SWOG S1406 Finds Vemurafenib Combo With Irinotecan, Cetuximab Effective for BRAF-Mutatant CRC

Simultaneous use of an EGFR plus a BRAF inhibitor combined with irinotecan was found to be effective in BRAF V600E–mutated colorectal cancer (CRC), according to results of the randomized SWOG S1406 trial (NCT02164916).¹

The study, published in the Journal of Clinical Oncology, was led by Scott Kopetz, MD, PhD, of The University of Texas MD Anderson Cancer Center.² Kopetz has tested a variety of combination therapies for BRAF-mutated CRC, including the regimen examined in the BEACON CRC trial (NCT02928224). This phase 3 trial demonstrated that cetuximab (Erbitux) and the BRAF inhibitor encorafenib (Braftovi) significantly shrank tumors and extended survival for this patient population compared with those who received standard treatment.

Kopetz and his colleagues found that those who received the triple combination of irinotecan, cetuximab (Erbitux), and vemurafenib (Zelboraf) in SWOG S1406 experienced better tumor response rates and remained cancer free for longer periods as compared with those being treated with cetuximab and irinotecan alone.

“That 1-2-3 action, that triple threat, shuts off a powerful growth pathway in these cancers,” Kopetz said. “In this trial, unlike in BEACON, we added chemo[therapy] and found that it makes for a more effective way to treat this aggressive form of colorectal cancer.”

SWOG S1406 evaluated the use of irinotecan and cetuximab with or without vemurafenib in patients with BRAF V600E­–mutated metastatic CRC who had been previously treated with 1 or 2 regimens. The study was the first cooperative group study in CRC to prospectively assess a molecular biomarker addressing a small patient subset.

Of note, patients on the control arm were allowed to cross over onto the experimental regimen following documented disease progression if appropriate eligibility criteria were still met.

The primary end point of the study was progression-free survival (PFS) per local evaluation by the investigator and was defined by time from random assignment to disease progression, symptomatic deterioration, or death. Secondary end points included toxicity, overall survival (OS), overall response rate (ORR), and ORR and PFS in patients who crossed over to the experimental regimen after disease progression on the control arm.

Patients remained on treatment until death or 3 years after being randomized, whichever occurred first.

Overall, PFS was found to have improved with the addition of vemurafenib, with medians of 4.2 versus 2.0 months in those treated with or without the BRAF inhibitor, respectively (HR, 0.50; 95% CI, 0.32-0.76; P = .001). In patients who received vemurafenib, the response rate was 17% compared with 4% for those who did not receive vemurafenib (P = .05). Corresponding disease control rates of 65% versus 21% were also observed (P <.001).

Among those who received vemurafenib, a decline in circulating tumor DNA BRAF V600Evariant allele frequency was also observed (87% vs 0% of patients who did not receive vemurafenib; P < .001), with a low incidence of acquired RAS alterations seen at the time of progression.

Moreover, RNA profiling revealed that treatment benefit was not dependent on previously established BRAF subgroups or the consensus molecular subtype.

Regarding safety, treatment with vemurafenib was associated with an increase in grade 3/4 adverse events (AEs), including anemia, neutropenia, and nausea or vomiting. However, the rates of secondary keratoacanthomas was found to be lower than those previously reported in data from single-agent BRAF inhibitor use. Rash was not significantly increased with the combination.

Importantly, previously reported vemurafenib-specific AEs of arthralgia and myalgia were observed, though symptoms were generally manageable with supportive medications and treatment interruptions.

“This [study] 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,” the study authors concluded.

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 Chemo Combo Improves CRC Outcomes. News release. Published December 23, 2020. Accessed January 11, 2021. https://www.swog.org/news-events/news/2020/12/23/triple-chemo-combo-improves-crc-outcomes