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March 5, 2024
Clinical Relevance: Tepotinib’s approval marks a pivotal advancement in targeted therapy for NSCLC, offering a highly specific treatment option for patients with MET exon 14 skipping mutations and underscoring the importance of genetic profiling in modern oncology practice.
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The availability of Tepmetko (tepotinib), should prompt ontologists to order genetic testing for all of their adult patients with metastatic non-small cell lung cancer (NSCLC) to identify those with a harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.
Although the mutation only occurs in 3-4% of NSCLC patients — or approximately 8,000 individuals annually — Tepmetko offers these individuals a targeted therapy, marking a significant advancement in treating this specific NSCLC variant.
”While it is a small fraction, thousands of patients could benefit given how common and serious lung cancer can be,” Dr. Balazs Halmos, MD, MS, associate director, clinical science, and director, thoracic oncology, at Montefiore Einstein Comprehensive Cancer Center tells SurvivorNet.
Related: ‘Practice Changing’ Lung Cancer Trial Shows Power Of The Drug Tagrisso
MET exon 14 skipping mutation
Dr. Halmos summarizes MET exon 14 skipping as a mutation in lung cancer cells where a critical component for regulating growth — exon 14 — is passed over, removing a key brake and allowing unchecked cancer growth.
Tepmetko, as a precision medicine, treats this mutation, Dr. Halmos notes.
It is a tyrosine kinase inhibitor that blocks the tyrosine kinase enzymes involved in many cell functions, including cell signaling, growth, and division. By blocking these enzymes, it halts the growth of cancer cells.
In other words it “does not fix the brake” caused by the skip mutation. It shuts down the overall MET protein engine in cancers where the MET protein is the driver.
The VISION Trial
Tepmetko was given accelerated approval for this indication in 2021, based on initial overall response rate (ORR) and duration of response (DOR) in the VISION trial (NCT02864992), a multicenter, non-randomized, open-label, multicohort study.
The VISION trial was a pivotal phase 2 clinical trial that enrolled patients with histologically or cytologically confirmed advanced (stage IIIB/IV) NSCLC. It specifically targeted patients with measurable disease and the MET exon 14 skipping alterations.
Patients received Tepmetko as an intravenous infusion every 6 weeks for a maximum of 6 cycles.
Tepmetko demonstrated robust and durable clinical outcomes across different lines of therapy:
- Among 164 treatment-naïve patients, the ORR was 57%, indicating a significant proportion of patients experiencing tumor shrinkage
- Among 149 previously treated patients, the ORR was 45%, demonstrating efficacy even in patients who had received prior treatments
- A substantial percentage of responders in both groups had a DOR of 12 months or longer
“While it was not specifically compared to conventional chemo or immunotherapy, the results are impressive and are felt to compare favorably to other chemo or immunotherapy based options,” Dr. Halmos says. “At minimum, tepotinib adds an extra option for our patients.”
Tepmetko was generally well-tolerated among trial subjects.
The most common adverse reactions included:
- Edema
- Nausea
- Fatigue
- Musculoskeletal pain
- Diarrhea
- Dyspnea
- Decreased appetite
- Rash
Treatment with Tepmetko requires confirmation of MET exon 14 skipping alterations through Next-Generation Sequencing (NGS).
“Also, there are other biomarkers that can help patients receive similar medicines, expanding the percentage of patients who can benefit from biomarker testing and targeted therapies, so a key message is to ensure that what is called expanded biomarker testing is done for basically all non-small cell lung cancer patients,” Dr. Halmos says.
Related:The Crucial Role of Genetic & Molecular Sequencing
Tepmetko versus immunotherapy
Tepmetko represents a significant advancement in the precision medicine approach for treating NSCLC, specifically targeting the MET exon 14 skipping mutations.
Unlike immunotherapy, which can benefit a wide range of patients but may not be effective for all, Tepmetko allows for the direct inhibition of the MET pathway. This specificity exemplifies the progress in understanding the genetic underpinnings of cancer and represents the continued shift towards personalized cancer treatment.
“…targeted medicines such as tepotinib are continuing to transform the landscape for our patients with advanced and now also earlier stage lung cancer. With optimal use of biomarker testing and tailored targeted and immunotherapies, a larger and larger fraction of our patients with lung cancer can benefit from more effective and less toxic therapies.” Dr. Halmos says.