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Patient Case: <i>MET</i>ex14+ NSCLC
How I Am Using Selective MET Inhibitors in Patients With MET Exon 14–Positive NSCLC

Released: August 14, 2020

Expiration: August 13, 2021

Karen L. Reckamp
Karen L. Reckamp, MD, MS
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Now that the FDA has approved the first selective MET inhibitor, oncologists can leverage targeted therapy to treat patients with non-small-cell lung cancer (NSCLC) harboring MET exon 14–skipping mutations. Here, I discuss a case from my practice to illustrate key considerations when using selective MET inhibitors in the setting of MET exon 14–positive NSCLC.

Case: Patient With MET Exon 14–Positive Lung Adenocarcinoma
The patient is a 69‑year‑old man who presented with cough to his primary care physician. A chest x‑ray showed a right lung mass; subsequent CT and PET/CT scans confirmed the right lung mass and also identified mediastinal lymph nodes with increased FDG uptake, and hypermetabolic activity in a 2-cm lesion within the liver. There was no evidence of brain metastases on MRI.

A biopsy of the right lung mass showed a moderately differentiated adenocarcinoma positive for TTF1 and napsin A, consistent with adenocarcinoma of the lung. PD‑L1 testing by IHC revealed a tumor proportion score of 5%. Next‑generation sequencing (NGS) was performed and identified a MET exon 14 splice site mutation, D1010Y, without other alterations. At the time, there were no targeted therapies approved for patients with MET exon 14 alterations, so the patient was enrolled on a clinical trial and received combination anti–CTLA-4/anti–PD‑L1 immune checkpoint inhibitor therapy. After 2 cycles, he unfortunately experienced disease progression within the lung and developed new tumors in the liver.

When the FDA approved capmatinib, the patient was placed on this selective MET inhibitor and had improvement in his cough within 2 weeks. CT imaging after 2 months of therapy showed that the right lung mass had decreased in size along with improvement in the liver masses.

Toxicity Considerations With Selective MET Inhibitors
Patient Education and Monitoring
When starting patients on a selective MET inhibitor, it is critical to educate them on potential drug toxicities they may experience as well as to establish close communication with them, all toward the goal of helping patients manage any adverse events before symptoms become severe. Specifically, we discuss potential on‑target, drug‑specific toxicities such as edema, counseling patients to be proactive, even before experiencing edema symptoms, by elevating their lower extremities. We also ask patients to alert us if they experience gastrointestinal toxicities such as diarrhea, constipation, and nausea, even if their symptoms are mild, and we discuss management strategies and potential drugs that we can provide if the gastrointestinal symptoms are persistent.

Toxicity Management
Returning to our case, the patient developed lower-extremity edema and intermittent diarrhea with capmatinib therapy but otherwise tolerated the treatment well and continued on the full dose.

For his edema, we recommended that he use compression hose and leg elevation, which enabled him to control the edema without need for medications. If a patient’s edema were to worsen, we would potentially try antidiuretics, with our first choice being furosemide. We have also provided lymphedema therapy to some patients, which can be particularly helpful for those on long-term MET inhibitor therapy.

The patient’s diarrhea was relatively mild and did not require antidiarrheals. If he had needed antidiarrheals, we usually start with loperamide, and if that is insufficient, we provide diphenoxylate/atropine. Most cases of diarrhea are controlled with these medications and most patients do not need them daily. If the diarrhea persists, then sometimes we must interrupt and dose reduce the MET inhibitor.

Is Immunotherapy Appropriate for MET Exon 14–Positive NSCLC?
The patient’s experience with first-line immunotherapy highlights an important question: Is immunotherapy appropriate for patients with MET exon 14–positive NSCLC? Current data are limited and conflicting on whether this population responds to PD‑(L)1 inhibition. The data suggesting that immunotherapy does elicit responses may be related to the greater frequency of a smoking history in those with MET exon 14–positive disease; recall that patients with a history of smoking have higher response rates with immunotherapy. In the IMMUNOTARGET study evaluating immune checkpoint inhibition across patients with advanced NSCLC harboring at least 1 actionable mutation, approximately 50% of patients with MET exon 14–positive NSCLC experienced disease progression on immune checkpoint inhibitor therapy. I would say that we don’t have a clear answer to this question, but in our case, the patient did not benefit from first-line combination immune checkpoint inhibition.

There is also some concern that toxicities with TKIs may be more severe post immunotherapy. We have seen this in patients with EGFR-mutated NSCLC who received immunotherapy before osimertinib and subsequently had more pronounced risk of interstitial lung disease. Whether this is universal to patients with other actionable alterations, such as MET exon 14–skipping mutations, remains to be determined.

Liquid Biopsy for NGS
To choose optimal upfront therapy for a patient with newly diagnosed NSCLC, it is imperative that clinicians use biomarker testing to identify potential actionable gene aberrations, now including MET exon 14–skipping mutations. This is typically accomplished by tissue-based NGS testing, but liquid biopsies can also be used when biopsy tissue is not available. For the case patient, we had sufficient biopsy tissue to identify his MET exon 14–skipping mutation through NGS, but if we hadn’t, it would have been important to have performed a liquid biopsy and used that blood sample for NGS. In particular for detection of MET exon 14–skipping mutations, the VISION trial reported that the ORR with the investigational MET inhibitor tepotinib was comparable in patients who had undergone liquid vs tissue biopsy to identify their mutation—indicating that either method is sufficient to identify candidates who could benefit from selective MET inhibition.

Treatment After Progression on a Selective MET Inhibitor
Because MET inhibitors are still new to routine practice, we have not yet established a standard of care for treatment at progression. The data that are out there, which are largely based on patients with progression on the multitargeted, type I MET inhibitor crizotinib, suggest that treatment with a type II MET inhibitor, such as cabozantinib, may be of benefit. Of note, the selective MET inhibitors capmatinib and tepotinib are also type I MET inhibitors. However, more information is needed on the mechanisms of resistance to MET inhibition. Currently, I would recommend clinical trials in the setting of progressive disease.

Your Thoughts?
What questions do you have about the use of selective MET inhibitors in your patients with MET exon 14–positive NSCLC? I encourage you to answer the polling question and post your thoughts and questions in the discussion box below.