A New First-Line Option in BRAF-Mutant Metastatic CRC?

The targeted therapy combination of encorafenib and cetuximab with FOLFIRI (leucovorin/5-fluorouracil [FU]/irinotecan) chemotherapy may be a new first-line option for patients with BRAF V600E-mutant metastatic colorectal cancer (CRC), according to new results from the BREAKWATER trial.

After a median follow-up of about 10 months, response rates were significantly better with encorafenib and cetuximab plus FOLFIRI than with FOLFIRI alone — without increasing side effects.

The findings, presented at the ASCO Gastrointestinal Cancers Symposium 2026, point to a potential new option for the 20%-25% of patients with BRAF V600E-mutant metastatic CRC who receive FOLFIRI as their chemotherapy.

Based on previous results from BREAKWATER, the FDA granted accelerated approval to first-line encorafenib (Braftovi) and cetuximab (Erbitux) plus mFOLFOX6 for this patient population. That regimen doubled median overall survival compared with standard chemotherapy with or without bevacizumab.

Cohort 3 of BREAKWATER was designed to address a specific question: Are the benefits with the targeted therapy duo a “FOLFOX-specific phenomenon?” lead investigator Scott Kopetz, MD, PhD, of MD Anderson Cancer Center, Houston, said during a press briefing.

Based on these early results, the answer is no. Instead, Kopetz said, there appears to be a “broader synergy” between the targeted therapies and cytotoxic chemotherapy.

Joel Saltzman, MD, ASCO expert in gastrointestinal cancers based at Taussig Cancer Center, Cleveland Clinic in Cleveland, agreed.

“The additional data from the BREAKWATER trial reveals that it is the targeted therapy backbone that provides the better disease control and response rate in BRAF V600E-mutant colorectal cancers,” he said.

BRAF V600E mutations occur in up to 12% of patients with metastatic CRC and are associated with poor outcomes. While many newly diagnosed patients receive FOLFOX (leucovorin/5-FU/oxaliplatin) in the first line, FOLFIRI is a common alternative — often due to concerns about oxaliplatin-associated peripheral neuropathy, Kopetz noted.

The safety lead-in portion of BREAKWATER showed that encorafenib and cetuximab plus FOLFIRI were tolerable and had promising antitumor activity.

Cohort 3 of the trial included 147 patients (mean age, 62 years; 46% male) with BRAF V600E-mutant metastatic CRC, no prior systemic treatment, and good performance status (Eastern Cooperative Oncology Group PS 0 or 1); 73 patients were randomly allocated to encorafenib and cetuximab plus FOLFIRI and 74 to FOLFIRI with or without bevacizumab. The primary endpoint was objective response rate assessed by blinded independent central review.

After a median follow-up of 10 months, patients in the targeted therapy group had an objective response rate of 64.4% vs 39.2% among patients who received FOLFIRI alone or with bevacizumab (odds ratio, 2.76; P = .001).

Responses to the targeted therapies were “rapid and durable,” Kopetz said. More than half (57.4%) of patients treated with encorafenib and cetuximab and FOLFIRI had a duration of response of 6 months or longer than 34.5% in the control group.

Data on overall survival, a secondary endpoint, were not yet mature, but there was a trend toward improved survival with targeted therapy.

Importantly, Kopetz reported, there were no new safety signals, and serious treatment-emergent adverse events occurred at a similar rate in both treatment groups: 39.4% in the targeted therapy group and 36.8% in the control group.

The most common adverse events in both groups included nausea, diarrhea, vomiting, fatigue, appetite loss, and alopecia. About 10% of patients in the targeted therapy group and 9% of those in the control group discontinued their treatment early, suggesting the severity of side effects was similar between the groups.

Kopetz cautioned that the data are still early and follow-up is ongoing. However, he said, the findings support the targeted drugs plus FOLFIRI as a “potential new standard of care” for this patient population.

“The addition of FOLFIRI chemotherapy in the frontline setting will give oncologists and patients more options when selecting a first-line regimen,” Saltzman said. “To have as many options as possible is certainly something we all hope for.”

The trial was funded by Pfizer. Kopetz reported consulting for Pfizer and several other pharmaceutical companies. Saltzman reported having no disclosures.

