Precision Medicine in Advanced Non-Small Cell Lung Cancer - Episode 3

Sequencing With Osimertinib in EGFR-Positive NSCLC


Benjamin P. Levy, MD: Are these data cemented, osimertinib in the frontline? There are still practitioners out there who may say, “Look, I’d like to save osimertinib. Is there a better tolerated drug for second-line therapy? What are we going to do after osimertinib anyway?” We’ll talk about that later, about mechanisms of resistance and next steps. What’s the message out there for the practitioners who may want to save osimertinib and start on a drug that they feel more comfortable with because they’ve been using it for quite some time? Any thoughts on that?

Zofia Piotrowska, MD: This is a question that comes up a lot, the sequencing question. If you have a good drug, do you use it up front? Or do you save it as a potential second-line therapy? I think the key message here is that osimertinib is effective in the second-line setting. But it’s really only effective for patients who develop T790M mutation. And at best, that is 50% to 60% of the population.

Benjamin P. Levy, MD: If everyone is tested.

Zofia Piotrowska, MD: Exactly, assuming that 100% of patients are tested. From real-world data, and even from some of the osimertinib studies, we’ve seen that testing is not universally performed. Not all patients may get to second-line therapy. Some progress and aren’t able to get second-line therapy. They aren’t able to get the testing done. There’s a real opportunity for patients to miss out on that second-line treatment. In the ALK space, as well, we’ve seen that when you have very effective therapies, moving them to the frontline setting really does improve progression-free survival. Although we haven’t yet seen the full, or last, data from the FLAURA study, I think there’s a lot of hope and an expectation that it will really improve overall survival as well.

Benjamin P. Levy, MD: Yes, I think your points are very well taken. No. 1, even if you assume that everyone gets tested, only 50% to 60% will be identified with T790M. Interestingly, in some of the prospective data we have from the LUX-Lung trials, 30% of patients didn’t go on and get a second-line drug after the TKI.

Zofia Piotrowska, MD: It’s really striking.

Benjamin P. Levy, MD: It’s striking. In clinical practice, I think that I do better than that. But maybe I don’t. Some of these patients fall off. So, at this time, I think you’ve got 1 shot on goal to get the best drug to the patient first.

Lyudmila A. Bazhenova, MD: We actually have numbers. I’m a numbers person. If you look at the FLAURA data, a percentage of the patients who were randomized to erlotinib never got osimertinib. It’s in the appendix of the paper. So, if you add that to the percentage who never develop the T790M mutation, plus the number who never get to second-line therapy, you have a group of patients who would get the chance to use osimertinib. To me, the decision is very clear.

Zofia Piotrowska, MD: I’ve actually had this conversation with patients. When we talk about this practice-changing study and how we make the selection, most patients really do say, “If there’s a chance I may not be able to get this drug later on, if I’m going to feel better on it, and it has better brain penetration and the outcomes are better overall, absolutely.”

Jonathan W. Riess, MD, MS: You bring up a critical point. The brain penetration has the ability to help prevent the development of brain metastases to control and spare them of not just radiation, but the potential side effects. We’ve seen less complications. We’ve seen the added detriment to quality of life in terms of radiation treatment and possible symptoms from brain metastases. I think this is a huge benefit for patients, and I wouldn’t underestimate. I think that’s absolutely critical. That, plus the suppression of T790M, is really driving the benefit of this drug. Bringing it to the first line, or using your best drug first, makes the most sense. However, some people may say it’s logically intuitive to sequence, given the magnitude of benefit. With the trend toward overall survival, showing benefit there as well, I think it’s become my standard of care and is widely accepted.

Transcript Edited for Clarity