Novartis Receives CDE Approval for Dabrafenib Plus Trametinib in BRAF V600-Mutant Advanced NSCLC

According to the official website of the Center for Drug Evaluation (CDE) under China’s National Medical Products Administration, Novartis’ clinical trial application for trametinib has received implicit approval. The indicated use is for trametinib in combination with dabrafenib for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring BRAF V600 mutations.

Melanoma as a Breakthrough Point

Dabrafenib and trametinib were developed by GlaxoSmithKline (GSK). In 2014–2015, Novartis and GSK executed a major asset swap, whereby Novartis acquired GSK’s oncology portfolio for $14.5 billion, thereby gaining ownership of these two drugs. Simultaneously, Novartis transferred its vaccine business, excluding influenza vaccines, to GSK for $7.1 billion plus royalties. Recently, however, GSK sold two of these vaccines—Rabipur, used for the prevention of rabies, and Encepur, used for the prevention of tick-borne encephalitis—for $1.06 billion.(See details: GSK Sells Two Vaccines for $1 Billion)。

Dabrafenib is a BRAF inhibitor that received U.S. FDA approval in May 2013 for the treatment of patients with metastatic melanoma and unresectable melanoma, becoming the third drug approved for metastatic melanoma after vemurafenib and ipilimumab. Trametinib is a KRAS/MEK inhibitor that also received U.S. FDA approval in May 2013 as monotherapy for patients with advanced melanoma harboring BRAF V600E/K mutations. It is also the first allosteric kinase inhibitor approved by the FDA.

In 2011, the FDA approved the first BRAF inhibitor, vemurafenib, marking a breakthrough in the treatment efficacy for melanoma. However, approximately 50% of patients treated with BRAF or MEK inhibitors as monotherapy develop resistance within 6–7 months after treatment. Further studies have revealed that in tumor cells harboring the BRAF V600E mutation, the combination of BRAF V600E and MEK inhibitors can increase the level of tumor cell apoptosis.

A series of trials have demonstrated that the combination of dabrafenib and trametinib exhibits stronger antitumor activity compared to either agent used as monotherapy. For instance, results from the phase III COMBI-AD study (NCT01682083; EudraCT No. 2012-001266-15) showed that adjuvant therapy with dabrafenib and trametinib in patients with stage III melanoma harboring BRAF mutations reduced the risk of recurrence or death by 53% compared with placebo. After a median follow-up of 2.8 years, the 3-year relapse-free survival rate was 58% in the dabrafenib and trametinib group versus 39% in the placebo group (HR 0.47; 95% CI, 0.39–0.58; P<0.001).

Since their market launch, the performance of both drugs has been noteworthy. According to the Prescription Drug Database (PDB), dabrafenib achieved a compound annual growth rate (CAGR) of over 36% from 2014 to 2017, with global sales reaching nearly USD 600 million in 2017 (see Figure 1); trametinib recorded a CAGR of 57% during the same period, with global sales approaching USD 500 million in 2017 (see Figure 2).

Strategic Expansion into High-Incidence Cancers to Capture Market Share

Dabrafenib and trametinib target BRAF and MEK1/2, respectively, which are two distinct kinases within the serine/threonine kinase family of the RAS/RAF/MEK/ERK pathway. This pathway plays a critical role in the initiation and progression of various cancers, including melanoma and non-small cell lung cancer.

In June 2017, the FDA approved dabrafenib in combination with trametinib for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations. This approval established BRAF V600E as the fourth genomic biomarker for metastatic NSCLC, following EGFR, ALK, and ROS1.

The aforementioned approval was based on the results of a three-cohort, multicenter, non-randomized, open-label Phase II study involving patients with Stage IV non-small cell lung cancer (NSCLC), with the primary endpoint being the objective response rate (ORR). In the study, one cohort consisted of 36 treatment-naïve patients, and the other comprised 57 previously treated patients. Patients in both cohorts received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. At a median follow-up of 9 months, the ORR in the first cohort was 61.1%, with 68% of patients remaining progression-free; the ORR in the second cohort was 63%. The study also demonstrated durable responses post-treatment, with a median duration of response of 12.6 months.

In addition to the aforementioned indications, dabrafenib in combination with trametinib has been approved for multiple indications to date: In January 2014, it received initial FDA approval for the treatment of patients with metastatic melanoma; one year later, it was also approved by the European Union for the treatment of adult patients with unresectable or metastatic melanoma harboring BRAF V600 mutations; in June 2017, it received FDA approval for the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) positive for BRAF V600 mutations; in May 2018, it received FDA approval for the treatment of patients with anaplastic thyroid cancer (ATC) who are positive for the BRAF V600E mutation and whose tumors are unresectable or have metastasized to other parts of the body.

The marketing applications for dabrafenib and trametinib as monotherapies submitted in China were accepted on January 7, 2019, under acceptance numbers JXHS1800081/JXHS1800082 and JXHS1800083/JXHS1800084, and were included in the Center for Drug Evaluation’s (CDE) priority review list in February. On July 11, the CDE accepted the marketing application for the combination of dabrafenib and trametinib, under acceptance numbers JXHS1900090/JXHS1900091 and JXHS1900092/JXHS1900093.

Data show that more than 80% of lung cancer cases in China are non-small cell lung cancer (NSCLC), and among all patients with NSCLC, 1%–3% harbor BRAF V600 mutations. These patients have previously relied primarily on chemotherapy. Therefore, industry insiders speculate that the first indications for which dabrafenib and trametinib will be filed in China are likely to be melanoma. That is, melanoma, despite its lower incidence in China, would serve as a breakthrough entry point, followed by strategic expansion into the NSCLC market to capture share.