Pierre Fabre Laboratories receives CHMP positive opinion for BRAFTOVI® (encorafenib) in combination with MEKTOVI® (binimetinib) for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with a BRAFV600E mutation

·       The positive CHMP opinion is based on results from the Phase II PHAROS trial,¹ which demonstrated an objective response rate (ORR) of 75% in treatment-naïve patients and 46% in previously treated patients. The safety profile is consistent with that observed in the approved metastatic melanoma indication¹

·       The European Commission decision for BRAFTOVI^® (encorafenib) + MEKTOVI^® (binimetinib) is expected later this year.

 

Castres, France, July 25^th, 2024 – Pierre Fabre Laboratories announced today that the Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending the approval of BRAFTOVI^® (encorafenib) in combination with MEKTOVI^® (binimetinib) for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with a BRAF^V600E mutation. The positive opinion will now be submitted to the European Commission (EC) with a decision on EU marketing authorisation (MA) expected later this year.

 

Eric Ducournau, Chief Executive Officer, Pierre Fabre Laboratories said: “The positive CHMP opinion marks a pivotal step in our commitment to delivering an additional effective targeted treatment option for patients with advanced NSCLC with a BRAF^V600E mutation, who at present have limited treatment options. We look forward to the European Commission's decision to make BRAFTOVI^® + MEKTOVI^® available to non-small cell lung cancer patients in Europe.”

 

The CHMP positive opinion is supported by data from the global, open-label, multicentre, non-randomised Phase II PHAROS trial, which included 98 patients from 56 study centres across 5 countries.¹

 

At primary analysis (cut-off date: September 22, 2022), the primary endpoint of the trial (objective response rate [ORR] determined by independent radiology review [IRR]) was met. The PHAROS trial showed that in patients with advanced NSCLC with a BRAF^V600E mutation, BRAFTOVI^® and MEKTOVI^® provided a meaningful clinical benefit with an ORR of 75% (95% CI: 62, 85) in treatment naïve patients (n=59), with 59% of them maintaining their response for at least 12 months. For those patients who had received prior therapy (n=39), the ORR was 46% (95% CI: 30, 63), with 33% maintaining their response for at least 12 months.¹

 

The median progression-free survival (PFS) according to IRR was not estimable (NE) for the treatment naïve group (95% CI: 15.7, NE) and was 9.3 months (95% CI: 6.2, NE) for the previously treated group. Median overall survival (OS) was NE for either subgroup.¹

 

The most common (≥20%) treatment-related adverse events (TRAE) observed in the PHAROS trial were nausea (50%), diarrhoea (43%), fatigue (32%) and vomiting (29%). Treatment-related serious AEs occurred in 14% of patients, with the most common being colitis (3%).¹ One grade 5 TRAE of intracranial haemorrhage was reported.

 

BRAFTOVI^® + MEKTOVI^® are currently approved in Europe for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF^V600 mutation.^2,3 BRAFTOVI^® in combination with cetuximab is also approved in Europe for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF^V600E mutation who have received prior systemic therapy.² On the 12^th October 2023, Pierre Fabre Laboratories’ partner Pfizer, announced the approval of BRAFTOVI^® + MEKTOVI^® by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with BRAF^V600E mutant metastatic NSCLC, as detected by an FDA approved test.⁴

 

About PHAROS

PHAROS (NCT03915951) is an on-going open-label, single arm, multicentre, non-randomised Phase II trial to determine the efficacy and safety of BRAFTOVI^® (encorafenib 450 mg QD) in combination with MEKTOVI^® (binimetinib 45 mg BID) in 98 patients with advanced NSCLC with a BRAF^V600E mutation who are either treatment-naive or who have been previously treated with platinum-based chemotherapy and/or anti-PD-1/PD-L1 inhibitor therapy. Mutations were identified using next-generation sequencing or polymerase chain reaction tests performed at the patient’s local laboratory. The primary endpoint is confirmed ORR per RECIST v1.1, by independent radiology review (IRR); secondary objectives comprise additional efficacy endpoints including duration of response (DOR), PFS, and OS as well as safety. The trial is being conducted across 56 sites in: Italy, the Netherlands, South Korea, Spain, and the U.S.

