Pfizer Presents Interim Analysis Results from Phase 3 BEACON CRC Trial of BRAFTOVI® (Encorafenib), MEKTOVI® (Binimetinib) and Cetuximab for the Treatment of BRAFV600E-Mutant Metastatic Colorectal Cancer
- Results to be presented during a late-breaking oral session at the 2019
- As previously announced, BRAFTOVI combinations showed statistically significant improvements in OS and ORR versus control –
As previously announced, the BRAFTOVI Triplet showed a median OS of 9.0 months for patients treated with the Triplet, compared to 5.4 months for Control ([HR 0.52, (95% CI 0.39-0.70), p<0.0001]). The BRAFTOVI Triplet also demonstrated a significantly improved ORR of 26% (95% CI: 18%, 35%) compared to 2% (95% CI: 0%, 7%) for Control (p<0.0001).
“We are pleased to share these data from the BEACON CRC trial with the oncology community,” said
The study also showed improvements in secondary efficacy endpoints. As previously announced, the BRAFTOVI Doublet showed a statistically significant improvement in OS (median 8.4 months vs. 5.4 months, [HR 0.60, 95% CI (0.45-0.79), p=0.0003]) compared to Control. Additional analysis showed depth of responses in favor of the BRAFTOVI Triplet.
“The BEACON CRC trial results show meaningful improvements compared to an available standard of care for patients with BRAFV600E-mutant mCRC," said
Further, the data provide additional details on the primary and secondary endpoints, including observations of response rates by number of lines of prior therapy, as well as a descriptive analysis of OS comparing the BRAFTOVI Triplet to the BRAFTOVI Doublet.
The BEACON CRC study was not powered to compare the two experimental arms directly and such a comparison is further limited by the interim nature of the analysis. In the data being presented at
As previously reported, the BRAFTOVI Triplet and Doublet were generally well-tolerated with no unexpected toxicities. Grade 3 or higher adverse events (AEs) were seen in 58%, 50% and 61% of patients in the BRAFTOVI Triplet, Doublet and Control arms, respectively. Discontinuation of therapy due to adverse events was seen in 7%, 8% and 11% of patients in the Triplet, Doublet and Control arms, respectively. The most common Grade 3 or higher AEs seen in patients treated with the BRAFTOVI Triplet were diarrhea (10% vs. 2% in the Doublet arm and 10% in the Control arm), abdominal pain (6% vs. 2% in the Doublet arm and 5% in the Control arm) and nausea (5% vs. <1% in the Double arm and 1% in the Control arm).
Details for the late-breaking oral presentation are below. The abstract can be accessed through the
Monday, September 30
About Colorectal Cancer
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 2018.1,2 In the U.S. alone, an estimated 140,250 patients were diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease each year.3BRAF mutations are estimated to occur in up to 15% of patients with mCRC and represent a poor prognosis for these patients.4,5,6,7,8,9 The V600 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.7,8 BRAFV600E-mutant mCRC is an area of high unmet need as there are currently no approved therapies specifically indicated for patients with BRAF-mutant mCRC.10,,11
About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and cetuximab in patients with BRAFV600E-mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAFV600E-mutant mCRC.
Thirty patients were treated in a safety lead-in conducted prior to initiation of the randomized part of the trial and received the Triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and cetuximab per label). Of the 30 patients, 29 had a BRAFV600 mutation. As previously announced, the Triplet combination showed an acceptable safety profile that supported initiation of the randomized portion of the trial.
The randomized portion of the BEACON CRC trial is designed to assess the efficacy of BRAFTOVI in combination with cetuximab with or without MEKTOVI compared to cetuximab and irinotecan-based therapy. 665 patients were randomized 1:1:1 to receive the Triplet combination, the Doublet combination (BRAFTOVI and cetuximab) or the control arm (irinotecan-based therapy and cetuximab). The study was amended to include an interim analysis of endpoints including ORR. The primary overall survival endpoint is a comparison of the Triplet combination to the control arm. Secondary endpoints address efficacy of the Doublet combination compared to the control arm, and the Triplet combination compared to the Doublet therapy. Other secondary endpoints include progression-free survival, duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial is being conducted at over 200 investigational sites in
About BRAFTOVI + MEKTOVI
BRAFTOVI is an oral small molecule BRAF kinase inhibitor and MEKTOVI is an oral small molecule MEK inhibitor which target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma, colorectal cancer, non-small cell lung cancer and others. In the U.S., BRAFTOVI + MEKTOVI are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an
Pfizer has exclusive rights to BRAFTOVI and MEKTOVI in the U.S. and
Indications and Usage
BRAFTOVI® (encorafenib) and MEKTOVI® (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an
Limitations of Use: BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma.