A version of this article first appeared on Medscape.com.

The targeted therapy combination of encorafenib and cetuximab with FOLFIRI (leucovorin/5-fluorouracil [FU]/irinotecan) chemotherapy may be a new first-line option for patients with BRAF V600E-mutant metastatic colorectal cancer (CRC), according to new results from the BREAKWATER trial.

After a median follow-up of about 10 months, response rates were significantly better with encorafenib and cetuximab plus FOLFIRI than with FOLFIRI alone — without increasing side effects.

The findings, presented at the ASCO Gastrointestinal Cancers Symposium 2026, point to a potential new option for the 20%-25% of patients with BRAF V600E-mutant metastatic CRC who receive FOLFIRI as their chemotherapy.

Based on previous results from BREAKWATER, the FDA granted accelerated approval to first-line encorafenib (Braftovi) and cetuximab (Erbitux) plus mFOLFOX6 for this patient population. That regimen doubled median overall survival compared with standard chemotherapy with or without bevacizumab.

Cohort 3 of BREAKWATER was designed to address a specific question: Are the benefits with the targeted therapy duo a “FOLFOX-specific phenomenon?” lead investigator Scott Kopetz, MD, PhD, of MD Anderson Cancer Center, Houston, said during a press briefing.

Based on these early results, the answer is no. Instead, Kopetz said, there appears to be a “broader synergy” between the targeted therapies and cytotoxic chemotherapy.

Joel Saltzman, MD, ASCO expert in gastrointestinal cancers based at Taussig Cancer Center, Cleveland Clinic in Cleveland, agreed.

“The additional data from the BREAKWATER trial reveals that it is the targeted therapy backbone that provides the better disease control and response rate in BRAF V600E-mutant colorectal cancers,” he said.

BRAF V600E mutations occur in up to 12% of patients with metastatic CRC and are associated with poor outcomes. While many newly diagnosed patients receive FOLFOX (leucovorin/5-FU/oxaliplatin) in the first line, FOLFIRI is a common alternative — often due to concerns about oxaliplatin-associated peripheral neuropathy, Kopetz noted.

The safety lead-in portion of BREAKWATER showed that encorafenib and cetuximab plus FOLFIRI were tolerable and had promising antitumor activity.

Cohort 3 of the trial included 147 patients (mean age, 62 years; 46% male) with BRAF V600E-mutant metastatic CRC, no prior systemic treatment, and good performance status (Eastern Cooperative Oncology Group PS 0 or 1); 73 patients were randomly allocated to encorafenib and cetuximab plus FOLFIRI and 74 to FOLFIRI with or without bevacizumab. The primary endpoint was objective response rate assessed by blinded independent central review.

After a median follow-up of 10 months, patients in the targeted therapy group had an objective response rate of 64.4% vs 39.2% among patients who received FOLFIRI alone or with bevacizumab (odds ratio, 2.76; P = .001).

Responses to the targeted therapies were “rapid and durable,” Kopetz said. More than half (57.4%) of patients treated with encorafenib and cetuximab and FOLFIRI had a duration of response of 6 months or longer than 34.5% in the control group.

Data on overall survival, a secondary endpoint, were not yet mature, but there was a trend toward improved survival with targeted therapy.

Importantly, Kopetz reported, there were no new safety signals, and serious treatment-emergent adverse events occurred at a similar rate in both treatment groups: 39.4% in the targeted therapy group and 36.8% in the control group.

The most common adverse events in both groups included nausea, diarrhea, vomiting, fatigue, appetite loss, and alopecia. About 10% of patients in the targeted therapy group and 9% of those in the control group discontinued their treatment early, suggesting the severity of side effects was similar between the groups.

Kopetz cautioned that the data are still early and follow-up is ongoing. However, he said, the findings support the targeted drugs plus FOLFIRI as a “potential new standard of care” for this patient population.

“The addition of FOLFIRI chemotherapy in the frontline setting will give oncologists and patients more options when selecting a first-line regimen,” Saltzman said. “To have as many options as possible is certainly something we all hope for.”

The trial was funded by Pfizer. Kopetz reported consulting for Pfizer and several other pharmaceutical companies. Saltzman reported having no disclosures.

