Novartis' Trametinib Plus Dabrafenib Combination Therapy Set for New Indication Approval in China for BRAF V600E-Mutant NSCLC

By Cai Cai

Recently, according to the NMPA website, the marketing application for the second indication of Novartis' trametinib (acceptance numbers: JXHS1900090, JXHS1900091) / dabrafenib (acceptance numbers: JXHS1900092, JXHS1900093) combination therapy has been changed to "under review," and it is expected to be approved for marketing in the near future. The predicted indication for this approval is non-small cell lung cancer. Last December, this combination therapy was already approved in China for melanoma.

(Source: NMPA)

Trametinib: The First FDA-Approved Allosteric Kinase Inhibitor

Trametinib (brand name: Mekinist/Maijining) is a MEK inhibitor initially identified through high-throughput cell-based activity screening. It was approved in May 2013 as monotherapy for patients with advanced melanoma harboring BRAF V600E/K mutations, becoming the first allosteric kinase inhibitor approved by the FDA.

Dabrafenib—The Third FDA-Approved Drug for the Treatment of Metastatic Melanoma

Dabrafenib (brand name: Tafinlar) is a BRAF inhibitor that was approved by the FDA in May 2013 for the treatment of patients with unresectable or metastatic melanoma. This drug is not indicated for wild-type melanoma, and testing for the BRAF V600E mutation is required prior to initiation of therapy. Dabrafenib is the third drug approved by the FDA for the treatment of metastatic melanoma, following vemurafenib and ipilimumab.

The Combined Power of Two Drugs Delivers Significant Efficacy—Approvals Granted for Melanoma, Small Cell Lung Cancer, and Thyroid Cancer

Trametinib and dabrafenib are like a pair of twins, typically used in combination therapy to combat cancer. Currently, the indications approved by the FDA include melanoma, small cell lung cancer, and thyroid cancer; the indication approved by the NMPA is melanoma.

BRAF is a proto-oncogene. Approximately 8% of human tumors harbor BRAF mutations, with the vast majority being the BRAF V600E mutation, which predominantly occurs in melanoma, thyroid cancer, and colorectal cancer. This mutation leads to constitutive activation of the downstream MEK/ERK signaling pathway, which is critical for tumor growth, proliferation, invasion, and metastasis. Further studies have demonstrated that in tumor cells with the BRAF V600E mutation, the combination of BRAF V600E and MEK inhibitors can increase the level of tumor cell apoptosis. A Phase I/II trial showed that dabrafenib combined with trametinib nearly doubled the duration of response and significantly improved progression-free survival (PFS) compared with monotherapy.

Due to the remarkable efficacy of the combination therapy with trametinib and dabrafenib, the FDA has successively approved this regimen for multiple indications, including melanoma, non-small cell lung cancer, and thyroid cancer.

In January 2014, the FDA approved dabrafenib in combination with trametinib for the treatment of patients with metastatic melanoma harboring BRAF V600E/K mutations;

In June 2017, the FDA approved the combination of dabrafenib and trametinib for patients with BRAF V600E-mutant non-small cell lung cancer (NSCLC), achieving an overall response rate exceeding 60% and a median duration of response of 12.6 months;

In May 2018, the FDA approved the combination of dabrafenib and trametinib for the treatment of patients with BRAF V600E mutation-positive, locally advanced or metastatic anaplastic thyroid cancer (ATC) who have no standard local treatment options;

In December 2019, the NMPA approved the combination of dabrafenib and trametinib for the treatment of unresectable or metastatic melanoma with BRAF V600 mutation-positive status.

New Therapies for NSCLC Patients with BRAF V600 Mutations

As the most prevalent cancer in China, lung cancer has an annual incidence of approximately 781,000 cases, with non-small cell lung cancer (NSCLC) accounting for over 80% of these cases. Among all NSCLC patients, approximately 1–3% harbor BRAF V600 mutations. Previously, chemotherapy was the primary treatment modality for this patient population; the emergence of the trametinib/dabrafenib combination therapy represents a significant milestone in the field of lung cancer treatment.

The approval of dabrafenib plus trametinib has established BRAF V600E as the fourth actionable genomic biomarker in metastatic non-small cell lung cancer (NSCLC), following EGFR, ALK, and ROS1; however, genomic testing must be performed in lung cancer patients prior to this intervention.

2019 sales reached $1.338 billion, a year-on-year increase of 16%.

According to the Menet database, following the approval and market launch of the trametinib/dabrafenib combination therapy, its global sales have risen year by year, reaching US$1.338 billion in 2019, a year-on-year increase of 15.8%.

(Data source: Menet)

Original Title: Indication | Good News for NSCLC Patients with BRAF V600E Mutation! Novartis' Trametinib + Dabrafenib New Indication is About to be Approved for Market Launch