Pfizer Inc. (NYSE: PFE) today announced positive topline results from the progression-free survival (PFS) analysis of the Phase 3 BREAKWATER study of BRAFTOVI® (encorafenib) in combination with cetuximab (marketed as ERBITUX® ) and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) in patients with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation. The trial showed a statistically significant and clinically meaningful improvement in PFS, one of its dual primary endpoints, as assessed by blinded independent central review (BICR) compared to patients receiving chemotherapy with or without bevacizumab. Further, the BRAFTOVI combination regimen demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), a key secondary endpoint in the trial.
"We are extremely pleased with the clinically meaningful progression-free survival and overall survival results from the BREAKWATER study, which have the potential to be practice-changing for this patient population that has historically had limited treatment options and poor outcomes," said Roger Dansey, M.D., Chief Oncology Officer, Pfizer. "The BRAFTOVI regimen is emerging as a new standard of care as the first targeted therapy approved for use as early as first-line for patients with mCRC with a BRAF V600E mutation. We look forward to discussing these data with global health authorities to bring this treatment to more patients around the world, as soon as possible."
The BRAFTOVI combination regimen received accelerated approval by the U.S. Food and Drug Administration (FDA) in December 2024 for treatment-naïve patients with BRAFV600E -mutant mCRC based on a clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR), the study's other dual primary endpoint. The ORR results were presented at the 2025 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) and were simultaneously published in Nature Medicinein January 2025.
At the time of the ORR analysis, the safety profile of BRAFTOVI in combination with cetuximab and mFOLFOX6 continued to be consistent with the known safety profile of each respective agent. No new safety signals were identified. Detailed results from this analysis will be submitted for presentation at an upcoming medical meeting.
The approval of the BRAFTOVI combination regimen was among the first in the industry to be conducted under the FDA's Project FrontRunner, which seeks to support the development and approval of new cancer drugs for advanced or metastatic disease. Pfizer will share these latest results with the FDA to potentially support full approval for BRAFTOVI in combination with cetuximab and mFOLFOX6 in patients with mCRC with a BRAF V600E mutation. The BREAKWATER data are also being discussed with other regulatory authorities around the world to support potential additional license applications for the BRAFTOVI combination regimen in this indication.
About BREAKWATER
BREAKWATER is a Phase 3, randomized, active-controlled, open-label, multicenter trial of BRAFTOVI with cetuximab, alone or in combination with mFOLFOX6 in participants with previously untreated BRAF V600E-mutant metastatic CRC. Patients were randomized to receive BRAFTOVI 300 mg orally once daily in combination with cetuximab (discontinued after randomization of 158 patients), BRAFTOVI 300 mg orally once daily in combination with cetuximab and mFOLFOX6 (n=236) or mFOLFOX6, FOLFOXIRI, or CAPOX each with or without bevacizumab (control-arm) (n=243). The dual primary endpoints are ORR, which was met at the time of analysis, and progression-free survival (PFS) as assessed by blinded independent central review (BICR). Overall survival is a key secondary endpoint.
About Colorectal Cancer (CRC)
CRC is the third most common type of cancer in the world, with approximately 1.8 million new diagnoses in 2022.1 It is the second leading cause of cancer-related deaths.2 Overall, the lifetime risk of developing CRC is about 1 in 24 for men and 1 in 26 for women.2 In the U.S. alone, an estimated 154,270 people will be diagnosed with cancer of the colon or rectum in 2025, and approximately 53,000 are estimated to die from the disease each year.3 For 20% of those diagnosed with CRC, the disease has metastasized, or spread, making it harder to treat, and up to 50% of patients with localized disease eventually develop metastases.4
BRAF mutations are estimated to occur in 8-12% of people with mCRC and represent a poor prognosis for these patients.5 The BRAF V600E mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAF V600E mutation is more than double that of patients with no known mutation present.5,6 Despite the high unmet need in BRAF V600E -mutant mCRC, prior to December 20, 2024 there were no approved biomarker-driven therapies specifically indicated for people with previously untreated BRAF V600E -mutant mCRC.7,8
About BRAFTOVI® (encorafenib)
BRAFTOVI is an oral small molecule kinase inhibitor that targets BRAF V600E. Inappropriate activation of proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK) has been shown to occur in certain cancers, including CRC.
Pfizer has exclusive rights to BRAFTOVI in the U.S., Canada, Latin America, Middle East, and Africa. Ono Pharmaceutical Co., Ltd. has exclusive rights to commercialize the product in Japan and South Korea, Medison has exclusive rights to commercialize the product in Israel and Pierre Fabre Laboratories has exclusive rights to commercialize the product in all other countries, including Europe and Asia (excluding Japan and South Korea).
