"MET-targeted therapy as a new personalized NSCLC solution"

Professor Ji-Youn Han, Department of Hemato-oncology, National Cancer Center

“Difficulties remain in diagnosis despite use of NGS, etc… needs improvement "

“Expectations rise for EGFR-TKI combo therapies… does not necessarily need to be used with 3rd generation EGFR-TKIs, 1st or 2nd generation can be enough”

Professor Ji-Youn Han

HER2, ALK, EGFR, ROS1, NTRK.

 

These keywords have been frequent visitors in articles on anticancer drugs recently.

 

With the discovery that effective anticancer treatments differ depending on the patient’s genetic mutation status, personalized treatments that target specific genes of each individual are being introduced.

 

And the development of precision medicine has heralded the paradigm shift of cancer treatments to ‘gene-specific treatment’ from ‘diseases-specific treatment.’ Amid rising expectations, the first anticancer treatment that targets the MET gene was newly introduced to Korea.

 

The treatment, Novartis’ ‘Tabrecta (capmatinib),’ was authorized for the treatment of metastatic non-small cell lung cancer (NSCLC) with MET exon 14 deletions.

 

The new introduction of an option in this rare type that occurs in approximately 3-4% of patients with NSCLC is gaining much attention in the medical community.

 

Dailypharm met with Ji-Youn Han, Professor of Hemato-oncology at the National Cancer Center to hear about the use and potential of MET-targeted anticancer therapies and personalized treatment that has been implemented but is yet unfamiliar to the general public.

 

- A treatment that targets the MET mutation has landed in Korea.

 

What significance does the introduction of this new drug bring to the lung cancer treatment paradigm? The MET exon 14 skipping mutation is very rare in lung cancer.

 

Various clinical trials have confirmed that exon 14 skipping mutation is an oncogenic driver mutation of lung cancer.

 

Also, patients who have MET amplification or overexpression have very poor prognoses.

 

In this sense, the approval of Tabrecta, a treatment that demonstrated clear efficacy in MET exon 14 skipping mutation, holds great significance as the prompt introduction of MET inhibitors has become ever important.

 

- Not many patients may be eligible to use the drug.

 

How many will be eligible, in Korea and what other characteristics do eligible patients have? In the West, patients with MET exon 14 skipping mutations account for approximately 3% of all NSCLC patients, In Korea, the reported rate is around 2-3%.

 

One clinical feature of the disease is that it occurs more often in elder patients than younger patients.

 

According to clinical studies, the median age of patients was around 70.

 

-How is the MET diagnosis environment in Korea? Several hospitals have brought in NGS testing devices after NGS-based gene panel tests were applied selective reimbursement in 2017.

 

The MET gene is an important oncogenic driver gene that is included in most NGS panels.

 

However, identification of MET exon 14 skipping mutation is diagnostically difficult and requires further considerations.

 

Also, by genetic mutations, some are more fit for RNA-based NGS tests rather than DNA-based NGS tests.

 

In particular, identifying MET exon 14 skipping mutation through a DNA-based NGS test requires further detailed diagnosis to identify hundreds of mutations that can cause exon 14 skipping mutations.

 

On the other hand, as an RNA-based NGS test can easily discern exon 14 skipping mutations, the RNA-based NGS test may be needed to identify exon 14 skipping mutations.

 

But in practice, RNA-based tests are used less than DNA-based tests.

 

- Commercialization of other MET inhibitors like tepotinib is also imminent.

 

The MET inhibitor tepotinib had differentiated patients according to treatment experience in its clinical design. According to the Phase II GEOMETRY mono-1 trial, patients who used Tabrecta as first-line had shown higher objective response rates (ORR).

 

On the other hand, the response rate was similar in patients using tepotinib regardless of treatment history.

 

The efficacy and safety of the two were comparable in clinical trials.

 

The IC50 value of the two drugs that determine how much of a drug is needed to inhibit cell growth by 50%, was slightly better for Tabrecta.

 

However, most anticancer drugs are best effective in the subject patients when prescribed at the earliest.

 

In particular, not all patients with MET exon 14 skipping mutations who have high PD-L1 expression respond to immunotherapy treatment.

 

Using a combination of immunotherapy-chemotherapy as first-line can increase the financial burden borne by the patients and even be less effective than Tabrecta.

 

This is why some advanced countries like Canada believe it is necessary to thoroughly check for MET exon 14 skipping mutations by using biopsy as well as liquid biopsies in order to reduce patient burden.

 

-Also, studies on the combined use of MET inhibitors and EGFR TKIs are also active.

 

In particular, there are expectations that the MET inhibitors may resolve the resistance issue of 3rd generation EGFR TKIs. Around 10% of the EGFR mutated lung cancers occur due to METs.

 

This is why a smart MET inhibitor partner may be needed to address the acquired resistance to EGFR TKI.

 

There had been a clinical trial that tested the combined use of Tabrecta and EGFR TKI.

 

As it is unclear which causes EGFR mutations in lung cancer - MET amplification or overexpression – the study enrolled both patients.

 

In the trial, a patient with EGFR exon 19 deletion mutation who have experienced primary resistance participated in the trial and reached complete remission (CR).

 

One thing to note is that we do not need to only use 3rd generation EGFR TKIs like ‘Tagrisso (osimertinib)’ when attempting combination therapies.

 

Not only because of the price, but I believe that 1st and 2nd generation EGFR TKIs can also be sufficient partners.

 

Also, a study on Tabrecta+Tagrisso in patients with EGFR resistance is in progress, which medical institutions in Korea are also planning to participate in.