It’s Complicated: Lung Cancer Targets Defy a One-Size-Fits-All Treatment Approach

Dr Mark Kris continues “It’s Complicated” with a look at therapy decisions for NSCLC patients with targets but no clear first-line standard.
https://www.medscape.com/viewarticle/...

-- TRANSCRIPT --
Mark Kris, again, from Memorial Sloan Kettering, continuing my series that I’ve titled, “It’s Complicated.”

I returned from the IASLC 2025 Targeted Therapies of Lung Cancer Meeting, and one of the conclusions [among] many of the speakers was how many decisions we have to make and the nuances in making those decisions.

I talked about those patients already that have a target with a tolerable drug and a high likelihood of benefit. Now, I’m going to talk about patients that have a target and a targeted therapy, but the decision of what to give first is not as clear. The list there would be BRAF, MET, HER2, EGFR exon 20, and the newest kid on the block, NRG.

I think, for all of these, the magnitude of benefit with a targeted therapy upfront is not as great as with some of the other ones I’ve mentioned before, such as ALK or EGFR. When you look at the data about whether you start with a targeted therapy or start with a standard therapy and use targeted therapy as a second-line [treatment], that is scant and there’s very little information to lead folks. There are a couple of thoughts and I think some consensus.

The first is for all KRAS, including KRAS G12C, where we have two available drugs right now. For any other KRAS, whether we do not have an available drug or only investigational therapies, I think that the standard of care up front should be chemotherapy with a checkpoint inhibitor, like we would treat anybody that did not have the driver. It seems there was general consensus that was true, but for all the others it was much tougher.

Let’s start with NRG. We have very little data there. Even with the agent we have available now, zenocutuzumab, the response rate is about one-third of the patients. I think it makes sense to start with chemotherapy and a checkpoint inhibitor and save the zenocutuzumab for the second line.

What about BRAF? There were some data presented at that meeting about giving BRAF-targeted drugs first or second line. A couple thoughts about BRAF. Number one, it’s a different population of patients. A huge proportion of them are not the never-smoking folks that we see make up the large populations of people with ALK and EGFR. Instead, many of them had been current and former smokers.

The second thought is that the two drugs that are the standards of care are much more difficult than a single agent, such as lorlatinib or crizotinib. The side effects are more pronounced. The other observation made when examining data from a number of centers: For those patients who had a history of smoking, they appeared to do better with the standard of care chemotherapy plus a checkpoint inhibitor, reserving the BRAF-targeted therapy as the second line. For patients who had a minimal smoking history, perhaps they fared better when you gave them targeted therapies.

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https://www.medscape.com/viewarticle/...