How meaningful is this approval for patients in this subset? Is it likely to be promising for a large number of patients with NSCLC, given the side effect profile?

The most common toxicity in MET inhibitors is peripheral edema and, relatedly, the impairment of kidney function. MET is, of course, a normal gene — and when it is inhibited, particularly by potent inhibitors such as tepotinib, normal function can be impaired, so we really need to watch out for issues in this patient population. Peripheral edema can be managed, and I sometimes prefer co-management of patients, generally with a nephrologist.

Sometimes dose reduction may also be necessary, though even on a half dose, the drug still appears to have targeted engagement, but that, of course, is not to say that patients should be started on a lower dose.


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Given, furthermore, that the MET inhibitor space is growing, it may be that some patients who react badly to one drug may be started on another, which may have a different side effect profile.

Is cross-resistance to other treatments a concern as tepotinib enters the real-world setting?

Research is ongoing to address this. Crizotinib and other class 1 MET inhibitors may be used after one another, but we do not have data on sequential use of type 1. Biologically, we do not know if use of more than one class 1 inhibitor will be beneficial and need more data in this space. But again, and this may depend on toxicities, the use of more than one type 1 MET inhibitor may be necessary where discontinuation is a result of patient reaction rather than lack of treatment efficacy.

What else do you see in the future with this drug? Could it be used in tandem with others in this patient population, and might it be used in other NSCLC settings?

Some patients with lung cancer may have a high number of copies of MET genes.  MET inhibition may be very promising in them, but we need to determine, relying as always on clinical trials, whether tepotinib or other MET inhibitors are safe and effective in this setting.

Another area of interest is among patients with epidermal growth factor receptor (EGFR) variants. These patients may be prescribed therapies that target these variants specifically but can also develop resistance to these treatments — and this resistance may actually involve METalterations, so there is some suggestion that a combination of EGFR/MET inhibition may be effective in these cases. It will be interesting to see how this area progresses.

Lastly, MET can be important in gastric and gastrointestinal cancers. My colleagues in the gastrointestinal space suggest that tepotinib may be promising in this setting, and that is something else we are monitoring.

Is there anything else you would like to add?

It has been great to see that this NSCLC patient group has a new and promising option, and it may help them to forego toxic chemotherapy. New compounds are coming to serve this population, and it has been an extremely interesting and exciting space to watch.

Disclosures: Some authors of the original study have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

References

  1. FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer [press release]. Silver Spring, MD; FDA; February 3, 2021.
  2. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931-943. doi:10.1056/NEJMoa2004407