What Is Tepotinib?
Tepotinib is an FDA-approved medication for patients with MET-mutated non-small cell lung cancer (NSCLC) that has progressed after at least one prior treatment. It is a targeted therapy designed to inhibit the MET receptor tyrosine kinase, which can be overactive in certain cancers due to specific genetic changes. By blocking MET, tepotinib aims to slow or stop the growth of cancer cells.
This medication is administered orally as film-coated tablets. It is being investigated in clinical trials for its effectiveness and safety, both as a standalone treatment and in combination with other therapies, across various types of cancer.
Uses and Conditions Under Study
Tepotinib is primarily studied for its role in treating various cancers, particularly those with specific genetic alterations. Clinical trials involving tepotinib have enrolled a total of 3,559 participants across 27 studies, with the first trial initiated in 2013.
- Non-Small Cell Lung Cancer (NSCLC): Tepotinib is extensively studied for NSCLC, especially in cases with MET gene mutations or amplification. A total of 5 trials focus on this condition, aiming to provide a new treatment option for patients whose cancer has progressed after initial therapies.
- Advanced Cancer and Solid Tumors: Tepotinib is also being investigated in a broader context for advanced cancer and solid tumors. 4 trials explore its efficacy and safety in patients with various advanced cancers, often identified through genomic or protein expression testing for potentially actionable variants.
- Gastrointestinal Cancers: Several trials are exploring tepotinib for cancers affecting the digestive system. This includes 1 trial for Colorectal Neoplasms, 1 trial for Gastric Cancer, 1 trial for Gastroesophageal-junction Cancer, and 1 trial for Gastrointestinal Cancer, totaling 3 trials in this category.
- Hepatocellular Carcinoma: There are 2 trials investigating tepotinib for Hepatocellular Carcinoma, a type of liver cancer. These studies aim to determine if tepotinib can be an effective treatment for this specific cancer type.
- Healthy Participants: In addition to cancer patients, 8 trials have involved healthy volunteers. These studies are typically conducted to understand how tepotinib is absorbed, distributed, metabolized, and eliminated by the body, which helps in determining appropriate dosing and potential drug interactions.
Dosing
Tepotinib is supplied as film-coated tablets for oral administration. The tablets are typically oval and white-pink, with the 250 mg strength containing excipients such as mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and Opadry II pink.
In clinical trials, tepotinib has been studied at various strengths, including 300 mg, 500 mg, and 1000 mg. The most frequently studied dose is 500 mg of tepotinib hydrochloride hydrate, taken orally once daily. This dosage has been explored both as a monotherapy and in combination with other anticancer drugs like gefitinib, paclitaxel, and ramucirumab, as well as other targeted agents.
Studies have also investigated tepotinib's interactions with other medications, such as itraconazole, carbamazepine, midazolam, and dabigatran etexilate, to understand its pharmacokinetic profile and potential effects on drug metabolism.
Side Effects
Safety data for Tepotinib comes from clinical trials in patients with non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC). It is important to note that specific adverse event names are not consistently provided in the available data; therefore, this section focuses on the overall rates of serious events, high-grade events, and events leading to treatment changes or death.
In a Phase 2 study (NCT01982955) for NSCLC patients without MET+ T790M mutations, comparing Tepotinib 500 mg + Gefitinib 250 mg to chemotherapy (pemetrexed and cisplatin/carboplatin):
- Nearly all patients in both groups experienced treatment-emergent adverse events (TEAEs): 96.8% of patients on Tepotinib + Gefitinib and 95.8% on chemotherapy.
- Serious TEAEs occurred in 41.9% of patients receiving Tepotinib + Gefitinib, compared to 29.2% of those on chemotherapy.
- Grade 3 or higher TEAEs were reported in 64.5% of patients on Tepotinib + Gefitinib, versus 58.3% on chemotherapy.
- Treatment discontinuation due to TEAEs occurred in 9.7% of patients on Tepotinib + Gefitinib, compared to 4.2% on chemotherapy.
- Deaths were reported in 67.7% of patients on Tepotinib + Gefitinib and 62.5% on chemotherapy, though specific causes are not detailed.