INDICATION AND USAGE
BRAFTOVI® (encorafenib) is indicated, in combination with cetuximab and mFOLFOX6, for the treatment of patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
BRAFTOVI is also indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.
Limitations of Use : BRAFTOVI is not indicated for treatment of patients with wild-type BRAF CRC.
IMPORTANT SAFETY INFORMATION
Refer to the prescribing information for cetuximab and individual product components of mFOLFOX6 for recommended dosing and additional safety information.
WARNINGS AND PRECAUTIONS
New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous, can occur. In BEACON CRC (previously treated BRAF V600E mutation-positive mCRC), cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC) skin papilloma was reported in 2.6%, basal cell carcinoma in 1.3%, squamous cell carcinoma of skin in 0.9%, keratoacanthoma in 0.4% and malignant melanoma in situ in 0.4% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies. Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment.
Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation using an FDA-approved test prior to initiating BRAFTOVI.
Cardiomyopathy: Cardiomyopathy manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. Assess left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (MUGA) scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Hepatotoxicity: Hepatotoxicity can occur. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 was 2.2% for alkaline phosphatase, 1.3% for ALT, and 0.9% for AST. Monitor liver laboratory tests before initiation of BRAFTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Hemorrhage: In BEACON CRC (previously treated BRAF V600E mutation-positive mCRC), hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%), and rectal hemorrhage (2.3%). In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), hemorrhage occurred in 30% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Uveitis: Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
QT Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), an increase of QTcF >500 ms was measured in 3.6% (8/222) of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms.
Embryo-Fetal Toxicity: BRAFTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose.
Risks Associated with Combination Treatment: BRAFTOVI is indicated for use as part of a regimen in combination with cetuximab, or in combination with cetuximab and mFOLFOX6. Refer to the prescribing information for cetuximab and individual product components of mFOLFOX6 for additional risk information.
Lactation: Advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the final dose.
Infertility: Advise males of reproductive potential that BRAFTOVI may impair fertility.
ADVERSE REACTIONS
BREAKWATER Trial (previously untreated BRAF V600E mutation-positive mCRC)
- Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Serious adverse reactions in >3% of patients included intestinal obstruction (3.5%) and pyrexia (3.5%).
- Fatal gastrointestinal perforationoccurred in 0.9% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6.
- Most common adverse reactions(≥25%, all grades) in the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control arm (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab) were peripheral neuropathy (62% vs 53%), nausea (51% vs 48%), fatigue (49% vs 38%), rash (31% vs 4%), diarrhea (34% vs 47%), decreased appetite (33% vs 25%), vomiting (33% vs 21%), hemorrhage (30% vs 18%), abdominal pain (26% vs 27%), and pyrexia (26% vs 14%).
- Most common laboratory abnormalities(≥10%, grade 3 or 4) in the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control arm (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab) were: increased lipase (51% vs 25%), decreased neutrophil count (36% vs 34%), decreased hemoglobin (13% vs 5%), decreased white blood cell count (12% vs 7%), and increased glucose (11% vs 2%).
BEACON CRC Trial (previously treated BRAF V600E mutation-positive mCRC)
- Most common adverse reactions(≥25%, all grades) in the BRAFTOVI with cetuximab arm compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were: fatigue (51% vs 50%), nausea (34% vs 41%), diarrhea (33% vs 48%), dermatitis acneiform (32% vs 43%), abdominal pain (30% vs 32%), decreased appetite (27% vs 27%), arthralgia (27% vs 3%), and rash (26% vs 26%).
- Other clinically important adverse reactionsoccurring in <10% of patients who received BRAFTOVI in combination with cetuximab was pancreatitis.
- Most common laboratory abnormalities (all grades) (≥20%) in the BRAFTOVI with cetuximab arm compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were: anemia (34% vs 48%) and lymphopenia (24% vs 35%).
DRUG INTERACTIONS
Strong or moderate CYP3A4 inhibitors: Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose.
Strong CYP3A4 inducers: Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers.
Sensitive CYP3A4 substrates: Avoid the coadministration of BRAFTOVI with CYP3A4 substrates (including hormonal contraceptives) for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. If the coadministration cannot be avoided, see the CYP3A4 substrate product labeling for recommendations.
Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI.
Avoid coadministration of BRAFTOVI with drugs known to prolong QT/QTc interval.
View the full Prescribing Information.
About Pfizer Oncology
At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and bispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world's most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives.
