Merck KGaA recently announced that the US Food and Drug Administration (FDA) has approved the targeted anticancer drug Tepmetko (tepotinib), which is a highly selective, once-daily oral MET inhibitor for Treatment of adult patients with advanced non-small cell lung cancer (NSCLC) carrying the MET exon 14 skipping change (METex14 skipping). Tepmetko received priority review and accelerated approval through the FDA Real-Time Oncology Review (RTOR) pilot program. The approval is based on data on the total response rate and duration of response, and continued approval for this indication will depend on the verification and description of clinical benefits in confirmatory trials.
In March 2020, Tepmetko received the world's first regulatory approval in Japan for the treatment of patients with unresectable, advanced or recurrent NSCLC who have skipped changes in METex14. In November 2020, the European Medicines Agency (EMA) accepted Teppetko's application and started the review process.
It is worth mentioning that Teppetko is the world's first oral MET inhibitor approved for the treatment of advanced NSCLC patients with MET genetic changes. In Japan, Teppetko was granted Orphan Drug Designation (ODD) and SAKIGAKE Designation (Innovative Drug). In the United States, Teppetko was granted Orphan Drug Designation (ODD) and Breakthrough Drug Designation (BTD).
Tepmetko is also the first and only MET inhibitor approved by the US FDA for the treatment of patients with METex14 skipped metastatic NSCLC. In September 2020, Novartis' targeted anticancer drug Tabrecta (capmatinib) was approved, which is the first MET inhibitor approved by the FDA to treat adult patients with METex14 skipping changes in metastatic NSCLC.
Both Tepmetko and Tabrecta are approved for use in patients who have not previously received treatment (first-line) and patients who have previously received treatment (treated). In terms of medication, Tepmekto is taken orally once a day, and Tabrecta is taken orally twice a day.
Tepmetko's regulatory approval is based on data from the pivotal Phase II VISION study (NCT02864992). This is the largest clinical study carried out so far in metastatic NSCLC patients with METex14 skip changes. A total of 152 NSCLC patients with METex skip changes received Tepmetko treatment.
The results showed that Teppetko had an overall response rate (ORR) of 43% in patients who had not previously received treatment (n=69, initial treatment group) and previously treated patients (n=83, treated group). 99%CI: 32-56) and 43% (95%CI: 33-55), the median duration of response (DOR) of the 2 groups were 10.8 months and 11.1 months, and the response time of the 2 groups was ≥ 6 months The proportions of patients were 67% and 75%, and the proportions of patients with remission time ≥ 9 months were 30% and 50%, respectively.
The safe population included 255 patients with METex14 skip change positive NSCLC who received Tepmetko treatment in the VISION study. 1 case (0.4%) died of pneumonia, 1 case (0.4%) died of liver failure, and 1 case (0.4%) died of dyspnea caused by excessive fluid. Serious adverse reactions occurred in 45% of patients treated with Tepmetko. Serious adverse reactions with an incidence of> 2%, including pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), deterioration of general health (3.5%), pulmonary embolism (2 %) and musculoskeletal pain (2%). The most common adverse reactions (≥20%) in patients taking Teppetko are edema, fatigue, nausea, diarrhea, musculoskeletal pain, and difficulty breathing.
Molecular structure of tepotinib (picture source: chemicalbook.com)
Globally, lung cancer is the most common type of cancer and the leading cause of cancer deaths, with 2 million diagnoses and 1.7 million deaths each year. At present, in many types of cancers, three MET signaling pathway changes (including METex14 skipping changes, MET amplification, and MET protein overexpression) have been discovered, which are related to tumor aggressive behavior and poor clinical prognosis. It is estimated that changes in the MET signaling pathway occur in 3-5% of NSCLC cases.
Tepotinib is an oral MET kinase inhibitor found in Merck, which can strongly and highly selectively inhibit the oncogenic signals caused by MET (gene) changes, including METex14 jumping changes, MET amplification, and MET protein overexpression. , Has the potential to improve the prognosis of aggressive tumor patients with these specific MET changes. In addition to NSCLC, Merck is also actively evaluating tepotinib combined with new therapies for other tumor indications.
In September 2019, the US FDA granted tepotinib breakthrough drug designation (BTD) for the treatment of patients with metastatic NSCLC who have progressed after receiving platinum-containing chemotherapy and carry METex14 jump changes.
Currently, Merck is also carrying out another study INSIGHT 2 (NCT03940703) to evaluate the combination of tepotinib and tyrosine kinase inhibitor (TKI) osimertinib for EGFR mutations and METs that have acquired resistance to previously accepted EGFR TKIs. Patients with expanded, locally advanced or metastatic NSCLC.