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BRAF MUTATED COLON CANCER
ARTHUR WINER MDHematology/Oncology Fellow
Fox Chase Cancer Center, Philadelphia, PA
October 19 th, 2019
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Dr. Arthur Winer does not have any relevant financial relationship to disclose.
DISCLOSURE
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5-FU, fluorouracil; CEA, carcinoembryonic antigen; CT, computerized tomography; FOLFOX, folinic acid fluorouracil oxaliplatin; IHC, immunohistochemistry; LN, lymph node; cM, colorectal distant metastasis; MSS, microsatellite stable; NCCN, National Comprehensive Cancer Network; PCP, primary care physician; pT, primary tumor stage; pN, Lymph node stage; Ro, basic reproduction rate
• 44 year old female without significant family history presented to her PCP with pica symptoms and was diagnosed with iron deficiency anemia. She eventually underwent a colonoscopy: sigmoid mass, CT with LN involvement, no distant disease
• She was taken for R0 left hemicolectomy revealing a 4 cm pT3,pN1a,cM0 (IIIB) adenocarcinoma, MSS by IHC
• She received adjuvant FOLFOX x 12 cycles (5-FU dose reduced C3+25% for oral ulcers, oxaliplatin decreased by 25% for neuropathy, held for cycle 12)
• She was followed per NCCN guidelines and 6 months after completion of adjuvant therapy was found to have rising CEA from 2.8 6.6
• Subsequent CT revealed bilateral ovarian metastases, peritoneal nodules, and enlarging mesenteric lymph nodes. A laparoscopic ovarian biopsy was consistent with colonic adenocarcinoma
CASE PRESENTATIONHISTORY OF PRESENT ILLNESS
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41L, first line; ERBB2, Erb-B2 receptor tyrosine kinase 2; FOLFIRI, folinic acid, fluorouracil and irinotecan; IHC, immunohistochemistry; MMR, mismatch repair; NGS, next generation sequencing; pMMR, mismatch repair proficient; RNF53, RING finger protein 53; TP53, tumor protein p53
• Local NGS testing covering 153 genes was undertaken from the ovarian sample to explore biomarker status
• Tumor was found to harbor a BRAF V600E mutation, no RAS alterations or ERBB2 alterations. Additional mutations were identified in TP53 and RNF53. MMR status was confirmed pMMR by IHC
• Germline testing was negative for pathogenic mutations
• In 10/2016 she was begun on 1L FOLFIRI + bevacizumab but progressed after 4 cycles with enlarging ovarian masses
CASE PRESENTATION CONTINUED
Now What?
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BRAF V600E MUTANT CRC
Patient characteristics
• Older (>70)
• Female
• Smokers
Tumor characteristics
• Right-sided
• Mucinous
• MSI
• Larger tumors
• Peritoneal spread
• BRAF V600E mutant CRC is seen in 5-10% (~15,000 cases/year)
• Mutually exclusive from KRAS or NRAS mutations.