In the non-randomized part of the same Phase 2 study (NCT01982955) for NSCLC patients with MET+ T790M mutations (10 participants), 11 participants experienced TEAEs and 13 participants experienced treatment-related TEAEs (the number of reported events exceeded the number of participants in this small group). Serious TEAEs occurred in 10% of participants, and Grade 3 or higher TEAEs were reported in 70%. Two participants (20%) discontinued treatment due to TEAEs, and 8 participants (80%) experienced death.
In Phase 1b of the NSCLC study (NCT01982955) involving smaller groups, 100% of participants in the Tepotinib 300 mg + Gefitinib 250 mg group (6 participants) experienced serious TEAEs and treatment-related TEAEs. In the Tepotinib 500 mg + Gefitinib 250 mg group (12 participants), 100% experienced TEAEs and 91.7% experienced treatment-related TEAEs. No dose-limiting toxicities were observed in either dose group.
For patients with hepatocellular carcinoma (HCC) in a Phase 1b study (NCT01988493), specific counts for TEAEs and serious TEAEs sometimes exceeded the number of participants in the small dose groups (e.g., 7 TEAEs in a 6-participant group for Tepotinib 300 mg). No dose-limiting toxicities were observed across Tepotinib 300 mg, 500 mg, or 1000 mg doses in this phase.
Clinical Trial Results
Non-Small Cell Lung Cancer (NSCLC)
In a Phase 2 randomized study (NCT01982955) for NSCLC patients who were MET+ and T790 negative, Tepotinib 500 mg + Gefitinib 250 mg was compared to standard chemotherapy (pemetrexed and cisplatin/carboplatin). The combination of Tepotinib and Gefitinib showed improved tumor response and progression-free survival:
- The objective response rate (ORR), meaning the percentage of patients whose cancer significantly shrank or disappeared, was 45.2% for Tepotinib + Gefitinib, compared to 33.3% for chemotherapy.
- The disease control rate (DCR), which includes patients with stable disease in addition to responses, was 83.9% for Tepotinib + Gefitinib, versus 70.8% for chemotherapy.
- Patients treated with Tepotinib + Gefitinib had a median progression-free survival (PFS) of 10.15 months, meaning half of the patients lived at least this long without their cancer worsening. This was significantly longer than the 4.34 months for patients on chemotherapy.
- Overall survival (OS) was similar between the two groups, with 17.25 months for Tepotinib + Gefitinib and 19.48 months for chemotherapy.
Another Phase 2 study (NCT02864992), known as VISION, investigated Tepotinib in NSCLC patients with specific MET alterations. This study demonstrated encouraging objective response rates:
- For patients with METex14 skipping alterations, the ORR was 46.7% in Cohort A and 54.7% in Cohort C (confirmatory part).
- For patients with MET amplification (Cohort B), the ORR was 41.7%.
Hepatocellular Carcinoma (HCC)
In a Phase 2 study (NCT01988493) for HCC patients, Tepotinib was compared to Sorafenib:
- The objective response rate (ORR) as assessed by an independent review committee was 10.5% for Tepotinib, while no responses (0%) were observed in the Sorafenib group.
- The disease control rate (DCR) was 50% for Tepotinib, compared to 21.6% for Sorafenib.
- Patients on Tepotinib experienced a median progression-free survival (PFS) of 2.8 months, doubling the 1.4 months seen with Sorafenib.
- Overall survival was 9.3 months for Tepotinib and 8.6 months for Sorafenib.
Another study (NCT02115373) in HCC patients treated with Tepotinib 500 mg (49 participants) showed an objective response rate (complete or partial response) of 8.2%. The disease control rate was 57.1%, and the median time to symptomatic progression was 4.86 months.
Currently Recruiting Trials
For patients interested in contributing to medical research, several clinical trials are currently recruiting participants to further investigate tepotinib. These studies explore its potential in various advanced cancers, often focusing on specific genetic mutations.