BRAFTOVI + MEKTOVI Important Safety Information
The information below applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.
Warnings and Precautions
New Primary Malignancies: Cutaneous and non-cutaneous malignancies can occur. In the
Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or V600K mutation prior to initiating BRAFTOVI.
Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the
Venous Thromboembolism (VTE): In the
Hemorrhage: In the
Ocular Toxicities: In the
Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.
Hepatotoxicity: In the
Rhabdomyolysis: In the
QTc Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the
Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.
The most common adverse reactions (≥20%, all Grades, in the
Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided. Avoid co-administration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval.
About Pfizer Oncology
At Pfizer Oncology, we are committed to advancing medicines wherever we believe we can make a meaningful difference in the lives of patients. Today, Pfizer Oncology has an industry-leading portfolio of 22 approved innovative cancer medicines and biosimilars across more than 30 indications, including breast, prostate, kidney and lung cancers, as well as leukemia and melanoma. Pfizer Oncology is striving to change the trajectory of cancer.
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DISCLOSURE NOTICE: The information contained in this release is as of
This release contains forward-looking information about the BRAFTOVI® (encorafenib), MEKTOVI® (binimetinib), and cetuximab (BRAFTOVI Triplet) combination as well as the BRAFTOVI Doublet combination (BRAFTOVI and cetuximab) and a potential new indication for the treatment of advanced BRAFV600E-mutant metastatic colorectal cancer, following one or two lines of therapy, including its potential benefits and the expected timing of a potential regulatory submission in the U.S., that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, uncertainties regarding the commercial success of BRAFTOVI® and MEKTOVI®; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; risks associated with interim data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications for the Triplet Combination for the potential new indication may be filed with regulatory authorities in any jurisdictions; whether and when regulatory authorities in any jurisdictions may approve any such applications, which will depend on myriad factors, including making a determination as to whether the product’s benefits outweigh its known risks and determination of the product’s efficacy and, if approved, whether the Triplet Combination for the potential new indication will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of BRAFTOVI®, MEKTOVI®or the Triplet Combination; and competitive developments.
A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended
1 Global Cancer Facts & Figures 3rd Edition.
3 Cancer Facts & Figures 2018.
4 Saridaki, Z., Tzardi, M., Sfakianaki, M., et al. (2013). BRAFV600E Mutation Analysis in Patients with Metastatic Colorectal Cancer (mCRC) in Daily Clinical Practice: Correlations with Clinical Characteristics, and Its Impact on Patients’ Outcome. PLoS ONE,8(12). doi:10.1371/journal.pone.0084604
5 Loupakis, F., Ruzzo, A., Cremolini, C., et al. (2009). KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. British journal of cancer, 101(4), 715–721. doi:10.1038/sj.bjc.6605177
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8 Safaee Ardekani, G., Jafarnejad, S. M., Tan, L., et al. (2012). The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PloS one, 7(10), e47054. doi:10.1371/journal.pone.0047054
9 Vecchione, L., Gambino, V., Raaijmakers, J., et al. (2016). A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility. Cell,165(2), 317-330. doi:10.1016/j.cell.2016.02.059
10 Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer. V.2.2019.
 Van Cutsem, E., Cervantes, A., Adam, R., et al. (2016).
11 Ursem, C., Atreya, C. E., & Van Loon, K. (2018). Emerging treatment options for BRAF-mutant colorectal cancer. Gastrointestinal cancer : targets and therapy, 8, 13–23. doi:10.2147/GICTT.S125940
12 BRAFTOVI® (encorafenib) Prescribing Information.
13 MEKTOVI® (binimetinib) Prescribing Information.
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