 42% and 50%, respectively. Fifty percent versus 54% of those in the control and investigational arms, respectively, had received 1 previous line of chemotherapy for advanced or metastatic disease; 34% and 40% of patients, respectively, had received 2 prior lines.

Seventeen percent of patients harbored PIK3CA mutations (n = 11/66), which were found to be associated with a numeric improvement in PFS (HR, 0.3) versus the PFS benefit in those with wild-type mutations (HR, 0.6); however, investigators noted that the study's sample size precludes definitive conclusions. Additionally, patients were able to achieve clinical benefit regardless of microsatellite instability–high status, which 18% of patients had (n = 13/72). Treatment outcomes were not significantly impacted by prior treatment with irinotecan or tumor location.

Additionally, circulating tumor DNA (ctDNA) was evaluable in 69 patients, with 61 samples testing positive for BRAF V600E mutations at a median variant allele fraction (VAF) of 5.0% (range, 0.06%-49.6%) and a sensitivity of 88% (95% CI, 78%-95%).

“Serial ctDNA testing of BRAF V600E has been previously validated as a sensitive marker of treatment response,” the authors of the study wrote. “In patients with at least 2 ctDNA time points, 87% demonstrated a reduction in VAF of BRAF V600E in the experimental arm, whereas no patients in the control arm demonstrated reduction in ctDNA levels [P = .001].”

Regarding safety, grade 3 and 4 adverse effects were more frequently reported in the triplet arm compared with the doublet arm; these toxicities included neutropenia (30% vs 7%, respectively), anemia (13% vs 0%, respectively), and nausea (19% vs 2%, respectively). In the triplet arm, 22% of patients (n = 11/50) discontinued treatment due to AEs versus 8% in the doublet arm (n = 4/50).

“The addition of vemurafenib to cetuximab and irinotecan represents an active combination that improves PFS,” the authors concluded. “This represents a rationally designed study building on a foundation of understanding of the mechanisms of adaptive resistance in CRC and provides insights for further combination studies in the CRC field in the future.”

References

1. Kopetz S, Guthrie KA, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). J Clin Oncol. Published online December 23, 2020. doi:10.1200/JCO.20.01994
2. Triple chemotherapy combination improves metastatic colorectal cancer outcomes. News release. Medical Xpress. December 24, 2020. Accessed January 4, 2021. http://bit.ly/2X8dpKe