Molecular tests and new therapies for NSCLC

Hossein Borghaei, DO, MS: In the world of lung cancer, we have all of the motor mutations we talked about, and we have immunotherapy, which comes with its own biomarker. Let’s briefly discuss what a motor mutation is, what a biomarker for immunotherapy is, and what you do in your clinic when someone walks in and says, “I don’t care what you say, give. me my immunotherapy ”.

Benjamin Lévy, MD: It never happens. No, just kidding, it happens all the time. It’s a complicated discussion. I have to tell patients, when they walk through the door, that we are testing their tumor DNA and genetic makeup, which will lead to a treatment decision with potential targeted therapy, most likely a pill. But we also test the protein levels on the surface of the tumor cell, and this protein is called PD-L1, which is a different test and can lead to a treatment decision for immunotherapy, which mainly comes in the form intravenous injections. It’s become unique, so we’ve dichotomized a lot of lung cancer into targeted therapies when we test DNA, like pills, and immunotherapy when we test cell surface protein expression.

What makes it so complicated is not that all patients will respond to immunotherapy despite the direct-to-consumer advertising that is being done. Andrea talked about setting the level, and what we need to do when patients show up at the door is say, “You might not be the right candidate for immunotherapy, even if your protein is PD-L1 is elevated, ”which is the biomarker that defines the subset of patients who will benefit from immunotherapy. In a very complicated way, we’re still trying to figure this out. Patients with underlying genetic alterations in DNA and RNA tests, as well as high levels of protein, generally do not do very well with immunotherapy. In fact, they really should be treated with targeted therapy.

In our clinic, we do both DNA and RNA genetic testing to make sure we are defining the right patients for the pills, the targeted therapy, but at the same time we are testing their protein level. As you know, the protein level returns first – within 24 to 48 hours – and a PD-L1 of 80% or 90% would suggest that this patient may benefit from immunotherapy. But we have to tell the patients, “We have to wait, we have to wait for the genetic tests, because if you have a genetic alteration of interest, you probably will not respond to immunotherapy despite your PD-L1, and secondly, if we let’s start with immunotherapy and then we need to sequence you into targeted therapy, we could have real problems in terms of toxicity. Andrea talked about adjusting the levels, and that’s one of the things we need to do. Very savvy patients will come and say, “I’ve already tested my PD-L1, I’m 80% ready for immunotherapy,” and we have to tell them that we have to wait for the genetic tests. before making that decision.

Andrea Ferris: Yeah, we actually have to do a lot of that education on our side as well because like you said a lot of people want immunotherapy and think it’s the holy grail. But we have to explain to people in non-medical terms, “If you do immunotherapy first, you might not qualify for something that is much more suitable for you – and you might not be able to take it afterwards, and it could have had better results. for you.”

Benjamin Lévy, MD: There is another thing that we have learned over the past two years. This is relatively new data. At first, when immunotherapy first appeared in KEYNOTE-024 data, which showed Keytruda or immunotherapy to be good for patients with elevated PD-L1, we really didn’t know we should maybe- be first to test the genes and really be lacking. My practice has changed over the past 24 months. Three or four years ago we were still trying to learn, and we have good data suggesting – at least in the EGFR space, and maybe in the ALK space and others as well – that immunotherapy , at least as a single agent drug, is probably not the right choice for the initial treatment of a patient with these genetic alterations.

Hossein Borghaei, DO, MS: I absolutely agree with that. This is an important message to get across.

This transcript has been edited for clarity.

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