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Immune mediated adverse events in the randomized phase 3 TOPAZ 1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer1 Topic1 Quiz
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Belantamab mafodotin plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma DREAMM7 updated overall survival analysis from a global randomised open label phase 3 trial1 Topic1 Quiz
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PACULit Daily Literature Update: Real-world patient profile and step-up dosing process of early initiators of teclistamab for multiple myeloma in US hospitals An analysis using the Premier Healthcare Database1 Topic1 Quiz
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PACULit Daily Literature Update: Effects of BojungikkiTang on immune response and clinical outcomes in NSCLC patients receiving immune checkpoint inhibitors a randomized pilot study1 Topic1 Quiz
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PACULit Daily Literature Update: Long acting lipegfilgrastim and antimicrobials as vigorous primary prophylaxis in bendamustine treated patients with indolent B cell non Hodgkin lymphoma a multicentric real life experience1 Topic1 Quiz
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First-line treatment with HDACis plus tislelizumab combined with chemotherapy in advanced NSCLC a single-arm phase II study1 Topic1 Quiz
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Comparison of outcomes with elranatamab and real world treatments in the UK for triple class exposed relapsed and refractory multiple myeloma1 Topic1 Quiz
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Phase I II clinical trial on the safety and preliminary efficacy of donor derived anti leukemia cytotoxic T lymphocytes for the prevention of leukemia relapse in children given haploidentical hematopoietic stem cell transplantation study rational and design1 Topic1 Quiz
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Brentuximab vedotin plus chemotherapy for the treatment of frontline systemic anaplastic large cell lymphoma subgroup analysis of the ECHELON2 study at 5 years followup1 Topic1 Quiz
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Talquetamab improves patient reported symptoms and health related quality of life in relapsed or refractory multiple myeloma Results from the phase 12 MonumenTAL1 study1 Topic1 Quiz
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Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer1 Topic1 Quiz
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Durvalumab Alone or Combined With Novel Agents for Unresectable Stage III Non Small Cell Lung Cancer Update From the COAST Randomized Clinical Trial1 Topic1 Quiz
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Real world patient profile and step up dosing process of early initiators of teclistamab for multiple myeloma in US hospitals An analysis using the Premier Healthcare Database1 Topic1 Quiz
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Brentuximab vedotin plus chemotherapy for the treatment of frontline systemic anaplastic large cell lymphoma1 Topic1 Quiz
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Optimal treatment duration in metastatic renal cell carcinoma patients responding to immune checkpoint inhibitors should we treat beyond two years1 Topic1 Quiz
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Effects of Metformin on Survival and Toxicity in Patients with Metastatic Non Small Cell Lung Cancer Treated with Nivolumab1 Topic1 Quiz
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ACPE Required Forms: PACULit Literature Updates September 2025: Oncology3 Topics
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Lesson 14,
Topic 1
In Progress
Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer
Lesson Progress
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Daily Literature Update
Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer
Elez E, Yoshino T, Shen L, et al. N Engl J Med. 2025 Jun 26;392(24):2425-2437. doi:10.1056/NEJMoa2501912.
Introduction
BREAKWATER phase 3 trial establishes encorafenib, cetuximab, and mFOLFOX6 as first-line therapy for BRAF V600E-mutated metastatic colorectal cancer, a subtype with historically poor prognosis.
Study Details
Study Type: Phase 3 randomized controlled trial
Population: 637 patients with untreated BRAF V600E-mutated metastatic colorectal cancer
Intervention: Encorafenib + cetuximab + mFOLFOX6 chemotherapy vs standard chemotherapy with/without bevacizumab
Outcomes: Objective response rate, progression-free survival, overall survival
Key Findings
- Median progression-free survival improved: 12.8 vs. 7.1 months (HR 0.53; P<0.0001)
- Median overall survival nearly doubled: 30.3 vs. 15.1 months (HR 0.49; P<0.0001)
- Objective response rate increased: 65.7% vs. 37.4%
- Grade 3/4 adverse events higher in EC+mFOLFOX6 (81.5%) vs SOC (66.8%) but manageable
Context & Related Research
- Elez et al., 2025: BREAKWATER trial confirms superior first-line efficacy of EC+mFOLFOX6 in BRAF V600E mCRC, improving survival outcomes drastically (PMID:39863775).
- Kopetz et al., 2019: BEACON CRC established EC backbone in previously treated patients, foundational to BREAKWATER’s hypothesis (PMID:31566309).
- Morris et al., 2023: ASCO guidelines underscore BRAF mutation testing as critical for directing targeted therapies in metastatic colorectal cancer (PMID:36252154).
Clinical Implications
- Adopt EC+mFOLFOX6 as preferred first-line regimen for patients with BRAF V600E-mutated mCRC.
- Routine BRAF testing should be performed to identify patients eligible for targeted therapy.
- Monitor and manage higher rates of adverse events with supportive care strategies.
Strengths & Limitations
| Strengths | Limitations |
|---|---|
| Large, global randomized design with robust endpoints | Open-label design; EC alone arm enrollment stopped early |
| Dual primary endpoints rigorously assessed by blinded review | Long-term survival and resistance mechanism data pending |
Future Directions
Comparative studies of EC+mFOLFOX6 versus EC without chemotherapy and longitudinal safety and resistance analyses are needed for continued optimization of treatment strategies.
Conclusion
First-line treatment with encorafenib, cetuximab, and mFOLFOX6 significantly improves survival in BRAF V600E-mutated metastatic colorectal cancer, establishing a new standard of care.
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Citations
- Elez E, Yoshino T, Shen L, et al. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med. 2025 Jun 26;392(24):2425-2437. doi:10.1056/NEJMoa2501912.
- Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N Engl J Med. 2019;381(17):1632-1643.
- Morris VK, Bekaii-Saab T. The Treatment of Metastatic Colorectal Cancer Guided by Molecular Testing. ASCO Educational Book. 2023;43:e152-e160.