Targeting MET Exon 14 Skipping Mutations in NSCLC
At a live virtual event, Martin Dietrich, MD, PhD, discusses treatment options for a patient with non–small cell lung cancer when molecular testing shows a MET exon 14 skipping mutation.
A 71-year-old woman presented to her primary care physician with rib pain after a fall and reported increasing shortness of breath and fatigue. She had no history of smoking. Imaging showed a right hilar mass, rib metastases, and adrenal metastases, but a brain MRI was negative for brain metastases. She had an ECOG performance score of 1 and was diagnosed with stage IV lung adenocarcinoma.
Molecular testing of lymph node tissue showed a MET exon 14 skipping alteration.
MARTIN DIETRICH, MD, PhD: She has a MET exon 14 skipping alteration. We have a lot of options but unfortunately not a lot of guidance in terms of sequencing. So what would you do next? Capmatinib [Tabrecta], or tepotinib [Tepmetko], or crizotinib [Xalkori] are the 3 available type 1 MET inhibitors; chemotherapy would be chemoimmunotherapy; an immune checkpoint inhibitor alone; or other, which we can assume is a clinical trial.
What would be your next step?
DIETRICH: The first in market, capmatinib, captured the largest share of the poll. That’s very interesting. Tepotinib has 2 votes and crizotinib has 2 votes, and none would use chemotherapy. Who would use the immune checkpoint inhibitor? It’s not wrong, but I’d just be just curious what the thought process was. Is it the label, is it that it’s not exclusive, like we had seen with the EGFR and other inhibitors?
DIMITRIOS AGALIOTIS, MD: I voted for that because I didn’t know the other agents that well.
DIETRICH: That’s why we’re here, so that’s a good thing. Aside from a [billable] standpoint, MET, unlike EGFR and ALK [inhibitors]—there’s nothing that speaks against immune checkpoint inhibitors in the first-line setting, with or without chemotherapy. Looking at the guidelines, I think we had a pretty good distribution between the targeted inhibitors and the checkpoint inhibitor. Who voted for the crizotinib? Did you care to comment? Is it a sequencing approach, where you do crizotinib first and use one of the newer MET inhibitors second?
ROBERT KOCH, MD: Well, I voted for crizotinib, and the reason is that I’m familiar with the drug, and I’ve used it in other patients with other mutations. These patients that we’re discussing here are so uncommon that I’m not as familiar with the other agents as maybe I should be.
DIETRICH: Familiarity with the drug is certainly a big factor for treatment. Crizotinib has multiple approvals in the settings of ALK, ROS1, and other mutations.
KOCH: Exactly, so that probably drove my decision to use crizotinib.
DIETRICH: That sounds very reasonable. Any thoughts on capmatinib vs tepotinib?
HARSH AMIN, MD: I chose capmatinib, like most of the people in the group, because based on the phase 2 trial, the first line and second line, the response rate of the first line was pretty high compared with a chemoimmunotherapy, if you take any trial of a chemoimmunotherapy. Based on that, and also [considering that] the PFS was higher, too, I chose capmatinib. Tepotinib could be a choice; I didn’t choose it because while there’s no [direct] comparison, I think tepotinib has a lower response rate numerically, whether the patient received prior chemotherapy or not, compared with capmatinib—a higher response rate in treatment-naive patients, around 70%. So that’s why I chose capmatinib.
DIETRICH: We’re fortunate to have, in a relatively small space, 3 approved agents for the mutation, 2 being highly selective with good response rates, and a very similar safety profile. There are some differences in terms of dosing and convenience, but from a performance standpoint, I think we have 2 very good choices.
Looking at the MET exon 14 skipping mutation discovered before first-line therapy, the 2 preferred agents [by the National Comprehensive Cancer Network] are capmatinib or tepotinib; crizotinib is an additional option.1 Then, basically in acknowledgment of the guidelines and the FDA labels, also the standard non-driver mutation regimens can be utilized in the first-line setting, with a recommendation upon progression to move back into one of the MET inhibitors. If you discovered the MET exon 14 mutation after initial treatment initiation, it becomes very difficult to decide how to switch, because there’s no real good data how to do that, whether you do it at progression, arbitrarily, or immediately upon the discovery of the mutation.
I think that the capmatinib and tepotinib data are a little bit cleaner than crizotinib, and mostly the paradigm of targeted therapy before chemoimmunotherapy, especially in this subtype. [MET] acts very similar to an EGFR mutation that is not as responsive to immunotherapy. I think I see a reasonable recommendation summary of the data. Has anybody used tepotinib yet in the first line, in the setting of MET alterations? What was your experience?
LUIS RAEZ, MD: It seems to be similar to capmatinib. I don’t see a major difference. We’re very biased because we don’t know which one is better. They were approved in different studies. Traditionally, we use capmatinib first, because it’s approved first, and now we have tepotinib later, also.
DIETRICH: My experience is similar. We see the MET on-target effects there, and the edema is probably the main handling issue. A little bit of hypoalbuminemia, sometimes a little bit of increase in kidney function, or liver function test abnormalities, but it’s pretty balanced. I think that’s the non-selective nature of MET targeting.
The FDA approval [of tepotinib] came earlier this year on February 3.2 Metastatic non–small cell lung cancer, any histology, with a MET exon 14 skipping alteration.
1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 7.2021. Accessed November 8, 2021. https://bit.ly/3025IKZ
2. FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. FDA. Published February 3, 2021. Accessed November 8, 2021. https://bit.ly/2YuQA86