Global Outlook on Advanced Nonsquamous NSCLC - Episode 6

Osimertinib as Frontline Therapy for EGFR-Positive NSCLC


Suresh S. Ramalingam, MD: What I would like to do at this point is shift gears and move on to targeted therapies, which are another exciting area in lung cancer.

Giorgio Scagliotti, MD, PhD: You made the cornerstone presentation in the last 2 days.

Suresh S. Ramalingam, MD: Thank you, we’re going to talk about that. Let’s start off with EGFR mutation-positive disease. As you know, the prevalence of EGFR activating mutations is about 15% to 35%, depending on whether you’re practicing in Europe, North America, or Asia. We have at least 3 TKIs that are used in the first line: erlotinib, gefitinib, and afatinib. Now, we heard about the data with osimertinib. I want to come to you, Marina, to get your thoughts on where you see the landscape changing. How is this going to affect practice moving forward?

Marina Garassino, MD: Thank you. I’m quite embarrassed to present the results that you presented in the plenary session, but it’s a pleasure. As you told us, we now have several EGFR tyrosine kinase inhibitors, which are doing the same thing—erlotinib, gefitinib, and afatinib—but they have very different toxicity profiles. We also have several data coming from a trial comparing dacomitinib to gefitinib, which is the first trial that is showing superiority to gefitinib. However, the drug is very toxic, and it’s not very easy to give the drug to all patients in clinical practice.

You presented, 2 days ago, the FLAURA study that was very expected by the scientific community, suggesting that osimertinib is much superior to gefitinib in terms of progression-free survival, and it also has more benefit in overall survival. So, the final results are suggesting that the progression-free survival is almost 19 months. And the study before was done with the first- or second-generation EGFR tyrosine kinase inhibitors. Then we had to test for the presence of T790M, in the blood or in the tissue. We know that this is present in about 60% of cases. And for this kind of patient, we had to continue with osimertinib again, where the progression-free survival was almost 10 months, not 19 months, as the first-line treatment.

Now the choice is to go first with osimertinib, which is a wonderful drug for its toxicity profile, and to go for almost 2 years with this kind of drug. Or, again, use the first-generation TKI, then ask for the T790M and go with a third-generation TKI.

I think that the story is evolving. We also have to consider that there are ongoing trials combining together the first- and second-generation TKIs with antiangiogenics, which can change the scenario, and putting osimertinib in second-line. But personally, with 19 months of progression-free survival, I think that we have to ask the patients what they really want and tell them that there are multiple strategies. But in my opinion, it’s quite a “game over” in favor of osimertinib.

Suresh S. Ramalingam, MD: Thank you. Benjamin, what are your thoughts on the FLAURA first-line study, osimertinib versus erlotinib or gefitinib?

Benjamin Besse, MD, PhD: The PFS is clearly much better, and it’s an easy strategy to start with osimertinib because you don’t have to rebiopsy the patients. It’s true that rebiopsy is much better with the liquid biopsy, but it’s something that takes time and energy, and there are probably 20% of patients in whom you can’t rebiopsy the tissue, because its bones are too small.

So, it’s an easy strategy. But I’m not yet sure it’s the best strategy. I think at the moment, until I have the mature overall survival data from FLAURA, I will continue with my current strategy, which is first generation or second generation and then osimertinib. I have to say that for the uncommon EGFR mutation—exon 18, for example—my preferred choice will be a second-generation inhibitor. We will run a study in which one arm will be osimertinib and 1 arm will be gefitinib followed by osimertinib, and this kind of sequence study is really needed in the field to help us understand which is the best strategy. These patients live quite a long time. So, it’s not just giving a first-line treatment. It’s sequencing all the treatments for all lines for the patients.

Suresh S. Ramalingam, MD: The caveat there, of course, is that not all patients will develop a T790 mutation. Only half of them will develop one, and that’s really the issue when you think about what drug goes first. We don’t have the ability, at this time, to predict who develops a T790 mutation down the road. Giorgio, how do you view the FLAURA data, and what does it mean for your patients on Monday morning next week?

Giorgio Scagliotti, MD, PhD: The study, as I said before—not because you presented the study—has the potential to be a game changer, to set a milestone in the treatment of patients with EGFR-positive disease. I can join in completely with what Benjamin said before and what Marina said before. The issue is that I totally agree that we need to have mature survival data, because with the data that you presented, the events are only 24% and you stated that the differences in survival are not statistically significant.

Based on the data that you presented 2 days ago, I truly believe that due to the limitation that we saw using gefitinib and erlotinib in the CNS penetration of these 2 drugs, if the drug will be available tomorrow, I will consider for those patients who are positive for brain metastases at diagnosis to start osimertinib in the front line. The issue is that we need to understand a little bit more about the biology of the disease. We need to understand exactly when you, the investigator, will be able to completely dissect the data. What is the contribution of having a drug that is eating the T790 mutation pretty early?

The study that Benjamin—I’m just promoting what Benjamin is doing—is doing is a study in the context of a comparative setting that is called the APPLE trial. In addition to the 2 arms that he was mentioning before, he also has another arm that is checking for the T790M mutation, as soon as the patients are becoming positive for the T790M mutation in the blood. They are switching from gefitinib to osimertinib. That is, at least for me, a reasonable way to address the issue of sequencing. Obviously, this is still an experimental way of following up on our patients. They call it clinical research. So, we need to trust the concept in which the study has been planned.

Marina Garassino, MD: I would like just to add just 1 thing. It was my feeling when I heard the presentation 2 days ago that not all the centers can to do the T790M testing. So, in a certain way, if you are not working in a big cancer center or in a specialized hospital, maybe you can lose the possibility to use the drug because you are not able to test for T790M. I think that we can discuss patient-by-patient, but maybe also hospital-by-hospital, for this sequence.

Suresh S. Ramalingam, MD: That’s an important issue. We need to make sure our patients do get testing. If a patient gets a first-generation or a second-generation inhibitor in the frontline setting and develops progression, testing for T790M is now considered a standard workup. And if they do have T790M-positivity, then in the second-line setting, osimertinib is already approved based on the strength of the AURA3 trial that Dr. Tony Mok presented recently.

Transcript Edited for Clarity