5CRC, colorectal cancer; MSI, microsatellite instability
Taieb J. et al., Annals of Oncology. 2017; Sanz-Garcia E. et al., Annals of Oncology. 2017; Gonsalves W.I. et al., J Natl Cancer Inst. 2014
KRAS exon 3 (2.2%)
NRAS exon 4 (0.1%)
KRAS exon 2 (41.2%)
RAS and BRAF WT(37.8%)
KRAS exon 4 (4.2%)
BRAF V600E(10.1%)
BRAF non V600E(1.1%)
NRAS exon 3 (1.6%)NRAS exon 2 (1.6%)
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FRONTLINE THERAPY FOR BRAF V600E
6NCCN Guidelines. V 2.2019 (5/15/2019)Loupakis F et al. N Engl J Med. 2014
Our PatientFrontline FOLFIRI + Bevacizumab consistent with NCCN guidelines
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FRONTLINE THERAPY FOR BRAF V600E
7Cremolini C, et al. Lancet Oncol. 2015;16(13):1306-15
Our PatientFrontline FOLFIRI + Bevacizumab consistent with NCCN guidelines
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FRONTLINE THERAPY FOR BRAF V600E
8FOLFIRI, folinic acid, fluorouracil and irinotecan; FOLFOXIRI, oxaliplatin, irinotecan and fluorouracil
Cremolini C, et al. Lancet Oncol. 2015;16(13):1306-15
Overall survival Progression-free survival Best response
Median (months)
Hazard ratio p value Median (months)
Hazard ratio p value Overall response
Odds ratio p value
BRAF-mutation-positive subgroup
FOLFIRI plus bevacizumab (n=12) 10.7 (3.1–24.8) 0.54 (0.24–1.20) – 5.5 (1.6–11.2) 0.57 (0.27–1.23) – 5 (42%) 1.82 (0.38–8.78) –
FOLFOXIRI plus bevacizumab (n=16) 19.0 (8.2–28.6) – – 7.5 (5.1–15.0) – – 9 (56%) –
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9NCCN Guidelines. V 2.2019 (5/15/2019)
SUBSEQUENT THERAPY FOR BRAF V600E
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DCR, disease control rate; ORR, objective response rate; PFS, progression-free survival; SWOG, South Western Oncology Group
Source figure: Bertotti, A., & Sassi, F. , Clinical Cancer Research. 2015Kopetz S. et al., Journal of Clinical Oncology. 2017;35 (no.15_suppl): abstract 3505.
• After a phase I showed activity, SWOG S1406 – Phase II –irinotecan+cetuximab (IC)+/-vemurafenib
• PFS: 4.4 in 3 drug vs 2 months (if no prior irinotecan, PFS 5.7 months vs 1.9 months)
• ORR: 16% vs 4% (p=0.08)
• DCR: 67% vs 22%
• Grade 3+ Toxicity: neutropenia (28% vs 7%), anemia (13% vs 0%), nausea (15% vs 0%). There was 46% cross over from IC to VIC (median PFS 6 months)
• Our patient: 3/2017-8/2017: VIC, imaging with stable disease in June 2017 before progression
2ND LINE TREATMENTVEMURAFENIB + IRINOTECAN+ CETUXIMAB (VIC)
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2ND LINE TREATMENT: COMBO EGFR (PANITUMUMAB), BRAF (DAFRAFENIB), MEK INHIBITION (TRAMETINIB)
11EGFR, epidermal growth factor; b.i.d., twice a day; Q2W, every 2 weeks; q.d., one a day
Source figure: Corcoran RB et al., Cancer Discov. 2018
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2ND LINE TREATMENT: COMBO EGFR, BRAF, MEK INHIBITION
12EGFR, epidermal growth factor, D, dabrafenib; P, panitumumab; PFS, progression-free survival; T, trametinib
Source figure: Corcoran RB et al., Cancer Discov. 2018
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2ND LINE TREATMENT: COMBO EGFR, BRAF, MEK INHIBITION
13EGFR, epidermal growth factor; D, dabrafenib; P, panitumumab; T, trametinib
Source figure: Corcoran RB et al., Cancer Discov. 2018
Figure 1 (S1): Overall Survival by Treatment Arm
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2ND LINE TREATMENT: BINIMETINIB + ENCORAFENIB + CETUXIMAB
• 30 BRAFv600E patients with mCRC
• Failed 1-2 prior regimens
• Safety lead in: encorafenib 300 mg daily, binimetinib45 mg daily, cetuximab 400 mg/m2
followed by 250 mg/m2
intravenously weekly in 28-day cycles
CR, complete response; mCRC, metastatic colorectal cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response
Source Clinical trial: Phase III BEACON study – ClinicalTrials.gov identifier: NCT02928224
Source figure: Van Cutsem E. et al., Journal of Clinical Oncology. 201914
ORR: 48%Median PFS: 8 moMedian OS: 15.3 mo
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2ND LINE TREATMENT: BINIMETINIB + ENCORAFENIB + CETUXIMAB
No. of patients (%) withGrade 3 or 4 event (N=30)
Total patients with any grade 3 or 4 adverse event 21 (70.0)
Fatigue 4 (13.3)
AST increased 3 (10.0)
Urinary tract infection 3 (10.0)
Anemia 3 (10.0)
Blood creatine phosphokinase increased 3 (10.0)
Decreased appetite 2 (6.7)
Dyspnea 2 (6.7)
Nausea 2 (6.7)
Vomiting 2 (6.7)
ALT increased 2 (6.7)
Hypokalemia 2 (6.7)
Hypophosphatemia 2 (6.7)
ALT, alanine aminotransferase; AST, aspartate aminotransferase
Source figure: Van Cutsem E. et al., Journal of Clinical Oncology. 2019 15
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WHAT HAPPENED TO OUR PATIENT?
