- Clinically meaningful and statistically significant results from the Phase 3 BREAKWATER trial show objective response rate of 61% with Pfizer’s BRAFTOVI combination regimen compared to 40% with investigator’s choice of chemotherapy, representing a doubling of the odds of achieving an objective response
- BRAFTOVI combination regimen is the first and only targeted therapy approved by the U.S. FDA for treatment-naïve patients with metastatic colorectal cancer with a BRAFV600E mutation
NEW YORK, NY, USA I January 25, 2025 I Pfizer Inc. (NYSE: PFE) today announced positive results from the Phase 3 BREAKWATER trial evaluating BRAFTOVI® (encorafenib) in combination with cetuximab (marketed as ERBITUX®) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) in patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. At the time of this analysis, the BRAFTOVI combination regimen demonstrated a clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) assessed by blinded independent central review (BICR) compared to patients receiving chemotherapy with or without bevacizumab (60.9% vs 40.0%, odds ratio =2.443, p=0.0008). These results will be presented today in an oral presentation (Abstract 16) at the 2025 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) and were simultaneously published in Nature Medicine.
“Despite the high unmet need in this patient population, prior to the recent encorafenib combination regimen approval, there were no approved biomarker-driven therapies indicated for people with previously untreated BRAF V600E-mutant metastatic colorectal cancer,” said Scott Kopetz, M.D., Ph.D., FACP, Professor and Deputy Chair of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center and co-principal investigator of the BREAKWATER trial. “These data from the BREAKWATER study show the potential for this targeted treatment regimen to become the new standard of care for people with BRAF V600E-mutant metastatic colorectal cancer, for whom long-term disease control is critical.”
The estimated median duration of response as assessed by BICR was 13.9 months (95% Confidence Interval [CI]: 8.5-not estimable [NE]) with BRAFTOVI plus cetuximab and mFOLFOX6 and 11.1 months (95% CI: 6.7-12.7) with chemotherapy with or without bevacizumab. Of patients on BRAFTOVI plus cetuximab and mFOLFOX6, 22.4% (n=15) had a response lasting 12 months or longer, compared to 11.4% (n=5) with chemotherapy with or without bevacizumab. The median time to response as assessed by BICR was 7.1 weeks (range 5.7-53.7) with BRAFTOVI plus cetuximab and mFOLFOX6 and 7.3 weeks (range 5.4-48.0) with chemotherapy with or without bevacizumab.
Overall survival (OS) data were immature at the time of this analysis but demonstrated a promising trend in favor of BRAFTOVI plus cetuximab and mFOLFOX6 compared to patients receiving chemotherapy with or without bevacizumab. Median OS with BRAFTOVI plus cetuximab with chemotherapy was not estimable (95% CI: 19.8-NE) and 14.6 months (95% CI: 13.4-NE) with chemotherapy with or without bevacizumab (Hazard Ratio [HR]: 0.47, 95% CI: 0.318-0.691). The BREAKWATER trial is ongoing for OS and progression-free survival (PFS), with PFS results expected in 2025.
“These results of this first analysis were the basis for the first approval of a targeted therapy regimen for use in the first-line setting for patients with metastatic colorectal cancer with a BRAF V600E mutation,” said Roger Dansey, M.D., Chief Oncology Officer, Pfizer. “We are highly encouraged by these response results, which are indicative of the clinically meaningful benefit of BRAFTOVI in reducing tumor size or having no detectable cancer, along with the promising interim analysis of overall survival. We look forward to additional read-outs from the BREAKWATER trial this year.”
The safety profile of BRAFTOVI in combination with cetuximab and mFOLFOX6 in the BREAKWATER trial was consistent with the known safety profile of each respective agent. No new safety signals were identified. Serious treatment-emergent adverse events occurred in 37.7% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 compared to 34.6% of patients receiving chemotherapy with or without bevacizumab.
BRAFTOVI in combination with cetuximab and mFOLFOX6 was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with BRAF V600E-mutant mCRC in December 2024. The approval 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. The BREAKWATER data are also being discussed with other regulatory authorities around the world to support potential future additional license applications for the BRAFTOVI combination regimen in this indication.
Pfizer is continuing its commitment to help non-scientists understand the latest findings with the development of abstract plain language summaries (APLS) for company-sponsored research being presented, which are written in non-technical language. Those interested in learning more can visit www.Pfizer.com/apls to access the summaries.
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 mCRC. 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 PFS as assessed by BICR. OS 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.
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.
About Pfizer: Breakthroughs That Change Patients’ Lives
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.com. In addition, to learn more, please visit us on www.Pfizer.com and follow us on X at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.
References
- American Cancer Society. Global Cancer Facts & Figures 5th Edition. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-2024.pdf. Last accessed: January 2025.
- American Cancer Society. Key Statistics for Colorectal Cancer. Available at: https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html. Last accessed: January 2025.
- American Cancer Society. Cancer Facts & Figures 2025. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2025/2025-cancer-facts-and-figures-acs.pdf. Last accessed: January 2025.
- Ciardiello F, Ciardiello D, Martini G, et al. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022;72:372–40.
- Josep Tabernero et al., The Evolving Treatment Landscape in BRAF-V600E–Mutated Metastatic Colorectal Cancer. Am Soc Clin Oncol Educ Book 42, 254-263(2022). DOI:10.1200/EDBK_349561
- Safaee Ardekani G, Jafarnejad SM, Tan L, et al. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PloS ONE. 2012;7(10):e47054.
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer. V.5.2024 © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed December 2024. To view the most recent and complete version of the guideline, go online to NCCN.org.
- Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10–32.
