Focus on combination therapies

Triple for colorectal cancer – for the first time, studies have shown clear superiority of a triple combination of encorafenib, binimetinib and cetuximab in progressive metastatic colorectal tumors.

Patients with metastatic colorectal cancer harboring a BRAF mutation represent a major challenge for treating physicians. The results of the BEACON CRC Phase III trial raise hope that a better objective response can be achieved in the future. A combination of encorafenib, binimetinib, and cetuximab significantly improved overall survival in affected individuals. The therapy was built on the basis of the growing understanding regarding the activation of cancer genes such as BRAF. Since tumor cells adapt by other mechanisms after initial treatment, the triple combination may have a broader spectrum of activity. Accordingly, the scientists advocate routine testing for ^BRAFV600E mutations.

Another advantage of the new treatment regimen is that it can be administered without combining it with chemotherapy. This saves the typical side effects that often make life difficult for patients. Currently, however, targeted therapy should still be reserved for the patient group treated in the study – advanced disease, despite one or two prior chemotherapies – until its use in other indications has been investigated. However, in the long term, experts also see an opportunity for patients with BRAF mutations in the adjuvant setting after primary surgery with curative intent.

Significant survival advantage due to triple combination

BRAFV600E mutations are detected in up to 15% of patients with metastatic colorectal cancer (mCRC) and result in a poor prognosis. In patients who do not respond to initial therapy, objective response rates (ORR) to standard chemotherapy and biologic combinations are generally less than 10%, with median progression-free survival (PFS) and overall survival (OS) of approximately 2 and 4-6 months, respectively.

We studied 665 patients with ^{BRAFV600E-mutant} colorectal cancer that had progressed after one or two previous treatment regimens. Randomized 1:1:1, they received either a triple combination of encorafenib, binimetinib, and cetuximab; dual therapy with encorafenib and cetuximab; or investigator’s choice of irinotecan or folic acid, fluorouracil, and irinotecan (FOLFIRI) and cetuximab. Median overall survival was 9 months for the triple combination compared with 5.4 months for the standard therapy group (HR 0.52; 95% Cl: 0.39, 0.7, p<0.0001). For doublet therapy, it was 8.4 vs. 5.4 months versus control (HR: 0.60; 95% CI: 0.45-0.79; p=0.0003). Overall, the treatment was well tolerated.

Subgroup analyses confirmed the superiority of triplet therapy compared with the control arm for all subgroups studied. Analysis of the first 331 randomized trial participants showed a response rate of 34% with triplet therapy for patients with only one prior line of therapy (doublet: 22%; control: 2%), but only 14% for patients with more than one prior therapy (doublet: 16%; control: 2%).

In terms of progression-free survival, a significant benefit of triple combination therapy was also seen. On median, patients on triplet therapy lived 4.3 months, on doublet therapy 4.2 months, and in the control arm 1.5 months without progression (HR: 0.38; 95% CI: 0.29-0.49 and HR: 0.40; 95% CI: 0.31-0.52, respectively; p<0.0001).

The combination of encorafenib, binimetinib, and cetuximab improved overall survival in patients with mCRC and BRAFV600E mutation compared with the current standard of care chemotherapy. The safety profile is consistent with the known profile of each agent. Chemotherapy-free targeted therapy should become the new standard of care for prospectively biomarker-selected patients based on the results presented.

Source:^21st World Congress on Gastrointestinal Cancer (WCGC)