Colorectal cancer (CRC) is the third most common cancer globally, with nearly two million new incident cases being diagnosed and 900,000 deaths associated with the disease every year. Of these global cases, 10% will have a BRAF V600E gene mutation implicated in carcinogenesis pathways and have a poor prognosis compared to other subtypes of CRC, such as KRAS mutations. Standard-of-care (SOC) chemotherapy options such as fluorouracil-oxaliplatin-folinic acid (FOLFOX) yield poor overall survival (OS) at 11.0 months for these patients.
Pfizer’s Braftovi (encorafenib) has received accelerated FDA approval for the treatment of BRAF V600E-mutated metastatic CRC patients due to its strong clinical benefits in an area of unmet need. The BREAKWATER clinical trial published clinical data earlier this year, detailing the efficacy of Braftovi in combination with cetuximab and mFOLFOX6 (Braftovi and cetuximab [EC] + FOLFOX6) compared to SOC alone, either FOLFOX6 or FOLFOXIRI, as a first-line treatment for BRAF-mutated metastatic CRC. A total of 474 patients were assigned to the EC group. The results confirmed that Braftovi + cetuximab + FOLFOX6 (EC + FOLFOX6) triplet therapy significantly improved confirmed objective response rates (cORR) compared with SOC alone (60.9% versus 40.0%; p=0.0008). A further subgroup analysis demonstrated that this response rate was more pronounced in patients younger than 65 years of age. While the data has not yet fully matured, the interim OS analysis shows a positive trend with EC + FOLFOX6 versus SOC (79.5% versus 66.1% at 12 months).
The safety data showed that grade 3/4 treatment-related adverse events were more common in the EC + FOLFOX6 arm compared to the SOC arm (69.7% versus 53.9%). Neurotoxicity was a serious grade 3/4 adverse event that was common in the EC + FOLFOX6 arm (11%) but was not present in the SOC arm. This adverse event is related to an increased incidence of delirium, seizures, and cerebral oedema, which can be fatal.
With Braftovi’s annual cost of therapy (ACOT) amounting to $110,000 in the US, this combination is unlikely to become the new SOC for BRAF-positive metastatic colorectal cancer (mCRC) patients older than 65 years. The response rate did not reach statistical significance in this age group, as demonstrated by the subgroup analysis of the BREAKWATER trial. The triplet combination of Pfizer’s Mektovi (binimetinib) + Braftovi + cetuximab (MEC) is also under investigation for these patients. The MEC combination has shown a cORR of 47.4% in untreated BRAF-mutant mCRC patients in the ANCHOR CRC Phase II trial, with seemingly less response with a comparable safety profile when judged against the results of EC + FOLFOX6 in the BREAKWATER study. The EC + FOLFOX6 combination will likely become the first-line treatment of choice for BRAF-mutant mCRC patients younger than age 65 years. The educed cost of this regimen (approximate ACOT of $64,000) compared to the MEC combination and its significant clinical benefit will establish it as a dominant therapy in this patient segment.
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By GlobalData