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Patients with BRAF mutant CRC should be treated on a clinical trial
Scott Kopetz, MD, PhD. Department of GI Medical Oncology MD Anderson Cancer Center
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Disclosures Research Support Advisory Boards
Roche/Genentech, AstraZeneca, Circadian Advisory Boards Amgen, Roche/Genentech/Ventana, AstraZeneca, GSK, Bayer, Onyx, MedImmune, Sanofi, Plexxikon, Jannsen, Bristol-Myer Squibb, Agendia
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Key Points BRAF mutant CRC is a unique subtype of CRC
Aggressive biology, poor prognosis Activity with standard chemotherapy is limited Combination regimens are working and trials are available
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Serrated Adenoma / BRAFmut Subgroup
BRAF mutations reflect a unique subset of CRC Distinct molecular biology Unique precursor lesion and metastasis pattern Poor outcomes with standard-of-care BRAF V600E >95% Bollag et al, Nature ‘10
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Unique BRAFmut Clinical Behavior
Atypical patterns of metastases Very short overall survival Hazard Ratio of 10.6 for OS Less than 1 year OS Morris et al , Clin Colorect al Cancer ‘13 Tran, Kopetz, et al, Cancer 2011
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BRAF mutant CRC is in a Unique Subtype by New Classification System
Guinney et al (submitted)
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Limited Benefit of Standard of Care for BRAFmut CRC Patients
N=127 patients Progression at First Restaging Morris, et al Clin Colorectal Cancer, 2014
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FOLFOXIRI+B Results: Magnifying Glass
Overall Survival BRAF mut HR=0.55 (0.24 to 1.23) P=Not Significant 19m 10m 12m
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How to treat these patients?
BRAF inhibitor BRAF mutation
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Targeting BRAF and/or MEK: Minimal Activity in CRC
BRAF + MEK inhibition BRAF inhibition -100 -75 -50 -25 25 50 75 100 %Change From Baseline (Sum of Lesion Size) 12% Response Rate 5% Response Rate GSK212 + GSK436 Vemurafenib Corcoran et al ASCO ‘12, Kopetz et al ASCO ‘10
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Key Finding: Feedback EGFR Signaling
BRAFmut PI3K AKT RAS MEK EGFR and others CDC25 Perhaps the problem is pathway reactivation… Treat with EGFR + BRAF inhibitors Prahallad et al Nature ’12, Corcoran et al Can Disc ‘12
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Synergy in Murine Models: BRAF + EGFR
BRAFmut PI3K AKT RAS MEK EGFR and others CDC25 Prahallad et al Nature ’12 Kopetz, unpublished; Yang et al Can Res ‘11
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Clinical Research Efforts in BRAFmut
BRAFi+ EGFRi BRAFi+ EGFRi + chemo BRAFi+ EGFRi + MEKi BRAFi+ EGFRi + novel agents
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Tumor Regression with Cetuximab and Vemurafenib combined with Irinotecan
Arm A: No response Arm B: 50% response and regression Arm C: 100% regression Arm A: Arm B: Arm C: Fang, et al , Can Res, ‘12
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Vemurafenib + Cetuximab + Irinotecan
* 4/8 = 50% Study completed with 18 patients D. Hong et al ASCO ‘14 Historical response rate is <10% for cetuximab and irinotecan, with PFS of 2.4 months for BRAFmut Amgen Corporate Template
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Cross-Trial Comparison: Phase 1B vs Historic Control for mBRAF CRC
7.7 months vs 2.4 months Van Morris
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Clinical Research Efforts in BRAFmut
BRAFi+ EGFRi BRAFi+ EGFRi + chemo BRAFi+ EGFRi + MEKi BRAFi+ EGFRi + novel agents
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Dabrafenib + Panitumumab +/- Trametinib
BRAF + EGFR inhibition 2/15 = 13% SD=87% BRAF + MEK + EGFR inhibition 6/15 = 40% SD=80% Bendell et al ASCO ‘14
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Cross-Study Comparison of Phospho-ERK Modulation Between CRC and Melanoma
Response Rate: 13% 12% 40% Corcoran et al ASCO ‘14 Bendell et al ASCO ‘14
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Summary of preliminary activity in studies of BRAFi-based therapy in BRAFmut CRC
Regimen Pathway PR/CR SD DCR Future plans D + T BRAF+MEK 12% 51% 63% None D + P BRAF+EGFR 13.3% 73.3% 86.6% V + C - 36.3% None* E + C 29% 50% 79.2% D + T + P BRAF+MEK+EGFR 40% 80% FOCUS4 study V + C + Ir BRAF+EGFR+ cytotoxic 100% SWOG RPh2 E + C + BYL BRAF+EGFR+PI3K 30% 60% 90% D = dabrafenib, T = trametinib, P = panitumumab, V = vemurafenenib, C = cetuximab, E = encorafenib, Ir = irinotecan, BYL = BYL719
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SWOG 1406: BRAF + EGFR with availability through other cooperative groups
Historical response rate is <10% for cetuximab and irinotecan, with PFS of 2.4 months for BRAFmut Target HR 0.5 for PFS, with 2-sided alpha 5%, power 80% N= 78 patients Currently enrolling, Kopetz, PI
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Patients with BRAF mutations can have durable responses!
Baseline Patients with BRAF mutations can have durable responses! Week 6 Week 16 OS of 3+ years with combination pathway Targeting and still going Patient of G. Falchook
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Key Points BRAF mutant CRC is a unique subtype of CRC
Aggressive biology, poor prognosis Activity with standard chemotherapy is limited Including FOLFOXIRI Combination regimens are working and trials are available Enroll patients on protocols!
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Acknowledgements Kopetz Lab Van Morris, MD Feng Tian, PhD
Camilla Jiang, MD, PhD Mike Lee, MD Jian Song, DVM Riham Katkhuda, MD Chris Lieu, MD Ali Kazmi, MD Pia Morelli, MD, PhD Michael Overman, MD MDACC Mike Overman, MD Cathy Eng, MD Dipen Maru, MD Lee Ellis, MD Jim Abbruzzese, MD Atin Agarwal, MD Robert Lemos Garth Powis, PhD Laurel Deaton Shanequa Manuel MDACC Collaborators (cont) Yvonne Lassere Gerald Falchook, MD Robert Wolff, MD Xifeng Wu, PhD Ju-Seog Lee, PhD Gordon Mills, MD Ignacio Wistuba, MD George Calin, MD Brian James, PhD Collaborators John Mariadson, PhD Jayesh Desai, MD, Ludwig Aus Rene Bernards, NKI Iris Simon, Agendia Curt Harris, NKI Aaron Schetter, NKI Chloe Atreya, UCSF Ryan Corcoran Funding: NIH, ASCO, Texas CPRIT, IPCT MD Anderson Cancer Center, Gilson Longenbaugh Foundation
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