One notable Phase 3 study, NCT06908993, is comparing tepotinib against standard treatment in patients with advanced non-small cell lung cancer (NSCLC) that has a MET Exon 14 mutation and has progressed after at least one prior first-line treatment. This trial, sponsored by the Intergroupe Francophone de Cancerologie Thoracique, aims to enroll 133 participants.
Another study, NCT06031688, is a Phase 2 Expanded Lung-MAP treatment trial. It is investigating tepotinib, both alone and in combination with ramucirumab, for advanced NSCLC with a MET Exon 14 skipping gene change. This trial, sponsored by the SWOG Cancer Research Network, is recruiting 56 participants with recurrent or Stage IV lung cancer.
Samsung Medical Center is sponsoring NCT06106802, a Phase 2 trial exploring lazertinib and tepotinib for EGFR mutant NSCLC in patients with MET overexpression or amplification who have progressed after lazertinib treatment. This study is designed for 47 participants with metastatic non-small cell lung cancer.
For patients with gastric and gastroesophageal-junction (GEJ) carcinoma, a Phase 1/Phase 2 study, NCT05439993, is evaluating tepotinib combined with paclitaxel. This trial, sponsored by Hallym University Medical Center, seeks to define the optimal dose and assess the efficacy of this combination as a second-line therapy, with an enrollment target of 42 participants.
Tepotinib is also included in broader national studies designed to facilitate patient access to targeted anti-cancer drugs. The Finnish National Study, NCT05159245, is a Phase 2 trial sponsored by Helsinki University Central Hospital, enrolling 250 participants with advanced solid tumors or haematological malignancies. Similarly, The Netherlands Cancer Institute sponsors The Drug Rediscovery Protocol (DRUP Trial), NCT02925234, a Phase 2 study for 1,550 participants with various advanced cancers and actionable genetic variants, where tepotinib is one of many targeted therapies being evaluated.
Where to Participate
Clinical trials for tepotinib have a broad geographic reach, offering opportunities for participation across the United States. These studies are conducted at 265 sites located in 219 cities across 42 states. This widespread network helps ensure that more patients can access these investigational treatments.
Some of the cities with the most active recruiting sites include:
- Flint, Michigan (4 sites)
- Portland, Oregon (4 sites)
- Kansas City, Missouri (4 sites)
- St Louis, Missouri (4 sites)
- York, Pennsylvania (3 sites)
- Springfield, Illinois (3 sites)
- Los Angeles, California (3 sites)
- Dayton, Ohio (3 sites)
- Des Moines, Iowa (3 sites)
- Sioux Falls, South Dakota (2 sites)
General eligibility criteria for these trials typically include participants aged 18 to 100 years, of all genders. It is important to note that these studies are designed for patients with specific medical conditions and do not recruit healthy volunteers, though some trials may include children depending on the specific research question.
Development Timeline
The clinical development journey for tepotinib began on November 13, 2013, with the initiation of its first clinical trial. Since that time, a total of 27 trials have been launched, involving 3,559 participants globally. The early stages of development saw a focus on Phase 1 trials, with 11 studies dedicated to understanding initial safety and dosing, alongside 9 Phase 2 trials and 6 Phase 1/Phase 2 combined studies. More recently, a Phase 3 trial has also commenced, indicating progression to later-stage research.
Initial research into tepotinib explored conditions such as IBS-C and hyperphosphatemia. However, the development pipeline quickly expanded, with key sponsors like Merck KGaA, Darmstadt, Germany, and EMD Serono Research & Development Institute, Inc., driving much of the research. The focus broadened significantly to various oncology indications, particularly Non-Small Cell Lung Cancer (NSCLC) with specific MET mutations, which became a prominent area of investigation. Other conditions studied include Hepatocellular Carcinoma, Gastric Cancer, Gastroesophageal-junction Cancer, and various solid tumors and haematological malignancies.
The latest trial for tepotinib was initiated on April 3, 2025, demonstrating ongoing commitment to exploring its potential. This expansion from initial indications to a wide range of cancers highlights the evolving understanding of tepotinib's therapeutic applications and its journey through the rigorous stages of clinical research.