Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC).

e14126 Background: Previous studies showed that gene mutations (NRAS, BRAF, PIK3CA) are associated with a poor prognosis or resistance of anti-EGFR antibody in metastatic colorectal cancer (mCRC) patients with wild type (WT) of KRAS codon 12/13 (KRAS-WT). However the significance of these biomarkers has not been clarified. In addition, EGFR immunohistochemistry (IHC) and EGFR gene amplification to evaluate the efficacy of anti-EGFR antibody treatment has not been reported for mCRC. Methods: We evaluated tumor response and survival in patients who received anti-EGFR antibody by mutation analysis of KRAS, NRAS, BRAF, and PIK3CA in KRAS-WT patients with mCRC. Tumor DNA samples are obtained from patients treated in our hospital with anti-EGFR antibody between August 2008 and August 2011. Results: A total of 117 patients were enrolled in this analysis, including 100 KRAS-WT patients. Seventy-one patients (60.7%) were all WT for KRAS, NRAS, BRAF, and PIK3CA, and 46 patients (39.3%) had at least 1 mutation or had insufficient DNA samples to analyze. Mutations of KRAS codon 61 (2 patients), KRAS codon 146 (5), BRAF V600E (2), PIK3CA exon9 (8), NRAS codon 12/13 (2), and NRAS codon 61 (5) were detected. No patients had a mutation of PIK3CA exon 20. Patients with at least 1 mutation had no response. Mutations of NRAS codon 61, KRAS codon 146, and BRAF V600E were associated with a shorter progression free survival (PFS) compared with all WT patients (p=0.049, p=0.004, p=0.036, respectively). Twelve patients (12% of KRAS-WT patients) with a mutation of NRAS codon 61, KRAS codon146, and BRAF V600E had poor prognosis compared with the other KRAS-WT patients (PFS, 6.4 vs 2.0 months, p<0.001; overall survival (OS), 13.7 vs 7.9 months, p=0.012). In all WT patients, moderate to strong EGFR IHC was associated with a better response rate than negative and weak IHC (p=0.046). Conclusions: Mutations of NRAS codon 61, KRAS codon 146, and BRAF V600E could be a strong prognostic factor of anti-EGFR antibody in patients with mCRC. Combination of IHC and DISH of EGFR could identify patients with a tumor response to anti-EGFR antibody in patients that are all WT for KRAS, NRAS, BRAF, and PIK3CA.

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Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.0786 ◽

2008 ◽

Vol 26 (35) ◽

pp. 5705-5712 ◽

Cited By ~ 1135

Author(s):

Federica Di Nicolantonio ◽

Miriam Martini ◽

Francesca Molinari ◽

Andrea Sartore-Bianchi ◽

Sabrina Arena ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Braf Inhibitor ◽

Braf V600e Mutation ◽

Braf V600e ◽

Wild Type ◽

Braf Mutations ◽

Kras Mutations ◽

Cellular Models ◽

Mutational Status

Purpose Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. Patients and Methods We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. Conclusion BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.

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Encorafenib (Lgx818), an Oral Braf Inhibitor, in Patients (Pts) with Braf V600E Metastatic Colorectal Cancer (Mcrc): Results of Dose Expansion in an Open-Label, Phase 1 Study

Annals of Oncology ◽

10.1093/annonc/mdu333.38 ◽

2014 ◽

Vol 25 ◽

pp. iv182 ◽

Cited By ~ 18

Author(s):

C.A. Gomez-Roca ◽

J. Delord ◽

C. Robert ◽

M. Hidalgo ◽

R. von Moos ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Phase 1 ◽

Braf Inhibitor ◽

Braf V600e ◽

Open Label ◽

Phase 1 Study ◽

Open Label Phase

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The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

Cancers ◽

10.3390/cancers13010137 ◽

2021 ◽

Vol 13 (1) ◽

pp. 137

Author(s):

Gianluca Mauri ◽

Erica Bonazzina ◽

Alessio Amatu ◽

Federica Tosi ◽

Katia Bencardino ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Mapk Pathway ◽

Treatment Options ◽

Braf Inhibitor ◽

Current Treatment ◽

Cytotoxic Chemotherapy ◽

Cytotoxic Agents ◽

Poor Prognostic Factor

The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.

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