Fred R. Hirsch, MD, PhD
Icahn School of Medicine at Mount Sinai, New York

Key Takeaways

  • Capmatinib and savolitinib exhibit similar results as first-line treatment options, although, based on available data, capmatinib’s endurable intracranial response may be more encouraging than savolitinib.
  • Crizotinib may be a treatment option for patients with multiple mutations since this drug is widely used in patients who are positive for ALK or ROS1 genes. However, as a first-line treatment option for patients with MET exon 14 (METex14) skipping non-small cell lung cancer (NSCLC), crizotinib has a response rate of approximately 32%.
  • Ongoing clinical trials have been designed to determine whether tepotinib or savolitinib could delay acquired treatment resistance when used in combination with osimertinib.
  • Patients who tolerate MET inhibitors may continue on these medications as long as they benefit from treatment and do not exhibit signs of toxicity.
  • Peripheral edema is one of the most common adverse events. Patients and clinicians together should review severity, comorbidities, and impact on quality of life prior to reducing the dose or continuing therapy.

Fred R. Hirsch, MD, PhD, is executive director at the Center for Thoracic Oncology and associate director of Biomarker of Discovery in The Tisch Cancer Institute at Mount Sinai in New York City, New York. Dr Hirsch is also the Joe Lowe and Louis Price Professor of Medicine at the Icahn School of Medicine at Mount Sinai. His research focuses on targeted therapies and early detection of lung cancer. Dr Hirsch’s findings have helped identify and validate prognostic lung cancer outcome markers and biomarkers for personalized lung cancer therapies.

Capmatinib and savolitinib are indicated as first-line treatments for patients with METex14 mutations. What factors might point a clinician towards one treatment option over the other?

Capmatinib, savolitinib, and tepotinib are all first-line treatment options for patients with METex14 NSCLC. In my opinion, both capmatinib and savolitinib are similar in terms of clinical toxicity and feasibility. They both have very good response rates. Capmatinib has a response rate of 68% in first-line settings and 48% in second-line settings. For primary effects, there were no differences between capmatinib and savolitinib. Edema is still an issue for both but in general, they don’t differ significantly from each other in terms of toxicity. Capmatinib has been reported to have a 54% endurable intracranial response, which is encouraging.1 However, clinically, there are several reports of similar responses with savolitinib but I have not seen a larger study to confirm those results. The bottom line is that there isn’t much of a difference in clinical utility for these 2 drugs.

While not yet approved for this setting, when would off-label use of crizotinib be clinically indicated for patients with METex14 NSCLC?

Crizotinib was originally developed as a MET-targeted therapy. For patients withMETex14 NSCLC, crizotinib has a response rate of around 30% to 35% with an impressive median duration of response at just over 9 months.1 I think it is not as effective for METex14, but crizotinib may be a treatment option for patients with multiple mutations since this drug is widely used in patients who are positive for ALK or ROS1. Edema and several ocular side effects have been reported. This drug might also have a lower risk of edema while several ocular side effects have been reported.1,2

I believe that mutation-guided second-line therapies are the future in the treatment of METex14 NSCLC, but we are not yet there in clinical practice.

While tepotinib is indicated in second-line clinical settings, why would prior treatment with MET inhibitors rule out patients from treatment with this oral medication?

The simple answer is that there are no studies yet to support the claim that tepotinib could be effective in patients who have previously been treated with MET inhibitors. It is for this reason that patients who were previously treated with a drug from this family will not be prescribed tepotinib. In the MET-positive space, when patients are resistant to capmatinib, savolitinib, or tepotinib, we know that they may have different resistant mutations. For instance, studies have shown that cross-resistance mechanisms could reduce the efficacy of capmatinib in patients with MET-altered NSCLC pretreated with crizotinib.3 I believe that mutation-guided second-line therapies are the future in the treatment of METex14 NSCLC, but we are not yet there in clinical practice.

Early VISION trial results seem to suggest a difference in patient response to tepotinib treatment based on whether METex14 identification was made via liquid or tissue biopsy. How might these response differentials be explained?4

The differences in the VISION trial ( Identifier: NCT02864992) reflected differences in a small group sampling. There were 32 patients in the tissue-biopsy group and 43 patients in the liquid-biopsy group, so the number of patients in the 2 analyses were different. When we are looking at small numbers, statistically speaking, there might not be an actual clinical difference.

