hematology/oncology fellow fox chase cancer center ......– swog 1406 preliminary data at 2017 asco...

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

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?

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

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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)

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.

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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

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

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

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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

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