BRAF MUTATED COLON CANCER

ARTHUR WINER MDHematology/Oncology Fellow

Fox Chase Cancer Center, Philadelphia, PA

October 19 th, 2019

2

Dr. Arthur Winer does not have any relevant financial relationship to disclose.

DISCLOSURE

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

3

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?

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%)

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

FRONTLINE THERAPY FOR BRAF V600E

7Cremolini C, et al. Lancet Oncol. 2015;16(13):1306-15

Our PatientFrontline FOLFIRI + Bevacizumab consistent with NCCN guidelines

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%) –

9NCCN Guidelines. V 2.2019 (5/15/2019)

SUBSEQUENT THERAPY FOR BRAF V600E

10

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)

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

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

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

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

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

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

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

SECOND LINE TREATMENT OF RAS/BRAF MUTATED mCRC

Jeremiah Boles, MDUNC Rex Healthcare

Raleigh, NC

October 18 th, 2019

DISCLAIMER

Dr. Jeremiah Boles does not have any relevant financial relationship to disclose.

19

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

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”

21

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

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

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

23

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

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).

24

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