Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer.

Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428-43. ©2018 AACR.See related commentary by Janku, p. 389See related article by Hazar-Rethinam et al., p. 417This article is highlighted in the In This Issue feature, p. 371.

[1]  L. Diaz,et al.  Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406). , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  Jeffrey W. Clark,et al.  Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAFV600E Colorectal Cancer. , 2018, Cancer discovery.

[3]  J. Desai,et al.  Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. , 2017, The Lancet. Oncology.

[4]  S. Jaeger,et al.  A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer. , 2017, Cancer discovery.

[5]  A. Grothey,et al.  Phase 1b/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with FOLFIRI +/- bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts). , 2017 .

[6]  L. Diaz,et al.  Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). , 2017 .

[7]  Gad Getz,et al.  Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma. , 2017, Cancer discovery.

[8]  C. Dreyer,et al.  BRAF-Mutated Colorectal Cancer: What Is the Optimal Strategy for Treatment? , 2017, Current Treatment Options in Oncology.

[9]  H. Groen,et al.  Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. , 2016, The Lancet. Oncology.

[10]  D. Schadendorf,et al.  Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. , 2016, The Lancet. Oncology.

[11]  Eric S. Lander,et al.  Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma , 2016, Cell reports.

[12]  A. Bardelli,et al.  MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition in BRAF-Mutated Colorectal Cancer. , 2016, Cancer discovery.

[13]  R. Bernards,et al.  Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer. , 2016, Cancer research.

[14]  Mari Mino-Kenudson,et al.  Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer. , 2016, Cancer discovery.

[15]  H. Groen,et al.  Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. , 2016, The Lancet. Oncology.

[16]  C. Atreya,et al.  Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  P. Gibbs,et al.  Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  L. Garraway,et al.  Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors , 2015, Molecular Cancer Therapeutics.

[19]  J. Blay,et al.  Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. , 2015, The New England journal of medicine.

[20]  J. Utikal,et al.  Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial , 2015, The Lancet.

[21]  Beatriz Bellosillo,et al.  Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients , 2015, Nature Medicine.

[22]  B. Vogelstein,et al.  PD-1 blockade in tumors with mismatch repair deficiency. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  Nikhil Wagle,et al.  Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations. , 2015, Cancer discovery.

[24]  M. Berger,et al.  Pilot Trial of Combined BRAF and EGFR Inhibition in BRAF-Mutant Metastatic Colorectal Cancer Patients , 2015, Clinical Cancer Research.

[25]  D. Barras,et al.  BRAF Mutation in Colorectal Cancer: An Update , 2015, Biomarkers in cancer.

[26]  A. Hauschild,et al.  Improved overall survival in melanoma with combined dabrafenib and trametinib. , 2015, The New England journal of medicine.

[27]  J. Utikal,et al.  Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. , 2014, The New England journal of medicine.

[28]  J. Fregnani,et al.  KRAS and BRAF mutations and MSI status in precursor lesions of colorectal cancer detected by colonoscopy. , 2014, Oncology reports.

[29]  S. Kopetz,et al.  Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. , 2014, Clinical colorectal cancer.

[30]  R. Govindan,et al.  Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436). , 2014, Clinical cancer research : an official journal of the American Association for Cancer Research.

[31]  I. Nagtegaal,et al.  Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS Studies , 2014, Clinical Cancer Research.

[32]  Bert Vogelstein,et al.  DETECTION OF CIRCULATING TUMOR DNA IN EARLY AND LATE STAGE HUMAN MALIGNANCIES , 2014 .

[33]  G. Freeman,et al.  Response to BRAF Inhibition in Melanoma Is Enhanced When Combined with Immune Checkpoint Blockade , 2014, Cancer Immunology Research.

[34]  J. Tabernero,et al.  Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. , 2013, The New England journal of medicine.

[35]  Reiko Nishihara,et al.  Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. , 2013, Journal of the National Cancer Institute.

[36]  K. Flaherty,et al.  TORC1 Suppression Predicts Responsiveness to RAF and MEK Inhibition in BRAF-Mutant Melanoma , 2013, Science Translational Medicine.

[37]  A. McCullough.  RAS Mutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors , 2013 .

[38]  Michael A. Davies,et al.  Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents , 2012, Clinical Cancer Research.

[39]  Ardavan Saeedi,et al.  The Prognostic Value of BRAF Mutation in Colorectal Cancer and Melanoma: A Systematic Review and Meta-Analysis , 2012, PloS one.

[40]  Mari Mino-Kenudson,et al.  EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. , 2012, Cancer discovery.

[41]  Yu Shyr,et al.  Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. , 2012, The New England journal of medicine.

[42]  R. Bernards,et al.  Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR , 2012, Nature.

[43]  A. Iafrate,et al.  BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation , 2010, Science Signaling.

[44]  K. Flaherty,et al.  Inhibition of mutated, activated BRAF in metastatic melanoma. , 2010, The New England journal of medicine.

[45]  Chao Zhang,et al.  RAF inhibitors transactivate RAF dimers and ERK signaling in cells with wild-type BRAF , 2010, Nature.

[46]  M. Belvin,et al.  RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth , 2010, Nature.

[47]  J. Reis-Filho,et al.  Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF , 2010, Cell.

[48]  J Jack Lee,et al.  A predictive probability design for phase II cancer clinical trials , 2008, Clinical trials.

[49]  P. Laird,et al.  CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer , 2006, Nature Genetics.

[50]  Frank Diehl,et al.  BEAMing: single-molecule PCR on microparticles in water-in-oil emulsions , 2006, Nature Methods.

[51]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.