NEW YORK, NY, USA I December 20, 2024 I
Pfizer Inc. (NYSE: PFE) today announced that the U.S. Food and Drug Administration (FDA) has approved BRAFTOVI
®
(encorafenib) in combination with cetuximab (marketed as ERBITUX
®
) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for the treatment of patients with metastatic colorectal cancer (mCRC) with a
BRAF V600E
mutation, as detected by an FDA-approved test.
i
The indication was approved based on a statistically significant and clinically meaningful improvement in response rate and durability of response in treatment-naïve patients treated with BRAFTOVI in combination with cetuximab and mFOLFOX6 from the Phase 3 BREAKWATER trial. Continued approval for this indication is contingent upon verification of clinical benefit. This accelerated approval is 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.
“Historically, treatment options have been limited and outcomes poor for patients diagnosed with metastatic colorectal cancer with
BRAF
mutations,” 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. “As the first and only combination regimen featuring a BRAF-targeted therapy for this patient population, usable even in first-line treatment, the encorafenib regimen has demonstrated high response rates that are rapid and durable. This represents an encouraging sign of continued disease control and a source of renewed hope for patients.”
The ongoing BREAKWATER trial is evaluating BRAFTOVI plus cetuximab with or without chemotherapy (mFOLFOX6) in previously untreated mCRC patients who harbor a
BRAF V600E
mutation. It is the only Phase 3 trial for a BRAF-targeted therapy regimen in first-line
BRAF V600E
-mutant mCRC. The trial met one of the dual primary endpoints of confirmed overall response rate (ORR), with a statistically significant improvement over standard of care: ORR 61% (95% confidence interval [CI]: 52, 70) for BRAFTOVI in combination with cetuximab and mFOLFOX6 compared with ORR 40% (95% CI: 31, 49) for chemotherapy, with or without bevacizumab (p=0.0008).
1
The median duration of response (DoR) was 13.9 months (95% CI: 8.5, not estimable) for the BRAFTOVI combination regimen versus 11.1 months (95% CI: 6.7, 12.7) for chemotherapy, with or without bevacizumab.
1
The Phase 3 BREAKWATER trial is ongoing, and results from the full dataset will be presented at upcoming medical meetings.
“For more than a decade, Pfizer has been a pioneer in delivering targeted therapies for molecular-driven cancers. With today’s accelerated approval of the BRAFTOVI regimen, patients with metastatic colorectal cancer with a
BRAF V600E
mutation now have a first-line treatment option, which contains a targeted therapy specifically for a mutation that is driving their cancer,” said Chris Boshoff, M.D., Ph.D., Chief Oncology Officer, Executive Vice President, Pfizer. “This milestone adds to our legacy of developing innovative medicines in BRAF tumors, some of the hardest-to-treat cancers. We look forward to continuing to expand our portfolio, including the exploration of a next-generation brain-penetrant BRAF inhibitor.”
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. The most common adverse reactions (≥25%) were peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia.
1
Among patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6, 12% experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common adverse reactions (≥1%) included elevated lipase levels.
“Finding out that your cancer has spread can be a frightening time for those with colorectal cancer and their loved ones. The prognosis for those receiving a metastatic colorectal cancer diagnosis has improved slightly in recent years, but the same cannot be said for those with a
BRAF
mutation who unfortunately face an especially aggressive disease and worse outcomes,” said Michael Sapienza, Chief Executive Officer of the Colorectal Cancer Alliance. “Today’s approval of the first combination regimen including a BRAF-targeted therapy for
BRAF
V600E
-mutant metastatic colorectal cancer, which can be used for previously untreated patients, offers new promise for the community and marks an important step forward in our collective mission to end this disease.”
This application was granted priority review, used the
Real-Time Oncology Review
(RTOR) pilot program, and was conducted under
Project Orbis
, with application reviews ongoing for Project Orbis partners, including Canada and Brazil. 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. This accelerated approval follows the previous FDA approval for BRAFTOVI in combination with cetuximab for adults with mCRC with a
BRAF V600E
mutation after prior therapy.
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.
2
Overall, the lifetime risk of developing CRC is about 1 in 23 for men and 1 in 25 for women.
3
In the U.S. alone, an estimated 152,810 people will be diagnosed with cancer of the colon or rectum in 2024, and approximately 53,000 are estimated to die from the disease each year.
4
For 20% of those diagnosed with CRC, the disease has metastasized, or spread, making it harder to treat.
5
BRAF
mutations are estimated to occur in 8-10% of people with mCRC and represent a poor prognosis for these patients.
6
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.
6,7
Despite the high unmet need in
BRAF V600E
-mutant mCRC, prior to today there were no approved biomarker-driven therapies specifically indicated for people with previously untreated
BRAF V600E
-mutant mCRC.
8,9
About BREAKWATER
BREAKWATER is a Phase 3, randomized, active-controlled, open-label, multicenter trial of BRAFTOVI with cetuximab, alone or in combination with chemotherapy, in participants with previously untreated
BRAF V600E
-mutant mCRC. In the Phase 3 portion of the study, 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 and progression-free survival (PFS), as assessed by blinded independent central review (BICR). Key secondary endpoints include DoR as assessed by BICR, time to response by BICR, overall survival, and safety.
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 has exclusive rights to commercialize the product in all other countries, including Europe and Asia (excluding Japan and South Korea).
U.S. 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 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
. There may be a delay as the document is updated with the latest information. It will be available as soon as possible. Please check back for the updated full information shortly.
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
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.
References
1
BRAFTOVI (encorafenib) Prescribing Information. Array BioPharma, Inc.; December 2024
2
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: December 2024.
3
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: December 2024.
4
American Cancer Society. Cancer Facts & Figures 2024. Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf.
Last accessed: December 2024.
5
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.
6
Djanani A, Eller S, Öfner D,
et al
. The role of BRAF in metastatic colorectal carcinoma-past, present, and future.
Int J Mol Sci
. 2020;21(23):9001.
7
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.
8
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.
9
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
