KRAS G12C Therapy, EGFR Advances, and the Future of Lung Cancer Treatment

Описание: Dr Mark Kris explores key 2024 lung cancer advances, including KRAS G12C therapy, EGFR treatments, and emerging challenges in care
https://www.medscape.com/viewarticle/...

-TRANSCRIPT-
This is Mark Kris, from Memorial Sloan Kettering, continuing a discussion of important developments in the field of lung cancer in 2024.

I think all of us have seen the dramatic benefit in patients receiving the KRAS G12C–specific drugs sotorasib and adagrasib. Clearly, patients who had disease progression on standard initial therapy have had important and long-lasting benefits from these drugs when given as a second treatment. I don’t think anyone doubts that.

What’s happened this year is that questions have come up over exactly how effective these drugs are. Much of this discussion followed the randomized trial comparing sotorasib with docetaxel, which showed between a 1- and 2-month benefit in disease-free survival. There were similar results in the trials of adagrasib.

It has raised the issue of: What is the most effective therapy? This is a tough decision because we are balancing the benefits observed in individual patients against data showing only a marginal advantage over docetaxel in randomized trials, along with substantial toxicities for individual patients.

We don’t have a way of selecting patients based on who’s going to get the benefit and who’s going to get the toxicity. I think we all were a bit shocked that neither of these drugs could beat docetaxel.

However, please remember that docetaxel is an active drug. It’s been our standard of therapy for much longer than any of us thought it would be, and many of us have learned how to give the drug in alternate schedules that make it much more tolerable. This is a great example of clear benefit for some patients, toxicity for every patient, and how to choose.

The other data that has come out is in the use of sotorasib. There’s been an addition to the FDA label, saying that you need to be very careful about giving sotorasib in the first 3 months after receiving a checkpoint inhibitor. I think there have been data from my colleague, Adam Schoenfeld, and others saying that there’s an increased risk for adverse effects after a checkpoint inhibitor, and you need to be very careful about giving sotorasib at that time.

I think the information now would be that if you chose to give a KRAS G12C inhibitor, you would use adagrasib instead of sotorasib after a checkpoint inhibitor as initial therapy. The development of these drugs in combination continues to be an area of study; there is no definitive evidence yet.

Other trials that seem to show clear benefit include the long overdue trial in patients with stage 3B EGFR-mutant disease getting concurrent chemotherapy and radiation. I think we all saw in the data from the PACIFIC trial that there was not a substantial benefit from adding in a checkpoint inhibitor.

Checkpoint inhibitors have not been shown to be particularly useful in patients with EGFR mutations. The trial that administered osimertinib to patients with EGFR mutations after they received concurrent chemotherapy and radiation showed a substantial disease-free survival benefit. I don’t think anyone would question that, and it makes sense. The one interesting thing in that trial is that, unlike other adjuvant trials where osimertinib was given for a prescribed length of time, here osimertinib was given indefinitely until disease progression.

I think many people have said that these drugs delay progression. I think the jury is still out as to whether that’s really how they work. I personally believe that some patients are going to be cured by these regimens.

I’m using imatinib as an example. I think folks made the same arguments with imatinib. It became very clear in the trials — which compared 1 vs 3 years of imatinib — that people were cured when they got a longer duration of imatinib. That also says, maybe we should be giving longer duration of drugs such as osimertinib after chemoradiation.

What do you do? I think the standard today, based on the data that are out there, is that after concurrent chemoradiation in patients with an EGFR mutation, patients should receive osimertinib and it should be administered indefinitely depending on patient tolerance.

I’ve given two examples here of new drugs clearly helping individual patients, but with questions about how long and who’s the right patient. People are living longer and living better; however, it’s going to be harder for us to decide who to give it to, for how long, and what’s the best sequence of therapies.

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