A version of this article first appeared on Medscape.com.

The targeted therapy combination of encorafenib and cetuximab with FOLFIRI (leucovorin/5-fluorouracil [FU]/irinotecan) chemotherapy may be a new first-line option for patients with BRAF V600E-mutant metastatic colorectal cancer (CRC), according to new results from the BREAKWATER trial.

After a median follow-up of about 10 months, response rates were significantly better with encorafenib and cetuximab plus FOLFIRI than with FOLFIRI alone — without increasing side effects.

The findings, presented at the ASCO Gastrointestinal Cancers Symposium 2026, point to a potential new option for the 20%-25% of patients with BRAF V600E-mutant metastatic CRC who receive FOLFIRI as their chemotherapy.

Based on previous results from BREAKWATER, the FDA granted accelerated approval to first-line encorafenib (Braftovi) and cetuximab (Erbitux) plus mFOLFOX6 for this patient population. That regimen doubled median overall survival compared with standard chemotherapy with or without bevacizumab.

Cohort 3 of BREAKWATER was designed to address a specific question: Are the benefits with the targeted therapy duo a “FOLFOX-specific phenomenon?” lead investigator Scott Kopetz, MD, PhD, of MD Anderson Cancer Center, Houston, said during a press briefing.

Based on these early results, the answer is no. Instead, Kopetz said, there appears to be a “broader synergy” between the targeted therapies and cytotoxic chemotherapy.

Joel Saltzman, MD, ASCO expert in gastrointestinal cancers based at Taussig Cancer Center, Cleveland Clinic in Cleveland, agreed.

“The additional data from the BREAKWATER trial reveals that it is the targeted therapy backbone that provides the better disease control and response rate in BRAF V600E-mutant colorectal cancers,” he said.

BRAF V600E mutations occur in up to 12% of patients with metastatic CRC and are associated with poor outcomes. While many newly diagnosed patients receive FOLFOX (leucovorin/5-FU/oxaliplatin) in the first line, FOLFIRI is a common alternative — often due to concerns about oxaliplatin-associated peripheral neuropathy, Kopetz noted.

The safety lead-in portion of BREAKWATER showed that encorafenib and cetuximab plus FOLFIRI were tolerable and had promising antitumor activity.

Cohort 3 of the trial included 147 patients (mean age, 62 years; 46% male) with BRAF V600E-mutant metastatic CRC, no prior systemic treatment, and good performance status (Eastern Cooperative Oncology Group PS 0 or 1); 73 patients were randomly allocated to encorafenib and cetuximab plus FOLFIRI and 74 to FOLFIRI with or without bevacizumab. The primary endpoint was objective response rate assessed by blinded independent central review.

After a median follow-up of 10 months, patients in the targeted therapy group had an objective response rate of 64.4% vs 39.2% among patients who received FOLFIRI alone or with bevacizumab (odds ratio, 2.76; P = .001).

Responses to the targeted therapies were “rapid and durable,” Kopetz said. More than half (57.4%) of patients treated with encorafenib and cetuximab and FOLFIRI had a duration of response of 6 months or longer than 34.5% in the control group.

Data on overall survival, a secondary endpoint, were not yet mature, but there was a trend toward improved survival with targeted therapy.

Importantly, Kopetz reported, there were no new safety signals, and serious treatment-emergent adverse events occurred at a similar rate in both treatment groups: 39.4% in the targeted therapy group and 36.8% in the control group.

The most common adverse events in both groups included nausea, diarrhea, vomiting, fatigue, appetite loss, and alopecia. About 10% of patients in the targeted therapy group and 9% of those in the control group discontinued their treatment early, suggesting the severity of side effects was similar between the groups.

Kopetz cautioned that the data are still early and follow-up is ongoing. However, he said, the findings support the targeted drugs plus FOLFIRI as a “potential new standard of care” for this patient population.

“The addition of FOLFIRI chemotherapy in the frontline setting will give oncologists and patients more options when selecting a first-line regimen,” Saltzman said. “To have as many options as possible is certainly something we all hope for.”

The trial was funded by Pfizer. Kopetz reported consulting for Pfizer and several other pharmaceutical companies. Saltzman reported having no disclosures.

A version of this article first appeared on Medscape.com.