On March 25, 2022, Novartis announced that the dual-targeted combination therapy drugs darafenib mesylate capsules (trade name: Tefeler) and trimetinib tablets (trade name: meginin) have been approved by the State Drug Administration of the Mainland (NMPA) for the treatment of braf V600 mutation-positive metastatic non-small cell lung cancer (NSCLC).
I have talked about too many drugs that target lung cancer EGFR and ALK gene mutations, and the mutant gene BRAF may be relatively unfamiliar. In fact, in the basic package of genetic testing, the BRAF gene is a required gene. BRAF is an important proto-oncogene in humans, and about 8% of malignant tumors are related to BRAF gene mutations. More than 30 mutations in this gene are known, of which BRAF V600E is the most common.
Characteristics of braf V600E mutations in lung cancer patients
1. BRAF V600 mutation is relatively rare in non-small cell lung cancer, about 2%-3%, which is a rare mutation.
2. BRAF mutations are more common in lung adenocarcinoma and are more common in patients with lung adenocarcinoma who smoke, which is different from EGFR and ALK gene mutations.
3. BRAF mutation will continue to activate the downstream MEK-ERK signaling pathway, which plays an important role in the growth and proliferation of tumors and invasion and metastasis, so BRAF mutations represent strong tumor aggressiveness and poor prognosis.
4. The chemotherapy and immunotherapy effects of advanced lung cancer patients with BRAF mutation are not satisfactory, and the median overall survival (OS) is 13.6 to 13.8 months.
Initially, scientists found that the incidence of BRAF mutations in melanoma is high, the vast majority of studies are in malignant melanoma, and developed BRAF inhibitors for melanoma, dallafinib and trimetinib. This dual-target combination employs an innovative mechanism that comprehensively inhibits the upstream and downstream pathways of MAPK. Darafenib is a selective BRAF kinase activity inhibitor; tremetinib is a reversible, highly selective allosteric inhibitor of MEK1 and MEK2 kinase activity, and the combination of the two can inhibit both BRAF and MEK targets, thereby achieving the effect of 1+1>2.
With the deepening of research, as the largest lung cancer patient, if there is a BRAF mutation, can the use of BRAF inhibitors also play a role? The results of the phase II clinical NCT1336634 study showed that the first-line treatment of BRAF V600E mutant advanced non-small cell lung cancer with DALAFINIL combined with trimetinib had an objective response rate of 64%, the median PFS was 10.9 months, and the median DOR was 10.4 months.
Can this result be replicated in Chinese groups? In a national multi-center Phase II clinical trial led by Professor Zhang Li of the Center for Cancer Prevention and Control of Sun Yat-sen University, the study confirmed the excellent efficacy of dalafenib combined with trimetinib on the metastatic NSCLC of BRAF V600E mutation.
Dallafinib combined with trimetinib is China's first braf V600 mutant lung cancer targeted therapy, marking the official application of dual-target therapy to non-small cell lung cancer patients in mainland China. In December 2019, dalafenib and trimetinib were listed in China, and the approved indications were advanced and unresectable melanoma and adjuvant therapy after stage III melanoma resection. Today, lung cancer patients with BRAF mutations have official approval for the use of these two targeted drugs, and they no longer have to worry about taking drugs for supra-indications.