The treatment options for Non-Small Cell Lung Cancer (NSCLC) have been flooded in recent years due to improved methods of molecular profiling and better diagnostic tools. The new molecular biomarkers with their efficacious treatments for NSCLC have changed the lives of patients where the clinical prognosis was very poor. Some rare biomarkers for NSCLC include METex14 skipping alterations, ALK rearrangements, HER-2 mutations, RET rearrangements, and many more. Despite a plethora of agents which are already available to target the receptor tyrosine kinase, MET, clinical outcomes have as yet been disappointing, leading to hopelessness about the role of MET in the pathogenesis of NSCLC. Apart from NSCLC, met is usually altered in various cancers like breast carcinoma, colorectal carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, gastric carcinoma, bladder carcinoma, and many more. There are various clinical studies that are in progress for different solid tumors.
METex14 skipping occurs in approximately 3% to 4% of NSCLC cases, and patients with this aggressive lung cancer are often elderly and face a poor clinical prognosis. Cancer metastasis consists of a sequential series of events and MET exon 14 skippings is recognized as a critical event for metastasis of carcinomas. One such therapy that has been recently approved by the US FDA is TEPMETKO (Tepotinib, Merck) for adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations (METex14 positive), having said that the patients were treatment-naïve and previously treated. The therapy has been approved after the Priority Review by the US FDA and has been granted the accelerated approval based on overall response rate and duration of response. The FDA also recently granted TEPMETKO Orphan Drug Designation for this patient pool.
Another such approval was made by the US FDA in May 2020 for Capmatinib (TABRECTA, Novartis) in adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors had a mutation that leads to MET exon 14 skipping as detected by an FDA-approved test, namely FoundationOne CDx assay. Tabrecta is approved for first-line and previously treated patients, regardless of prior treatment type.
The efficacy and safety analysis for TEPMETKO (Tepotinib) was studied in Phase II VISION study evaluating TEPMETKO as monotherapy in patients with advanced NSCLC with METex14 skipping alterations. TEPMETKO demonstrated an overall response rate of 43% in treatment-naïve patients
(n=69) and 43% in previously treated patients.
The efficacy and safety analysis for Capmatinib (TABRECTA) was studied in Phase II GEOMETRY mono-1 trial evaluating Capmatinib as monotherapy in patients metastatic NSCLC with confirmed MET exon 14 skipping. Among the
28 treatment-naïve patients, the ORR was 68% with a response duration of 12.6 months. Among the 69 previously treated patients, the ORR was 41% with a response duration of 9.7 months. Despite reduced ORR in treatment-naïve patients and similar response rates in previously treated patients of the VISION trial, one advantage that outweighs Capmatinib in the GEOMETRY mono-1 trial is the dosing regimen of TEPMETKO (Tepotinib). TEPMETKO is the first and only FDA-approved MET inhibitor that offers once-daily oral dosing and is administered as two 225 mg tablets (450 mg). Patients with metastatic NSCLC should be selected for treatment with TEPMETKO based on the presence of MET exon 14 skipping alterations. On the other side, the recommended dosage for Capmatinib is 400 mg orally twice daily.
Until the First-ever approval of Capmatinib (Novartis), how NSCLC patients with met exon 14 skipping alterations were treated?
Prior to the entry of capmatinib in the Non-small cell lung cancer market, there was no MET inhibitor approved for patients with mNSCLC with METex14 skipping mutations. These patients could receive crizotinib (off-label use) or standard of care treatments similar to patients without a driver mutation, such as pembrolizumab monotherapy, pembrolizumab in combination with chemotherapy, or platinum doublet chemotherapy.
The most recent National Comprehensive Cancer Network (NCCN) guideline for mNSCLC noted patients with METex14 skipping mutations has a modest response to immunotherapy, even those with high PD-L1 levels; after the FDA approval, capmatinib has been recommended as a category 2A therapy option (preferred) for patients with METex14 skipping mutations, while crizotinib and other systemic therapy options are designated as useful in certain circumstances.
Launch Price of Capmatinib Vs Tepotinib?
Capmatinib when launched bore a list price of $17,950 for a 28-day supply, which is comparable to the cost of other existing therapies prescribed for this aggressive form of lung cancer whereas the launch price of Tepotinib is yet to be decided by the company. The reimbursement and market pricing are going to have a great impact on the sales of the above two, however, the patients are now going to have choices for this segment exhibiting poor prognosis in NSCLC.
Expected Forecast of Capmatinib Vs. Tepotinib?
With the growing awareness about molecular profiling and improved diagnostics, met mutations had 7,689 NSCLC prevalence in the United States in the year 2020. The number is expected to gradually increase during the forecast period of 2021-2030. Apart from the increase in the incident population, the newer therapies are also going to boost the market. According to Delveinsight, “the expected market sizes of Capmatinib and Tepotinib in the year 2030 are USD 250.7 and 213.1 million in the United States. These targeted therapies are going to revolutionize the treatment of c-met mutations in lung cancers”.
APL-101 by Appollomics is being investigated in subjects with NSCLC with c-Met eXON 14 skip mutations and c-Met dysregulation advanced solid tumors. APL-101 is a novel, highly selective small-molecule c-Met inhibitor (c-METi) that targets the c-Met-dysregulated pathway in several tumors. APL-101 has demonstrated tumor inhibitory effect in a variety of human primary gastric, hepatic, pancreatic, and lung tumor xenograft animal models with c-Met dysregulations. It is under investigation for Sparta Phase I/II clinical trial. The target indications include non-small cell lung cancer (NSCLC) with MET exon 14 skipping alterations, Glioblastoma multiforme with MET amplification and fusions, and Solid tumors with MET amplification and fusions.
Merestinib by Lilly, Inc is a multi-targeted TKI that can inhibit MET, RON, AXL, MER receptor tyrosine kinase (MERTK), TIE-2, TIE-1, ROS1, and discoidin domain receptor tyrosine kinase 1. This may induce cell death in tumor cells overexpressing c-Met protein or expressing the constitutively activated c-Met protein. c-Met, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis. The agent is currently in phase II for advanced or metastatic biliary tract cancer, NSCLC, and Solid Tumors. According to the Delveinsights Analysts, “the drug is expected to show a market size of USD 18.3 million in the year 2030”.
With so much research going on for METex14 skipping, it’s quite obvious that this segment is going to emerge as a significant pool in which patients are going to ample amount of choices with clinically improved survival rates. Not only the patients, but the physicians are also going to benefit from the availability of treatment options for the patients who have already been treated with chemotherapies and combinations and have progressed with acquired resistance to previous therapies provided. The patients can now breathe a sigh of relief with improved survival outcomes and better quality of life.