A Treatment Option for Metastatic Colorectal Cancer Patients with BRAFV600E Mutation in Singapore

Pierre Fabre Singapore receives approval from the Ministry of Health (“MOH”), Singapore, for the listing of BRAFTOVI on the Cancer Drug List (“CDL”)¹.

An approved therapeutic product registered with Health Sciences Authority,2 BRAFTOVI, in combination with cetuximab, has been indicated in CDL as a treatment for adult patients with BRAFV600E-mutant¹ metastatic colorectal cancer (“mCRC”). These patients must have had prior systemic therapy¹.

BRAF mutations are estimated to occur in approximately 8–12% of patients with mCRC, and V600E is the most common mutation3-11 Patients with mCRC who have BRAFV600E-mutant tumours generally have a poor prognosis and therefore represent an unmet medical need12. Currently, there are no other approved targeted treatments in Singapore specifically indicated for this patient population¹.

BRAFTOVI (encorafenib) is an oral small-molecule BRAF kinase inhibitor that targets a key enzyme in the MAPK signalling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma and colorectal cancer.

The BRAFTOVI and cetuximab combination regimen represents an option to treat BRAFV600E-mutant mCRC patients after prior systemic therapy. According to the Phase 3 BEACON CRC trial, a randomised Phase 3 trial designed to investigate a BRAF combination targeted therapy in BRAFV600E-mutant mCRC, BRAFTOVI in combination with cetuximab significantly improved overall survival in patients with BRAFV600E-mutant mCRC and reduced the risk of death by 40%13.

The Phase 3 BEACON CRC trial demonstrated a well-tolerated safety profile with no unexpected toxicities in the trial. The most common adverse drug reactions (>25%), observed in the BEACON CRC trial, were fatigue, nausea, diarrhoea, dermatitis acneiform, abdominal pain, arthralgia/musculoskeletal pain, decreased
appetite, rash and vomiting2, 13.

In Singapore, there are no other approved targeted treatments specifically indicated for this mCRC BRAFV600E-mutant patient population¹. Such patients who are Singaporeans or Singapore Permanent Residents can claim MediShield Life of up to S$1,800 per month, and withdraw from Medisave of up to S$600 per month from their Central Provident Fund (CPF) accounts¹.

“The approval of BRAFTOVI for its indication in Singapore reflects our long-term commitment to advancing care for patients living with difficult-to-treat cancers,” said Mr. Jairo Pardey, General Manager, Pierre Fabre Singapore. “Listed on the Cancer Drug List by Ministry of Health, Singapore, the BRAFTOVI and cetuximab combination targeted regimen provides an option as a cost-effective cancer drug treatment for this population.”

Colorectal cancer is one of the most common cancers among males and female aged 50 years and above in Singapore14. According to Singapore Cancer Registry Annual Report, it is the second deadliest cancer in Singapore and the mortality rate of colorectal cancers had risen from 2.9 to 13.0 per 100,000 from 1968 to 202015. Singapore Cancer Society also reports an increasing trend of colorectal cancer among young adults14.

¹ The Ministry of Health, Singapore, Cancer Drug List.
² Health Sciences Authority, Singapore, Register of Therapeutic Products, Registration No. SIN16824P.
³ Maughan TS, et al. MRC COIN Trial Investigators. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet.2011 Jun 18;377(9783):2103-14.
4 Souglakos J, et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009 Aug 4;101(3):465-72.
5 Richman SD, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009 Dec 10;27(35):5931-7.
6 Tran B, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011 Oct 15;117(20):4623-32.
7 Yokota T, et al. BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer. 2011 Mar 1;104(5):856-62.
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9 Loupakis F, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009 Aug 18;101(4):715-21.
10 Tveit KM, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012 May 20;30(15):1755-62.
11 Vecchione L, et al. A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility. Cell. 2016 Apr 7;165(2):317-30.
12 Taieb J, et al. Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer. J Natl Cancer Inst.
2016 Dec 31;109(5):djw272.
13 Kopetz S et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. NEJM. 2019; 381: 1632-1643.
14 Singapore Cancer Society, Colorectal Cancer: A New Subset in Younger Individuals, Cancer Focus, Vol 1, 2016.
15 Health Promotion Board, Singapore, National Registry of Diseases Office, Singapore Cancer Registry Annual Report 2020, Updated 23 Dec 2022.
16 The Global Cancer Observatory, 2018. International Agency for Research on Cancer, World Health Organization. Accessed May 2020.
17 EuropaColon. Colorectal Cancer in Europe: A Framework for Improving Outcomes for Patients. Accessed May 2020.
18 F. Sclafani, G. Gullo, K. Sheahan, J. Crown, BRAF mutations in melanoma and colorectal cancer: A single oncogenic mutation with different tumour phenotypes and clinical implications, Crit Rev Oncol Hematol. 2013;87:55–68.
19 Safaee Ardekani G, Jafarnejad SM, Tan L, Saeedi A, Li G. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One. 2012;7(10):e47054.

Images: Pierre Fabre Singapore

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