Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: BEACON CRC trial findings indicate that patients with metastatic colorectal cancer (CRC) positive for the BRAF V600E mutation may benefit from second- or third-line treatment targeting BRAF, EGFR and MEK.
The study findings were published in The New England Journal of Medicine to coincide with their presentation at the ESMO 2019 Congress in Barcelona, Spain by investigator Josep Tabernero, from Vall d’Hebron University Hospital in Barcelona.
“This initial analysis […] showed that a triplet regimen of encorafenib, binimetinib, and cetuximab or a doublet regimen of encorafenib and cetuximab, as compared with current standard therapy, resulted in a significant and clinically relevant benefit with respect to overall survival and objective response rate”, the authors say.
Prespecified interim analysis after a median follow-up of 7.8 months gave a median overall survival (OS) of 9.0 months for the 224 patients who were randomly assigned to receive open-label treatment with the BRAF inhibitor encorafenib 300 mg/day, the EGFR inhibitor cetuximab at an initial dose of 400 mg/m2 followed by 250 mg/m2 per week, and the MEK inhibitor binimetinib 45 mg twice daily.
This was significantly longer than the median OS of 5.4 months for the 221 patients who instead were given an investigators’ choice of cetuximab plus irinotecan alone or alongside folinic aid and fluorouracil, giving a hazard ratio (HR) for death of 0.52.
Doublet therapy with encorafenib and cetuximab in 220 participants also significantly improved OS compared with cetuximab plus chemotherapy, with a median duration of 8.4 months and a HR for death of 0.60.
The researchers explain that “[t]he trial was not powered to compare the two experimental groups directly, and such a comparison is further limited by the interim nature of this analysis.”
Nevertheless, they observe that the OS showed a trend that favoured use of the triplet over the doublet regimen with a HR of 0.79, and this was also reflected in a waterfall plot detailing change in the target lesions size.
Progression-free survival was also significantly better in both the triplet and doublet therapy groups compared with the control arm (HR=0.38 and 0.40, respectively), as were the objective response rates, at 26% and 20% versus 2%.
The team reports that grade 3 and more severe adverse events occurred in a comparable 58% of the triplet therapy, 50% of the doublet therapy and 61% of the control groups, despite treatment lasting a median of 21, 9 and 7 weeks in these groups, respectively.
Noting that patients given encorafenib plus cetuximab experienced more headache, musculoskeletal pain, arthralgia and myalgia than those who were also given binimetinib, the researchers comment that this finding “is consistent with the ability of MEK inhibition to mitigate some toxic effects associated with BRAF inhibition”.
Josep Tabernero et al conclude: “The side-effect profiles of both combination regimens allowed maintenance of high dose intensity for the majority of patients and are consistent with the known profile of each agent.
“Further follow-up is needed to better define the relative benefits of the triplet and doublet regimens.”
References
Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med; Advance online publication 30 September 2019. DOI: 10.1056/NEJMoa1908075
Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E–mutant metastatic colorectal cancer: Expanded results from a randomized, 3-arm, phase III study vs the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). ESMO 2019 Congress; Barcelona, Spain: 27 September–1 October. LBA32
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