COMMENTARY

Next Advances in Lung Cancer Target MET, KRAS

Mark G. Kris, MD

Disclosures

August 14, 2019

This transcript has been edited for clarity.

This is Mark Kris from Memorial Sloan Kettering Cancer Center, discussing new therapeutic strategies and new targets reported at the 2019 meeting of the American Society of Clinical Oncology (ASCO). Many believed that this ASCO meeting was lacking in dramatic findings being reported. And yes, there wasn't some huge phase 3 trial that people could point to, but there were many, many encouraging presentations and also information about new ways we can help our patients.

A lot of discussion focused on the MET gene. At least here at Memorial Sloan Kettering, when we test our patients upfront for targets for therapy, we find almost as many cases with MET as with ALK. So it's common and it's targetable. There were two presentations about drugs in clinical development now, capmatinib[1] and tepotinib.[2] Both of those were drugs that we could deliver and both seem to lead to responses in the 50% range. Adding those drugs to already available drugs such as crizotinib gives us a way to target MET. MET is not on the list of gene mutations to always test for, but it really should be. I urge you to look for MET, use crizotinib today, and anticipate these new drugs coming forward.

There was also a presentation about the acquired resistance to MET-targeted therapies, mainly crizotinib.[3] Now, an interesting finding was that the presence of MET protein in some way predicted who responded and who didn't. So we have one way of checking for acquired resistance, looking for the presence of MET protein; those who don't have it are likely to not benefit from the MET-targeted therapy. That may be a way of selecting people for targeted therapy. MET is relatively common, so look for it and target it when you can.

Another group of agents that were discussed included either new constructs or agents for different targets. One is U3-1402, an antibody drug conjugate with an irinotecan-like drug on a HER3 antibody. The data from a phase 1 study[4] showed this to be effective in patients with EGFR-mutant lung cancer and acquired resistance to anti-EGFR therapy. You can connect the dots and find a good reason why a HER3-targeted therapy would be useful in that scenario. But all 13 evaluable patients had responses to the drug and I think people were surprised.

Other antibody-drug conjugates coming down the line relevant to lung cancer are the HER2-targeted agents. More and more positive data are being reported in the breast cancer world. Trastuzumab deruxtecan is the name of the drug being developed. I believe we're going to see it used in lung cancer more and more, and trials are underway right now.

The second drug that generated a lot of interest was AMG 510. This drug is a direct KRAS inhibitor specifically targeting the G12C KRAS mutation. The KRAS mutation is the most common target that we find in lung cancer, and G12C is a very common KRAS mutation. A phase 1 trial[5] reported encouraging responses to this new drug. Other direct KRAS G12C inhibitors are in clinical trials right now, so there's a lot of excitement about these drugs.

The third agent was also unexpected, a drug called JNJ 372. This is a bi-specific antibody targeting EGFR and MET. The drug was deliverable, and interestingly, the drug appeared to have activity in EGFR exon 20.[6] EGFR exon 20 has been another one of our "undruggable" targets at this point; it rarely responds to a traditional tyrosine kinase inhibitor, as some exon 20 mutations do. The drugs in testing now are not easy to give but may lead to some substantial benefits. They're not as well tolerated as a drug like osimertinib. But having another drug and a different class of drugs targeting EGFR makes a lot of sense and gives great encouragement.

This past ASCO brought us new information about targets to go after as well as new constructs: antibody drug conjugates, bi-specific antibodies, and antibodies directly targeting KRAS. These new agents are encouraging and will fill in some of the gaps in our current therapies.

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