 

The PHAROS trial is sponsored by Pfizer Inc. and conducted with support from Pierre Fabre Laboratories.

 

About BRAF^V600E mutant advanced Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer-related deaths, with almost 1.8 million deaths worldwide annually.¹⁴ Globally, lung cancers make up 12.4% of all cancers with over 2.2 million new cases every year. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 80% of all lung cancers. ^5,6

 

Currently, it is estimated that up to 69% of advanced NSCLC patients have druggable mutations in numerous genes.¹³

These mutations can occur in several genes; one of these is known as a v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation, which causes 1-5% of all NSCLCs.¹⁶

 

BRAF mutations stimulate tumor cell growth and proliferation by altering the MAP kinase

(MAPK) signaling pathway.¹ One of the most common BRAF mutations is BRAF^V600E which occurs in approximately 1-2% of NSCLC cases. ⁷

 

Inhibition of both BRAF and the downstream mitogen activated protein kinase (MEK) pathway has been shown to improve response rates in patients compared with BRAF inhibition alone.¹²

 

Precision medicine has made great progress in the treatment of lung cancer for NSCLC patients with genetic alterations, such as BRAF^V600E mutations, that can be detected using biomarker tests.^9,10 Advances in targeted therapy and more widespread use of biomarker testing have been associated with significant improvements in population-level NSCLC mortality in recent years.¹¹

 

About BRAFTOVI^® + MEKTOVI^®

BRAFTOVI^® (encorafenib), a potent and highly selective BRAF inhibitor with a distinct pharmacological profile compared with other BRAF inhibitors, and MEKTOVI^® (binimetinib), a potent and selective MEK inhibitor, inhibit kinases in the MAPK pathway – which is constitutively activated in BRAF^V600 mutant NSCLC - resulting in clinically relevant anti-tumour activity.

Uncontrolled activation of this pathway has been shown to occur in many cancers, including melanoma, CRC, and NSCLC.^1,15

 

In 2018, the EC approved BRAFTOVI^® + MEKTOVI^® for adult patients with unresectable or metastatic melanoma with a BRAF^V600 mutation. The approval was based on results from the randomised, active-controlled, open-label, multicentre Phase III COLUMBUS trial.

 

In 2020, the EC approved BRAFTOVI^® in combination with cetuximab, for the treatment of adults with metastatic CRC with a BRAF^V600E mutation who have received prior systemic therapy. The approval was based on results from the randomised, active-controlled, open-label, multicentre Phase III BEACON CRC trial.

 

Pfizer has exclusive rights to commercialise BRAFTOVI^® and MEKTOVI^® in the U.S., Canada, and all countries in the Latin American, African, and Middle Eastern regions. Ono Pharmaceutical Co., Ltd. has exclusive rights to commercialise both products in Japan and South Korea, Medison has exclusive rights in Israel, and Pierre Fabre Laboratories has exclusive rights in all other countries, including Europe and Asia-Pacific.

 

The full product and safety information for the use of BRAFTOVI^® and MEKTOVI^® are outlined in the Summary of Product Characteristics (SmPC), published in the European public assessment report (EPAR) and available in all official EU languages. The full SmPCs can be accessed at: https://www.ema.europa.eu/en/documents/product-information/braftovi-epar-product-information_en.pdf  and https://www.ema.europa.eu/en/documents/product-information/mektovi-epar-product-information_en.pdf

 

About Pierre Fabre Laboratories 

Pierre Fabre Laboratories is one of Europe's leading pharmaceutical companies. For over 40 years, it has established itself as an international player in oncology, mastering the entire value chain from R&D to marketing. Its portfolio of oncology specialties covers colorectal, breast, lung and skin cancers, as well as certain hematologic malignancies and precancerous dermatological conditions such as actinic keratosis. In 2023, its oncology revenue amounted to nearly 500 million euros, over 90% of which was generated outside France.

In 2023, Pierre Fabre Laboratories posted 2.83 billion euros in revenue, 70% of which came from international sales in 120 countries. Its portfolio includes several international brands and medical franchises such as Pierre Fabre Innovative Oncology, Pierre Fabre Medical Dermatology, Pierre Fabre Pharmaceutical Care, Eau Thermale Avène, Ducray, A-Derma, Klorane, René Furterer and Même Cosmetics.  

