Evolving Landscape for Rare Biomarkers in Non-Small Cell Lung Cancer

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 that 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 are recognized as critical events 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.

The US FDA approved Capmatinib (TABRECTA, Novartis) in May 2020 for 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, the 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 with 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.

Timeline of Approval and Milestones

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, no MET inhibitor was approved for patients with mNSCLC with METex14 skipping mutations. These patients could receive crizotinib (off-label use) or standard-of-care treatments similar to those for 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 have 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?

When it comes to the treatment of metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutations, two key drugs stand out: Capmatinib (Tabrecta) and Tepotinib (Tepmetko). These therapies, both FDA-approved, offer significant advances in treatment options for patients with this specific mutation, but their prices vary considerably.

Capmatinib received FDA approval on May 6, 2020, and launched with a wholesale acquisition cost (WAC) of approximately $9,469 per month. This price point positioned it as a relatively more affordable option for patients needing targeted therapy. On the other hand, Tepotinib, which gained FDA approval a bit later, on February 3, 2021, came with a significantly higher WAC of around $20,899 per month.

In essence, Capmatinib’s launch price is notably lower than Tepotinib’s, making it a more cost-effective choice for patients and healthcare providers navigating the landscape of treatment options for NSCLC with MET exon 14 skipping mutations.

Tepotinib vs. Capmatinib

Expected Forecast of Capmatinib Vs. Tepotinib?

The forecast for Capmatinib and Tepotinib in the treatment of metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutations reveals distinct cost-effectiveness profiles, as recent analyses suggest. These therapies, both FDA-approved, provide vital options for patients with this specific genetic mutation, but their value propositions differ when evaluated through the lens of cost-effectiveness and clinical outcomes.

When it comes to cost-effectiveness, Tepotinib has been found to dominate Capmatinib, particularly in frontline treatment settings. The incremental cost-effectiveness ratio (ICER) for Tepotinib in these contexts is estimated at approximately $274,514 per quality-adjusted life year (QALY). This suggests Tepotinib provides value when used in subsequent treatment lines, with incremental QALYs and costs of 0.3330 and $91,401, respectively. In a more general, line-agnostic approach, Tepotinib also holds its ground, yielding an ICER of $105,383/QALY. These figures suggest that under certain conditions, Tepotinib can be considered a cost-effective option, offering significant benefit for patients with MET exon 14 mutations.

In terms of clinical efficacy, Tepotinib has shown impressive results, with an overall response rate (ORR) of 51.4% and a median duration of response (mDOR) of 18.0 months in clinical trials. These outcomes reflect its effectiveness in treating patients with this genetic alteration. Capmatinib, however, has demonstrated even stronger initial efficacy, with an ORR of 68% in pivotal trials, underscoring its potent impact on patient outcomes.

Ultimately, while both Capmatinib and Tepotinib prove effective for treating NSCLC with MET exon 14 alterations, Tepotinib may offer a more favorable cost-effectiveness profile and clinical outcomes in certain settings. However, the true value of these drugs should always be evaluated in the context of individual patient responses and specific treatment circumstances. As such, decisions regarding their use should consider not only clinical efficacy but also the broader economic and patient-centered factors that shape treatment choices.

What next?

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 the 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.

The KUNPENG study for non-small cell lung cancer (NSCLC), conducted from January 2020 to August 2022, evaluated vebreltinib, a selective MET inhibitor. The study reported a 75% objective response rate, a median duration of response of 15.9 months, and a manageable safety profile. Common adverse events included peripheral edema, QT prolongation, and elevated serum creatinine. Vebreltinib demonstrated strong efficacy and tolerability, making it a promising treatment for METex14-mutant NSCLC.

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 by overexpressing the 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. 

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.