• 3/2017-8/2017: VIC, imaging with stable disease in June 2017 before progression
• 9/2017-12/2017: DTP
• 12/2017: Progression of disease
• 12/2017-4/2018: FOLFIRI+Avastin
• Restaging during FOLFIRI+Avastin initially with SD in 2/2018 then POD in 4/2018
• 3/5/2018-10/23/18: FOLFIRI+Ziv-Aflibercept. SD on restaging imaging in 6/2018 and again in 8/2018
• 10/23/18: Expired
• Time from diagnosis of metastatic disease to death: ~24 months
16DTP, dafrafenib+trametinib+panitumumab; POD, progression of disease; SD, stable disease; VIC, vemurafenib+irinotecan+cetuximab
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SUMMARY
• BRAF mutated CRC has a poor prognosis (median ~12 months vs ~33+ in WT disease)
• BRAF mutation predicts lack of response to anti-EGFR monotherapy when combined with chemo
• Targeting BRAF alone is similar insufficient (CRC is not melanoma)
• Combination therapy is promising and should be considered for these patients… Although there is still a long way to go in this population
17CRC, colorectal cancer; EGFR, epidermal growth factor receptor; FOLFIRI, folinic acid, fluorouracil and irinotecan
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SECOND LINE TREATMENT OF RAS/BRAF MUTATED mCRC
Jeremiah Boles, MDUNC Rex Healthcare
Raleigh, NC
October 18 th, 2019
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DISCLAIMER
Dr. Jeremiah Boles does not have any relevant financial relationship to disclose.
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SECOND LINE RAS MUTATED
• Generally accepted that activating mutations in RAS result in resistance to anti-EGFR therapy
• Chemotherapy backbone at progression
– if treated with FOLFOX, most patients offered FOLFIRI and vice versa
• Role of continued anti-angiogenesis therapy at progression
EGFR, epidermal growth factor receptor; FOLFOX: folinic acid, fluorouracil and oxaliplatin; FOLFIRI: folinic acid, fluorouracil and irinotecan20
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SECOND LINE RAS MUTATED
• NCCN: 2.2019 –“When an angiogenic agent is used in this setting, the panel prefers bevacizumab over ziv-aflibercept and ramucirumab, because of toxicity and/or cost”
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FOLFOX: folinic acid, fluorouracil and oxaliplatin; FOLFIRI: irinotecan, fluorouracil and folinic acid; NCCN, National Comprehensive Cancer Network; OS, overall survival, VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor
ML18147 trial: Bennouna J Lancet Oncol. 2013;14(1):29-37; VELOUR trial: Van Cutsem E et al. J Clin Oncol. 2012;30(28):3499-506; RAISE trial: Tabernero J. et al. Lancet Oncol 2015;16(5):499-508
Drugs Study name Design Median OS Comments
Bevacizumab(recombinant monoclonal antibody against VEGF-A)
ML18147 chemotherapy+bevacizumabvs
chemotherapy at first progression
11.2 monthsvs
9.8 months
Patients who receive 1st
line bevacizumab-containing therapy, use of bevacizumab in 2nd line is appropriate
Aflibercept (recombinant fusion protein - VEGF Trap)
VELOUR 2nd line FOLFIRI+afliberceptvs
FOLFIRI in patients who progressed on
FOLFOX+bevacizumab
13.5 monthsvs
12.1 months
Unclear if aflibercept is superior to bevacizumab in 2nd line and may be more toxic and expensive
Ramucirumab (recombinant monoclonal antibody against VEGFR-2)
RAISE 2nd line FOLFIRI+ramucirumabvs
FOLFIRI
13.3 monthsvs
11.7 months
Unclear if superior to bevacizumab and there are similar concerns about toxicity and cost
