Targeted therapy regimen, BRAFTOVI® (encorafenib) in combination with cetuximab, included on MOH Cancer Drug List, for the treatment of adult patients with BRAFV600E-mutant metastatic colorectal cancer who have received prior systemic therapy.

SUMMARY OF KEY POINTS

• BRAFTOVI in combination with cetuximab has been included on MOH CDL, for patients with BRAFV600E-mutant metastatic colorectal cancer who have received prior systemic therapy.
• Singaporeans & Permanent Residents can claim using MediShield Life and withdraw from MediSave from their CPF accounts.

SINGAPORE - Media OutReach Newswire - 18 December 2023 - 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 therapy.¹

BRAF mutations are estimated to occur in approximately 8–12% of patients with mCRC, and V600E is the most common mutation.^3-11 Patients with mCRC who have BRAFV600E-mutant tumours generally have a poor prognosis and therefore represent an unmet medical need.¹² Currently, there are no other approved targeted treatments in Singapore specifically indicated for this patient population.¹

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 vomiting.^{2, 13}

In Singapore, there are no other approved targeted treatments specifically indicated for this mCRC BRAFV600E-mutant patient population.¹ Such patients who are Singaporeans or Singapore Permanent Residents can claim MediShield Life of up to SGD1,800 per month, and withdraw from MediSave of up to SGD600 per month from their Central Provident Fund ("CPF") accounts.¹

"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 Singapore.¹⁴ 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 2020.¹⁵ Singapore Cancer Society also reports an increasing trend of colorectal cancer among young adults.¹⁴

REFERENCES

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.

8. Tie J, et al. Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer. 2011 May 1;128(9):2075-84.

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.

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The issuer is solely responsible for the content of this announcement.

About colorectal cancer

Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.8 million new diagnoses in 2018. Globally in 2018, approximately 881,000 deaths were attributed to colorectal cancer.¹⁶ Every year more than 450,000 people in Europe are diagnosed with colorectal cancer and approximately 230,000 will die of their disease. ¹⁷ BRAF mutations are estimated to occur in approximately 8-12% of patients with mCRC and represent a poor prognosis for these patients.^3-11 The V600E mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF.^17-19

About BRAFTOVI^® (encorafenib)

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, colorectal cancer and others.

About BEACON CRC

BEACON CRC is a randomised, open-label, global Phase 3 trial evaluating the efficacy and safety of BRAFTOVI® (encorafenib) +/- MEKTOVI® (binimetinib) in combination with cetuximab in patients with BRAFV600E-mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is a Phase 3 trial designed to test a BRAF combination targeted therapy in BRAFV600E-mutant mCRC. A total of 665 patients were randomised 1:1:1 to one of the following treatment arms:

1. BRAFTOVI 300 mg orally once daily in combination with cetuximab (BRAFTOVI/cetuximab arm)
2. BRAFTOVI 300 mg orally once daily in combination with cetuximab and binimetinib
3. Irinotecan with cetuximab or FOLFIRI with cetuximab (control arm)

The study was amended to include an interim analysis of endpoints, including ORR. The primary OS endpoint is a comparison of BRAFTOVI + binimetinib in combination with cetuximab with the control arm. Key secondary endpoints assess the efficacy (OS) of BRAFTOVI in combination with cetuximab and BRAFTOVI + binimetinib in combination with cetuximab, in comparison with the control arm respectively. Other secondary endpoints include progression-free survival, duration of response, safety and tolerability.

The trial was conducted at over 200 investigational sites in North America, South America, Europe and the Asia Pacific region. The BEACON CRC trial was conducted with support from Ono Pharmaceutical Co. Ltd., Pierre Fabre Laboratories, Pfizer and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

About Pierre Fabre Laboratories

Pierre Fabre Laboratories is a French medical and beauty care company with four decades of experience in innovation, development, manufacturing, and commercialisation in oncology. The company dedicated about 80% of its R&D spendings to oncology in 2022 and has recently declared targeted therapies as its main R&D priority. Its current commercial portfolio in oncology covers colorectal, breast and lung cancers, melanoma, haematology, and pre-cancerous skin conditions like actinic keratosis.

In 2022, Pierre Fabre Laboratories posted 2.7 billion euros in revenues, 69% of which came from international sales in 120 countries. Established in the South-West of France since its creation in 1962, the Group manufactures over 90% of its products in France and employs some 9,600 people worldwide. The company is 86%-owned by the Pierre Fabre Foundation, a government-recognized public-interest foundation, and secondarily by its own employees through an international employee stock ownership plan. Pierre Fabre Laboratories' sustainability policy has been assessed by the independent AFNOR Certification body at the "Exemplary" level of its CSR label (ISO 26 000 standard for sustainable development).

Further information about Pierre Fabre Laboratories can be found at www.pierre-fabre.com, @PierreFabre.