Targeted Therapies for MET-Dependent Lung Cancers

At the Great Debates & Updates in Lung Cancer meeting in New York, New York, Natasha Leighl, MD, discussed developments and advances in targeted therapies for patients with MET-dependent lung cancers.

Transcript: 

Hi, my name's Natasha Leighl, I'm from the Princess Margaret Cancer Center in Toronto, and I'm at the Great Debates & Updates in Lung Cancer here today. I'm talking about MET inhibitors in lung cancer.

There's certainly different types of MET alterations. The most common that we see are patients with MET exon 14 skip mutations, this is in about 2% to 4% of patients, most commonly in adenocarcinoma. We also see MET amplification. By itself this is rare, so probably less than 1% of patients, but as a mechanism of resistance we probably see it in about 15% of oncogene-addicted lung cancers, like EGFR or KRAS and different types of oncogene addiction. There's a very small number of patients that have a true MET fusion. This is rare, but I think it's really important when you read those NGS reports that a MET 13-MET 15 fusion, that intergene fusion, that's not really a fusion, that's a MET exon 14 skip mutation.

There are great new drugs approved, selective MET tyrosine kinase inhibitors. Here in the US, it's capmatinib and tepotinib. We've seen some great data, response rates up to 68% in the first-line setting. In second-line these are a bit lower, around 40% to 45%, and so it really brings up the importance of getting these patients tested and onto treatment as soon as possible. Other treatments — immunotherapy, chemoimmunotherapy, chemotherapy by itself — they just don't seem to work as well based on the data we have. The other concern is that if you start your patients on chemoimmunotherapy or immunotherapy first, they might have an increased risk of immune-mediated toxicity when you switch them to the targeted therapies. We've just published a piece on that, from our team in Toronto, showing an increased risk of hepatotoxicity and pneumonitis if you sequence the checkpoint inhibitor first and the MET TKI second, as opposed to the better way to do it which is the TKI first.

There are also a lot of new agents in development. Recently, I presented data from amivantamab, which is a bispecific MET and EGFR targeting antibody. We presented those data at World Conference on Lung Cancer. In patients with MET exon 14 skip mutations, we saw an overall response rate of 33%; 50% in patients who were treatment-naive. Durations of response were just over 11 months and so again, potentially exciting but probably can't overtake TKIs first-line. Going forward, we're going to combine these in the METalmark study, combining amivantamab and capmatinib, targeting both the extracellular and intracellular part of MET signaling.

Key toxicities of course with all the MET inhibitors is edema and low albumin and so really important to get on top of that and stay ahead of it. Patients often benefit from massage and stockings. Sometimes you need to dose reduce. Things like diuretics can be helpful, but to a limited extent and I find things like steroids aren't very helpful.

Moving forward though there are lots of new drugs and new combinations, MET [antibody drug conjugates] ADCs like telisotuzumab and other exciting new TKIs.

We also talked a bit about resistance and targeting EGFR- and MET-amplified lung cancer. We see that in about 15% to 20% of patients that have failed osimertinib. There are great data now adding tepotinib to osimertinib and also savolitinib, another MET inhibitor, that's approved currently in China. And we see very good response rates, especially over 50% in patients with very high gene copy number (copy numbers of 10 or more) and so this is an exciting way forward.

Certainly, in clinical practice even though we don't have FDA-approved agents, we want to test for MET amplification. The best tests are going to be FISH or NGS, and then you're going to want to try and get your patient on a trial or some sort of program where they're able to access both combined EGFR and MET inhibition.

Moving forward, also in this space, lots of exciting work happening adding telisotuzumab vedotin to osimertinib, really increasing responses. Adding amivantamab to lazertinib, also a third-generation EGFR TKI, also very exciting, especially when we select patients by MET expression. We really see very high response rates, 50% and more. We've seen data like that at ASCO and World Lung and we're looking forward to a lot more.

Source:

Leighl N. Targeted Therapy for MET-Dependent Lung Cancers: Have We Met Our Match? Presented at Great Debates & Updates in Lung Cancer; September 21-23; New York, NY.