In my practice, we use both liquid and tissue biopsies — we actually try to do both in parallel — because there are some cases in which the tissue biopsy is positive and the liquid biopsy is negative. There are also some rare cases in which the liquid biopsy is positive and the tissue biopsy is negative. In both cases, one is prone to missing out on key clinical details if only one of the biopsies is done. It is well known that if the liquid biopsy sample is positive, you can almost certainly say that the tissue biopsy sample will be positive as well. But, if the liquid biopsy sample is negative, you will still not have absolute certainty because the sensitivity on a liquid biopsy is 70% to 75%, which could lead to false negative cases.

Tepotinib adverse events
Adverse events commonly reported for tepotinib include edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea.

Patients may develop acquired treatment resistance with both capmatinib and tepotinib. What strategies can clinicians employ to delay this resistance?

This is a tough one. There are no clinical factors that could delay resistance, but I think you may be able to do so by combining capmatinib or tepotinib with another drug. There are some ongoing clinical trials, such as INSIGHT 2 ( Identifier: NCT03940703) and SAVANNAH ( Identifier: NCT03778229), in which tepotinib or savolitinib is given in combination with osimertinib,5,6 but this is specific to patients with EGFR-mutant NSCLC.

Many patients receiving oral METex14 inhibitors are at an increased risk for certain adverse events, such as peripheral edema, due to their age. How can a clinician determine if adverse events are treatment emergent or related?

In general, peripheral edema seen in patients who are older is related to cardiovascular disease. Clinical history will be the best way to distinguish the cause of adverse events. Therapy-induced edema usually begins a few weeks after the start of treatment for patients with METex14 NSCLC, so that timeframe should be a clear indication that the adverse event is treatment-induced. For my patients and for my own confidence, I would still check for cardiovascular disease and related issues, but the timing of the edema is a main factor in making this determination.

If adverse events are related to treatment, when would dose reduction or cessation of treatment be indicated?

That depends on the severity of the edema. There is no strict rule for when to reduce or stop treatment. That call should be made by the physician on a case-by-case basis in collaboration with the patient. Severity, grade of the edema, and the presence of comorbidities such as cardiovascular disease are clinical factors that must be considered before altering treatment.

What does follow-up care look like for patients who are tolerating oral METex14 inhibitors well?

If they are doing well and responding to treatment, I will continue dosing with follow-up visits every 3 or 4 weeks. We have learned to utilize telemedicine for patient care during the COVID-19 pandemic, so any follow-up protocol can be catered to the individual. To the best of my knowledge, the US Food and Drug Administration (FDA) does not recommend a time limit for these medications, so patients can continue on the oral METex14 inhibitors as long as they benefit from the treatment and do not exhibit signs of toxicity that would limit the use of therapy. As always, clinicians should remember that they are dealing with an emerging field and new developments occur frequently. My hope is that sequence therapy will be the future of treatment for patients with METex14 NSCLC. While we are not yet there in clinical practice, we can eventually get there one step at a time.

This Q&A was edited for clarity and length.


Fred R. Hirsch, MD, PhD, reported affiliations with Genentech, Inc.; Daiichi Sankyo Company, Limited.; Sanofi Genzyme; Regeneron Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Amgen Inc.; Merck & Co, Inc.; OncoCyte Corporation; Novocure Inc.; Nectin Therapeutics; and NextCure, Inc.


1.   Socinski MA, Pennell NA, Davies KD. MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerationsJCO Precis Oncol. 2021;5:PO.20.00516. doi:10.1200/PO.20.00516
2.   Das J, Das N. Chronic conjunctival chemosis-a new ocular side effect of crizotinibOphthalmic Plast Reconstr Surg. 2021;37(1):e18-e21. doi:10.1097/IOP.0000000000001710
3.   Dagogo-Jack I, Moonsamy P, Gainor JF, et al. A phase 2 study of capmatinib in patients with MET-altered lung cancer previously treated with a MET inhibitorJ Thorac Oncol. 2021;16(5):850-859. doi:10.1016/j.jtho.2021.01.1605
4.   Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutationsN Engl J Med. 2020;383(10):931-943. . doi:10.1056/NEJMoa2004407
5.   Smit EF, Dooms C, Raskin J, et al. INSIGHT 2: a phase II study of tepotinib plus osimertinib in MET-amplified NSCLC and first-line osimertinib resistanceFuture Oncol. 2022;18(9):1039-1054. doi:10.2217/fon-2021-1406
6.   Sequist LV, Han JY, Ahn MJ, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b studyLancet Oncol. 2020;21(3):373-386. doi:10.1016/S1470-2045(19)30785-5

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Reviewed May 2022