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BRAF
• Component of RAS-RAF-MAPK pathway
• Activating mutations found in 5-10% of mCRC patients
– 78% are V600E – associated with poor prognosis and lack of response to EGFR antibody therapy
– Non V600E mutations have better median OS than V600E (61 vs 11 months) and perhaps even better than BRAF WT (61 vs 43 months)1
• At least 2 meta analysis demonstrate response to EGFR-targeted therapy is unlikely in patients with BRAF V600E2
– As a consequence such therapy is not recommended by NCCN or ESMO
221Jones JC et al. J Clin Oncol. 2017;35(23):2624-2630; 2Pietrantonio F et al. Eur J Cancer. 2015;51(5):587-94; Rowland A et al. Br J Cancer. 2015;112(12):1888-94
BRAF, B-Raf proto-oncogene, serine/threonine kinase; EGFR, epidermal growth factor receptor; ESMO, European Society of Medical Oncology; MAPK, mitogen-activated protein kinase; mCRC, metastatic colorectal cancer; NCCN, National Comprehensive Cancer Center Network; OS, overall survival; RAF, rapidly accelerated fibrosarcoma; WT, wild-type
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BRAF V600E MUTANT2ND LINE OPTIONS
• Monotherapy with single agent BRAF inhibitor (vemurafenib) has been ineffective
– Phase 2 trial of 21 patients only 1 PR (5% RR) with median PFS of 2.1 months1
• Therefore current options include:
A. Clinical trial
B. 16-33% of mCRC patients with BRAF V600E mutations have high levels of microsatellite instability (MSI-H)
– Checkpoint inhibitor immunotherapy
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BRAF, B-Raf proto-oncogene, serine/threonine kinase; PR, partial response; RR, response rate; PFS, progression-free survival; mCRC, metastatic colorectal cancer; MSI-H, microsatellite instability high1Kopetz, et al. J Clin Oncol. 2015;33(34):4032-8
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BRAF V600E MUTANTOVERCOMING EGFR TARGETEDRESISTANCE – 2ND LINE OPTIONS
C. Therapy with a BRAF and MEK inhibitor (dabrafenib plus trametinib)– 12% PR, 2% CR, 56% had stable disease1
– Notably lower disease control rates than seen in melanoma and NSCLC
D. Triple therapy with vemurafenib, cetuximab, and irinotecan– SWOG 1406 preliminary data at 2017 ASCO – median PFS 4.4 vs 2.0 months and
ORR 16% vs 4% in triplet compared to irinotecan + cetuximab
E. Combination of BRAF inhibitor, EGFR inhibitor and a MEK inhibitor– Phase 3 Beacon RAS WT, BRAF V600E2
• Randomized to cetuximab, encorafenib (BRAF inhibitor) with or without binimetinib(MEK inhibitor) vs irinotecan + cetuximab.
• The mOS was 9.0 months in the triplet-therapy group and 5.4 months in the control group (HR, 0.52; 95% CI, 0.39 to 0.70; P<0.001).
• The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001).
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ASCO, Americal Society of Clinical Oncology; BRAF, B-Raf proto-oncogene, serine/threonine kinase; CI, confidence interval; CR, complete response; EGFR, epidermal growth factor receptor; HR, hazard ratio; mCRC, metastatic colorectal cancer; MEK, MAPK/ERK kinase; mOS, median overall survival; MSI-H, microsatellite instability high; NSCLC, non-small-cell lung carcinoma; ORR, overall response rate; PFS, progression free survival; PR, partial response; SWOG, Southwest Oncology Group; WT, wild-type;
1. Corcoran RB et al. J Clin Oncol, 2015;33(34):4023-31; 2. Kopetz S. et al. N Engl J Med. 2019; 381:1632-1643