Meeting News

Triplet therapy extends survival in BRAF V600E-mutant metastatic colorectal cancer

Scott Kopetz, MD, PhD
Scott Kopetz

A combination of encorafenib, binimetinib and cetuxumab significantly improved OS and overall response rate compared with standard-of-care chemotherapy among patients with BRAF V600E-mutant metastatic colorectal cancer, according to findings from the randomized phase 3 BEACON CRC study presented at ESMO World Congress on Gastrointestinal Cancer.

The triplet therapy also exhibited a safety profile concordant with the known safety profiles of each individual agent.

One in seven patients with metastatic colorectal cancer has a BRAF mutation. According to the researchers, the study findings suggest that the three-drug combination should replace chemotherapy as standard of care for these patients.

“These are very exciting results, because we’ve been trying to target BRAF-mutant colorectal cancer for many years,” Scott Kopetz, MD, PhD, associate professor in the department of gastrointestinal medical oncology in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, said in a press release. “Colorectal cancer does not respond to BRAF therapy alone because tumor cells adapt through other mechanisms after initial treatment. With this triple targeted therapy, we are using a very scientifically logical combination to inhibit BRAF and these other mechanisms.”

In a lead-in to the multicenter, open-label, phase 3 BEACON CRC study, the triplet showed acceptable safety and promising activity among 30 patients with BRAF V600E-mutant metastatic colorectal cancer who failed one or two previous regimens.

The randomized portion of the study included 665 such patients assigned to one of the following: encorafenib (Bravtofi, Array Pharmaceuticals), cetuximab (Erbitux, Bristol-Myers Squibb) and binimetinib (Mektovi, Array Pharmaceuticals; n = 224); a doublet combination of encorafenib and cetuximab (n = 220); or a control regimen consisting of investigator’s choice of either irinotecan or FOLFIRI plus cetuximab (n = 221).

OS and ORR comparing the triplet group with the control group, determined by blinded central review, served as the study’s primary endpoints. OS for the doublet group vs. the control group, as well as PFS, duration of response and safety, served as secondary endpoints.

Patients on the triplet regimen achieved median OS of 9 months (95% CI, 8-11.4) compared with 5.4 months (95% CI, 4.8-6.6) for the control group (HR = 0.52; 95% CI, 0.39-0.7).

Patients assigned the doublet combination achieved median OS of 8.4 months (95% CI, 7.5-11), also significantly longer than that of the control group (HR = 0.6; 95% CI, 0.45-0.79).

ORR was 26% (95% CI, 18-35) with the triplet therapy vs. 2% (95% CI, 0-7) with the control regimen.

Future analyses will investigate the potential benefits of the triplet vs. doublet combinations, according to researchers.

The targeted therapies appeared well-tolerated, with adverse events consistent with those observed in previous trials with each combination. Grade 3 or higher adverse events occurred among 58% of patients in the triplet group, 50% in the doublet group and 61% in the control group.

The findings underscore the need for patients with metastatic colorectal cancer to be tested for BRAF mutations, according to Andrés Cervantes, MD, PhD, of the biomedical research institute INCLIVA at University of Valencia in Spain.

“We now have a specific treatment that can change the natural course of the disease in patients with BRAF mutations and is better than previous therapy, so it is essential that patients are routinely tested,” Cervantes, who was not involved with the study, said in the press release.

Cervantes said these findings ultimately may have broader implications for patients with BRAF mutations.

“At present, targeted therapy should probably be limited to the patient group treated in the BEACON CRC trial who had progressed after one or two previous lines of chemotherapy,” he said in the release. “However, it is important that we investigate its use in other settings where more patients with BRAF mutations may benefit, including those with less advanced metastatic disease and possibly in the adjuvant setting after primary surgery with curative intent.” – by Jennifer Byrne

Reference:

Kopetz S, et al. Abstract LBA-006. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain.

Disclosures: HemOnc Today could not confirm the authors’ relevant financial disclosures at the time of publication.

