Earlier this month the U.S. Food and Drug Administration (FDA) approved encorafenib (Braftovi®; Pfizer) in combination with cetuximab (Erbitux®; Eli Lilly and Company) for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAFV600E mutation, as detected by an FDA-approved test, after prior therapy.
The approval is based on results from the BEACON CRC trial, the only Phase III trial to specifically study patients with previously treated metastatic CRC with a BRAFV600E mutation.
Commenting on the approval of the treatment combination, Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development, noted: “We are pleased by the FDA’s approval … we’re committed to developing targeted medicines [designed to ] help people living with certain mutation-driven cancers. Looking ahead, we’re committed to continuing to investigate this treatment regimen across earlier lines of therapy.”
In the BEACON CRC trial, encorafenib + cetuximab showed a median overall survival (OS) of 8.4 months (95% CI: 7.5, 11.0) compared with 5.4 months (95% CI: 4.8, 6.6) for Control (irinotecan with cetuximab or FOLFIRI with cetuximab) ([HR 0.60, (95% CI: 0.45, 0.79), p=0.0003]). Additionally, encorafenib + cetuximab showed an improved objective response rate (ORR) of 20% (95% CI: 13%, 29%) compared with 2% (95% CI: 0%, 7%) for Control (p<0.0001) and median progression-free survival (mPFS) was 4.2 months with BRAFTOVI plus cetuximab (95% CI: 3.7, 5.4) versus 1.5 months with Control (95% CI: 1.4, 1.7) ([HR 0.40, (95% CI: 0.31, 0.52), p<0.0001]).
“BRAF mutations are estimated to occur in up to 15% of people with metastatic colorectal cancer and represent a poor prognosis for these patients,” said Scott Kopetz, M.D., Ph.D., FACP, Associate Professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center. “As the first-and-only targeted regimen for people with BRAFV600E-mutant metastatic CRC who have received prior therapy, encorafenib in combination with cetuximab is a much-needed new treatment option for these patients.”
The most common adverse reactions (AR) (≥ 25%) seen in patients treated with encorafenib in combination with cetuximab were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia and rash.
The FDA granted this application Priority Review and Breakthrough Therapy designation. The FDA grants Priority Review to medicines that may offer significant advances in treatment or may provide a treatment where no adequate therapy exists.
“Colorectal cancer is the second leading cause of cancer death in men and women combined,” stated Sung Poblete, Ph.D., R.N., Chief Executive Officer of SU2C.
Worldwide, colorectal cancer is the third most common type of cancer in men, and the second most common in women, with approximately 1.8 million new diagnoses in 2018.  In the U.S. alone, an estimated 147,950 people will be diagnosed with cancer of the colon or rectum in 2020, and approximately 53,000 are estimated to die of their disease each year.  BRAF mutations are estimated to occur in up to 15% of people with metastatic CRC and represent a poor prognosis for these patients.
The BRAFV600E mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF. BRAFV600E-mutant metastatic CRC is an area of high unmet need as there are currently no approved therapies specifically indicated for people with BRAFV600E-mutant metastatic CRC. 
Across the US and Canada, approximately, this new treatment could potentially help between 17,500-26,000 patients each year.
Stand Up To Cancer
The FDA’s approval of the combination of encorafenib and cetuximab is the 7th in which research funded by Stand Up To Cancer (SU2C) contributed to the approval. SU2C-funds helped accelerate the pace of research.
Research by the SU2C and the Dutch Cancer Society’s (KWF) Translational Research Team’s approach of prospective use of DNA-guided personalized cancer treatment contributed to the development of this novel treatment.
“This is the seventh approval by the U.S. Food and Drug Administration (FDA) for a new cancer therapy supported by SU2C research,” said Nobel Laureate Phillip A. Sharp, Ph.D, chair of the SU2C Scientific Advisory Committee, and Institute professor, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology.
“The work of this team demonstrates how SU2C’s research accelerates development of new effective treatments showing promise in patients,” Sharp added.
Contribution to research
“Stand Up To Cancer is proud to have contributed to the development of this new targeted treatment option for people with the historically difficult to treat colorectal cancer whose cancer has progressed, despite receiving prior therapy,” Poblete observed.
The SU2C-KWF Research Team participated in a Phase Ib/ Phase II multi-institutional dose-escalation clinical trial (NCT01719380) which studied the effects of encorafenib, alpelisib and cetuximab in BRAF-mutated colorectal cancers. The study compared a two-drug combination of encorafenib and cetuximab and a triple-drug combination of encorafenib, alpelisib, and cetuximab.
Both combinations showed promise for treating metastatic colorectal cancer characterized by BFAF mutations and were well tolerated by the patients. The team made an important observation that patients carrying key mutations in genes associated with the MAP kinase signaling pathway were more responsive to the combination.
Supported by the team’s findings, the FDA granted Breakthrough Therapy Designations for both the combination of encorafenib, binimetinib, and cetuximab and the combination of encorafenib and cetuximab for patients with BRAF V600E-mutant metastatic colorectal cancer, which sped regulatory review.
“We now have clinical proof that science can guide smart treatment combinations which will further stimulate intelligent use of combinations of targeted anti-cancer drugs,” said Emile Voest, MD, Ph.D, professor of Medical Oncology, medical director of the Netherlands Cancer Institute, and leader of the SU2C-KWF Translational Research Team: Prospective Use of DNA-Guided Personalized Cancer Treatment.
“These results highlight how novel insights gained from basic research can lead to novel therapeutic options for cancer patients,” said Rene Bernards, Ph.D, Netherlands Cancer Institute, and co-leader of the Research Team.
This Research Team engaged just over a dozen scientists from the Netherlands Cancer Institute, Erasmus Medical Center, University Medical Center Utrecht in the Netherlands, and University of California San Diego and UC San Francisco.
Study of LGX818 and Cetuximab or LGX818, BYL719, and Cetuximab in BRAF Mutant Metastatic Colorectal Cancer – NCT01719380
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