Novartis' Dual-Targeted Therapy Dabrafenib/Trametinib Nominated for Priority Review in China for BRAF V600-Mutant Advanced NSCLC

By | Pharma Observer

The latest announcement from the Center for Drug Evaluation (CDE) under China's National Medical Products Administration (NMPA) indicates that Novartis's classic dual-target combination therapy—dabrafenib/trametinib—is proposed for priority review for the treatment of patients with advanced non-small cell lung cancer (NSCLC) positive for BRAF V600 mutations.

Screenshot Source: CDE Official Website

Dabrafenib and trametinib respectively target distinct kinases within the serine/threonine kinase family of the RAS/RAF/MEK/ERK pathway—BRAF and MEK1/2, which are commonly found in cancers such as non-small cell lung cancer (NSCLC) and melanoma. When used in combination, these agents simultaneously inhibit both BRAF and MEK targets, and their efficacy in slowing tumor growth has been proven superior to that of monotherapy.

It is worth noting that dabrafenib and trametinib were originally owned by GlaxoSmithKline (GSK), with the developmental code names GSK2118436 and GSK1120212, respectively. In March 2015, Novartis reached an acquisition agreement with GSK to acquire the latter's oncology business, including the exclusive rights to dabrafenib and trametinib, for a total cash consideration of $16 billion.

In China, the dabrafenib/trametinib combination therapy was first approved in December 2019 for the treatment of unresectable or metastatic melanoma positive for BRAF V600 mutations. In March 2020, the combination therapy received approval for a second indication in China for the adjuvant treatment of patients with stage III BRAF V600 mutation-positive melanoma following complete resection. This approval also officially ushered in the era of dual-targeted therapy for melanoma patients in China.

This combination therapy has been proposed for priority review by the CDE, indicated for patients with advanced non-small cell lung cancer (NSCLC) harboring BRAF V600 mutations. According to statistics, approximately 1–3% of NSCLC patients carry BRAF protein mutations. These patients are in urgent need of appropriate treatment, as tumors with such mutations are more aggressive, demonstrate poorer responses to standard chemotherapy, and are more likely to result in worse prognostic outcomes.

Screenshot source: CDE Official Website

As early as June 2017, the dabrafenib/trametinib combination therapy was approved by the U.S. FDA for the treatment of patients with non-small cell lung cancer (NSCLC) whose tumors harbor the BRAF V600E mutation. This approval was based on the results of the Phase II clinical trial BRF113928. The study enrolled 93 patients with advanced NSCLC harboring the BRAF V600E mutation. Among them, 36 treatment-naïve patients received the combination therapy once daily, achieving an overall response rate (ORR) of 61%; the remaining 57 patients, who had previously been treated with chemotherapy, received the same dosage, achieving an ORR of 63% and a median duration of response of 12.6 months.

According to an earlier press release from Novartis, this marks a significant milestone in the field of lung cancer. The approval of the dabrafenib/trametinib combination therapy establishes BRAF V600E as the fourth actionable genomic biomarker in metastatic non-small cell lung cancer, following EGFR, ALK, and ROS-1.

(Abridged)

References:

[1] Center for Drug Evaluation (CDE), National Medical Products Administration. Retrieved Aug 26, 2021, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=20

[2] Tafinlar (dabrafenib) and Mekinist (trametinib) Approved for Marketing in China. Retrieved Dec. 19, 2019, from https://www.prnasia.com/story/268607-1.shtml

[3] Dual-Target Therapy, Double Approval——Tafinlar® and Mekinist® Approved for Adjuvant Therapy Indications. Retrieved March 09, 2020, from https://mp.weixin.qq.com/s/gD26VdaI_6r2J_G1arOW4A

[4]Novartis AG (NVS) Combination Targeted Therapy Tafinlar + Mekinist Receives FDA Approval For BRAF V600E Mutant Metastatic Non-Small Cell Lung Cancer (NSCLC). Retrieved Jun 22，2017, from https://www.novartis.com/news/media-releases/novartis-combination-targeted-therapy-tafinlar-mekinist-receives-fda-approval-braf-v600e-mutant-metastatic-non-small-cell-lung-cancer-nsclc#:~:text=Basel%2C%20June%2022%2C%202017%20-%20Novartis%20today%20announced,%28NSCLC%29%20whose%20tumors%20express%20the%20BRAF%20V600E%20mutation.

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