SOURCE: Pfizer
Post Views: 2,416
- Clinically meaningful and statistically significant results from the Phase 3 BREAKWATER trial show objective response rate of 61% with Pfizer’s BRAFTOVI combination regimen compared to 40% with investigator’s choice of chemotherapy, representing a doubling of the odds of achieving an objective response
- BRAFTOVI combination regimen is the first and only targeted therapy approved by the U.S. FDA for treatment-naïve patients with metastatic colorectal cancer with a BRAFV600E mutation
NEW YORK, NY, USA I January 25, 2025 I Pfizer Inc. (NYSE: PFE) today announced positive results from the Phase 3 BREAKWATER trial evaluating BRAFTOVI® (encorafenib) in combination with cetuximab (marketed as ERBITUX®) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) in patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. At the time of this analysis, the BRAFTOVI combination regimen demonstrated a clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) assessed by blinded independent central review (BICR) compared to patients receiving chemotherapy with or without bevacizumab (60.9% vs 40.0%, odds ratio =2.443, p=0.0008). These results will be presented today in an oral presentation (Abstract 16) at the 2025 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) and were simultaneously published in Nature Medicine.
“Despite the high unmet need in this patient population, prior to the recent encorafenib combination regimen approval, there were no approved biomarker-driven therapies indicated for people with previously untreated BRAF V600E-mutant metastatic colorectal cancer,” said Scott Kopetz, M.D., Ph.D., FACP, Professor and Deputy Chair of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center and co-principal investigator of the BREAKWATER trial. “These data from the BREAKWATER study show the potential for this targeted treatment regimen to become the new standard of care for people with BRAF V600E-mutant metastatic colorectal cancer, for whom long-term disease control is critical.”
The estimated median duration of response as assessed by BICR was 13.9 months (95% Confidence Interval [CI]: 8.5-not estimable [NE]) with BRAFTOVI plus cetuximab and mFOLFOX6 and 11.1 months (95% CI: 6.7-12.7) with chemotherapy with or without bevacizumab. Of patients on BRAFTOVI plus cetuximab and mFOLFOX6, 22.4% (n=15) had a response lasting 12 months or longer, compared to 11.4% (n=5) with chemotherapy with or without bevacizumab. The median time to response as assessed by BICR was 7.1 weeks (range 5.7-53.7) with BRAFTOVI plus cetuximab and mFOLFOX6 and 7.3 weeks (range 5.4-48.0) with chemotherapy with or without bevacizumab.
Overall survival (OS) data were immature at the time of this analysis but demonstrated a promising trend in favor of BRAFTOVI plus cetuximab and mFOLFOX6 compared to patients receiving chemotherapy with or without bevacizumab. Median OS with BRAFTOVI plus cetuximab with chemotherapy was not estimable (95% CI: 19.8-NE) and 14.6 months (95% CI: 13.4-NE) with chemotherapy with or without bevacizumab (Hazard Ratio [HR]: 0.47, 95% CI: 0.318-0.691). The BREAKWATER trial is ongoing for OS and progression-free survival (PFS), with PFS results expected in 2025.
“These results of this first analysis were the basis for the first approval of a targeted therapy regimen for use in the first-line setting for patients with metastatic colorectal cancer with a BRAF V600E mutation,” said Roger Dansey, M.D., Chief Oncology Officer, Pfizer. “We are highly encouraged by these response results, which are indicative of the clinically meaningful benefit of BRAFTOVI in reducing tumor size or having no detectable cancer, along with the promising interim analysis of overall survival. We look forward to additional read-outs from the BREAKWATER trial this year.”
The safety profile of BRAFTOVI in combination with cetuximab and mFOLFOX6 in the BREAKWATER trial was consistent with the known safety profile of each respective agent. No new safety signals were identified. Serious treatment-emergent adverse events occurred in 37.7% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 compared to 34.6% of patients receiving chemotherapy with or without bevacizumab.
BRAFTOVI in combination with cetuximab and mFOLFOX6 was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with BRAF V600E-mutant mCRC in December 2024. The approval 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. The BREAKWATER data are also being discussed with other regulatory authorities around the world to support potential future additional license applications for the BRAFTOVI combination regimen in this indication.
Pfizer is continuing its commitment to help non-scientists understand the latest findings with the development of abstract plain language summaries (APLS) for company-sponsored research being presented, which are written in non-technical language. Those interested in learning more can visit www.Pfizer.com/apls to access the summaries.
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 mCRC. 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 PFS as assessed by BICR. OS 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.
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.
About Pfizer: Breakthroughs That Change Patients’ Lives
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.com. In addition, to learn more, please visit us on www.Pfizer.com and follow us on X at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.
References
- American Cancer Society. Global Cancer Facts & Figures 5th Edition. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-2024.pdf. Last accessed: January 2025.
- American Cancer Society. Key Statistics for Colorectal Cancer. Available at: https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html. Last accessed: January 2025.
- American Cancer Society. Cancer Facts & Figures 2025. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2025/2025-cancer-facts-and-figures-acs.pdf. Last accessed: January 2025.
- Ciardiello F, Ciardiello D, Martini G, et al. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022;72:372–40.
- Josep Tabernero et al., The Evolving Treatment Landscape in BRAF-V600E–Mutated Metastatic Colorectal Cancer. Am Soc Clin Oncol Educ Book 42, 254-263(2022). DOI:10.1200/EDBK_349561
- Safaee Ardekani G, Jafarnejad SM, Tan L, et al. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PloS ONE. 2012;7(10):e47054.
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer. V.5.2024 © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed December 2024. To view the most recent and complete version of the guideline, go online to NCCN.org.
- Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10–32.
SOURCE: Pfizer
Post Views: 2,416