Historically based in the southwest of France and manufacturing 95% of its products in France, Pierre Fabre Laboratories employs over 10,000 people worldwide. Its annual R&D budget amounts to nearly 200 million euros, of which about 50% is dedicated to targeted therapies in oncology and 40% to skin health and care solutions.  

Pierre Fabre Laboratories' majority shareholder (86%) is the eponymous Foundation, which is recognized by the French government as being a public–interest foundation. This capital structure guarantees the company's independence and long-term vision. Dividends paid to the Pierre Fabre Foundation enable it to design and finance humanitarian healthcare-access programs in developing countries. Employees are the company's secondary shareholder, through an international employee shareholding plan.  

Pierre Fabre Laboratories’ sustainability policy has been assessed by the independent AFNOR Certification body and has been awarded the "Exemplary" level of its CSR label (ISO 26 000 standard for sustainable development).  

For more information, visit www.pierre-fabre.com, @Pierre Fabre Oncology.

 

Pierre Fabre Laboratories Media Contact:

Laurence Marchal

+33 7 88 88 54 47

Laurence.marchal@pierre-fabre.com

 

 

References

 

¹ Riely GJ, Smit EF, Ahn MJ. Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non–Small-Cell Lung Cancer. Journal of Clinical Oncology.2023;41:21,3700-3711.

 

² European Medicines Agency. BRAFTOVI® (encorafenib) Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/braftovi. Last accessed: November 2023.

 

³ European Medicines Agency. MEKTOVI® (binimetinib) Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/mektovi. Last accessed: July 2023.

 

⁴ Pfizer Inc. U.S. FDA Approves Pfizer’s BRAFTOVI® + MEKTOVI® for BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer. Available at: https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-braftovir-mektovir-braf-v600e. Last accessed: November 2023.

 

⁵ World Health Organization. International Agency for Research on Cancer. GLOBOCAN 2020: Lung cancer fact sheet. Available at: http://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Last accessed: November 2023.

 

⁶ American Cancer Society. What is lung cancer? Available at: https://www.cancer.org/cancer/lung-cancer/about/what-is.html. Last accessed: November 2023.

 

⁷ Planchard, D., Sanborn, R.E., Negrao, M.V. et al. BRAF^V600E-mutant metastatic NSCLC: disease overview and treatment landscape. npj Precis. Onc. 8, 90 (2024). https://doi.org/10.1038/s41698-024-00552-7

 

⁸ Yan N, Guo S, Zhang H, et al. BRAF-Mutated Non-Small Cell Lung Cancer: Current Treatment Status and Future Perspective. Front Oncol. 2022;12:863043. doi: 10.3389/fonc.2022.863043.

 

⁹ Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(Suppl. 4), iv192-iv237. Doi:10.1093/annonc/mdy275.

 

¹⁰ König D, Savic Prince S, Rothschild SI. Targeted therapy in advanced and metastatic non-small cell lung cancer. An update on treatment of the most important actionable oncogenic driver alterations. Cancers. 2021;13(4), 804. doi:10.3390/cancers13040804.

 

¹¹ Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383(7), 640–649. doi:10.1056/NEJMoa1916623.

 

¹² Khunger et al. Dabrafenib in combination with trametinib in the treatment of patients with BRAFv600-positive advanced or metastatic non-small cell lung cancer: clinical evidence and experience. Ther Adv Respir Dis 2018, Vol. 12: 1–9.

¹³ Fois S. S et al. Molecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer Int. J. Mol. Sci. 2021, 22, 612.

¹⁴ Cancer Today. All Cancers Factsheet. Available at: https://gco.iarc.who.int/media/globocan/factsheets/populations/900-world-fact-sheet.pdf. Last accessed: July 2024.

¹⁵ Delord J-P, et al. Clin Cancer Res. 2017;23(18):5339-5348.

 

¹⁶Planchard, David et al. Journal of Thoracic Oncology, 2021 Volume 17, Issue 1, 10 - 115