Photo credit: European Society of Medical Oncology.

Scott Kopetz, MD, PhD
Scott Kopetz

A combination of encorafenib, binimetinib and cetuxumab significantly improved OS and overall response rate compared with standard-of-care chemotherapy among patients with BRAF V600E-mutant metastatic colorectal cancer, according to findings from the randomized phase 3 BEACON CRC study presented at ESMO World Congress on Gastrointestinal Cancer.

The triplet therapy also exhibited a safety profile concordant with the known safety profiles of each individual agent.

One in seven patients with metastatic colorectal cancer has a BRAF mutation. According to the researchers, the study findings suggest that the three-drug combination should replace chemotherapy as standard of care for these patients.

“These are very exciting results, because we’ve been trying to target BRAF-mutant colorectal cancer for many years,” Scott Kopetz, MD, PhD, associate professor in the department of gastrointestinal medical oncology in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, said in a press release. “Colorectal cancer does not respond to BRAF therapy alone because tumor cells adapt through other mechanisms after initial treatment. With this triple targeted therapy, we are using a very scientifically logical combination to inhibit BRAF and these other mechanisms.”

In a lead-in to the multicenter, open-label, phase 3 BEACON CRC study, the triplet showed acceptable safety and promising activity among 30 patients with BRAF V600E-mutant metastatic colorectal cancer who failed one or two previous regimens.

The randomized portion of the study included 665 such patients assigned to one of the following: encorafenib (Bravtofi, Array Pharmaceuticals), cetuximab (Erbitux, Bristol-Myers Squibb) and binimetinib (Mektovi, Array Pharmaceuticals; n = 224); a doublet combination of encorafenib and cetuximab (n = 220); or a control regimen consisting of investigator’s choice of either irinotecan or FOLFIRI plus cetuximab (n = 221).

OS and ORR comparing the triplet group with the control group, determined by blinded central review, served as the study’s primary endpoints. OS for the doublet group vs. the control group, as well as PFS, duration of response and safety, served as secondary endpoints.

Patients on the triplet regimen achieved median OS of 9 months (95% CI, 8-11.4) compared with 5.4 months (95% CI, 4.8-6.6) for the control group (HR = 0.52; 95% CI, 0.39-0.7).

Patients assigned the doublet combination achieved median OS of 8.4 months (95% CI, 7.5-11), also significantly longer than that of the control group (HR = 0.6; 95% CI, 0.45-0.79).

ORR was 26% (95% CI, 18-35) with the triplet therapy vs. 2% (95% CI, 0-7) with the control regimen.

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Future analyses will investigate the potential benefits of the triplet vs. doublet combinations, according to researchers.

The targeted therapies appeared well-tolerated, with adverse events consistent with those observed in previous trials with each combination. Grade 3 or higher adverse events occurred among 58% of patients in the triplet group, 50% in the doublet group and 61% in the control group.

The findings underscore the need for patients with metastatic colorectal cancer to be tested for BRAF mutations, according to Andrés Cervantes, MD, PhD, of the biomedical research institute INCLIVA at University of Valencia in Spain.

“We now have a specific treatment that can change the natural course of the disease in patients with BRAF mutations and is better than previous therapy, so it is essential that patients are routinely tested,” Cervantes, who was not involved with the study, said in the press release.

Cervantes said these findings ultimately may have broader implications for patients with BRAF mutations.

“At present, targeted therapy should probably be limited to the patient group treated in the BEACON CRC trial who had progressed after one or two previous lines of chemotherapy,” he said in the release. “However, it is important that we investigate its use in other settings where more patients with BRAF mutations may benefit, including those with less advanced metastatic disease and possibly in the adjuvant setting after primary surgery with curative intent.” – by Jennifer Byrne

Reference:

Kopetz S, et al. Abstract LBA-006. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain.

Disclosures: HemOnc Today could not confirm the authors’ relevant financial disclosures at the time of publication.

Photo credit: European Society of Medical Oncology.