Pfizer's Targeted Therapy Shows Promising Results for Metastatic Colorectal Cancer with BRAF V600E Mutation
Pfizer has shared positive outcomes from its Phase 3 BREAKWATER trial, which evaluated a combination therapy involving encorafenib (BRAFTOVI), cetuximab, and mFOLFOX6 in individuals with metastatic colorectal cancer (mCRC) carrying the BRAF V600E mutation. The therapy demonstrated a significant improvement in response rates compared to standard chemotherapy options, marking an important milestone in cancer treatment.
Key Findings from the BREAKWATER Trial
The study revealed that the combination therapy achieved a notable objective response rate (ORR) of 60.9%, assessed by an independent review, compared to 40% in participants treated with chemotherapy (with or without bevacizumab). This represents more than double the odds of achieving a clinical response.
Additional Outcomes:
Duration of Response: The median duration of response for the combination therapy was 13.9 months, significantly longer than the 11.1 months observed in the chemotherapy group.
Sustained Responses: Over 22% of patients treated with the combination therapy had responses lasting a year or more, compared to just 11.4% in the chemotherapy group.
Median Time to Response: The combination therapy resulted in a response within a median time of 7.1 weeks, comparable to the 7.3 weeks seen with chemotherapy.
Although overall survival (OS) data is still maturing, early analysis indicates a favorable trend for the combination therapy. Median OS for patients on the combination regimen was not yet estimable but surpassed the chemotherapy group, where median OS was 14.6 months.
Regulatory Approval and Future Prospects
In December 2024, this combination therapy received accelerated approval from the U.S. Food and Drug Administration (FDA) for patients with BRAF V600E-mutant mCRC. The approval was part of the FDA’s Project FrontRunner, which aims to expedite the development and approval of innovative cancer treatments for advanced diseases.
Pfizer is engaging with regulatory bodies globally to expand approvals for this therapy. The BREAKWATER trial continues to monitor OS and progression-free survival (PFS), with PFS results expected in 2025.
About the BREAKWATER Trial
The BREAKWATER study is a Phase 3, randomized, open-label trial assessing the safety and effectiveness of encorafenib combined with cetuximab, with or without mFOLFOX6, versus standard chemotherapy regimens in previously untreated patients with BRAF V600E-mutant mCRC.
Participants were divided into three groups:
Encorafenib with cetuximab (monotherapy cohort, discontinued after enrolling 158 patients).
Encorafenib with cetuximab and mFOLFOX6 (236 patients).
Standard chemotherapy (mFOLFOX6, FOLFOXIRI, or CAPOX, with or without bevacizumab) (243 patients).
The primary endpoints of the trial were ORR and PFS, while OS served as a key secondary endpoint.
Colorectal cancer is the third most frequently diagnosed cancer globally, with approximately 1.8 million new cases reported in 2022. It is also the second leading cause of cancer-related deaths worldwide.
Bristol Myers Squibb Unveils Promising Results from CheckMate -8HW Trial on Combination Opdivo + Yervoy for Metastatic Colorectal Cancer
Bristol Myers Squibb has shared groundbreaking findings from the CheckMate -8HW trial, which examined the combination of nivolumab and ipilimumab compared to nivolumab alone in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC).
The study revealed a significant 38% reduction in the risk of disease progression or death with the dual therapy compared to nivolumab monotherapy after a median follow-up of 47 months.
Key Findings from CheckMate -8HW
Progression-Free Survival (PFS): Patients treated with nivolumab and ipilimumab experienced a 38% lower risk of disease progression or death compared to those on nivolumab alone. PFS rates at 12, 24, and 36 months were also higher with the combination therapy, reaching 76%, 71%, and 68%, respectively, compared to 63%, 56%, and 51% with monotherapy.
Overall Response Rate (ORR): The dual therapy achieved a significantly higher ORR of 71% versus 58% with monotherapy.
Safety Profile: The combination therapy’s safety was consistent with prior findings, with manageable side effects. Grade 3/4 treatment-related adverse events were reported in 22% of patients on combination therapy, compared to 14% with monotherapy. No new safety concerns were identified.
Earlier results from the trial demonstrated that the combination therapy reduced the risk of disease progression or death by 79% compared to chemotherapy, a finding that contributed to its approval by the European Commission for first-line treatment of MSI-H/dMMR mCRC in December 2024.
About the CheckMate -8HW Study
This Phase 3, randomized, open-label trial enrolled 839 participants to compare nivolumab plus ipilimumab, nivolumab alone, and chemotherapy (with or without bevacizumab or cetuximab) in MSI-H/dMMR mCRC patients. Dual primary endpoints included PFS for combination therapy versus chemotherapy in the first-line setting and PFS for combination therapy versus monotherapy across all treatment lines.
Colorectal cancer is one of the most prevalent cancers globally, with nearly 1.93 million new cases reported in 2020, making it the second leading cause of cancer-related deaths. MSI-H and dMMR are specific genetic traits seen in 5–7% of metastatic colorectal cancer cases. These patients often respond poorly to standard chemotherapy and face a challenging prognosis, making advancements in treatment, such as combination immunotherapy, critically important.
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