Transcript:Benjamin P. Levy, MD: What is the global perspective on the FLAURA data, and have they changed practice? We’ll start with Switzerland. Has this uptake now happened, and are you using it frontline?

Solange Peters, MD, PhD: Yes. It a standard frontline treatment. I think we have to be really convinced. Of course, we wait for the survival data. All survival data with TKIs [tyrosine kinase inhibitors] are always fully conditioned by the crossing over. We have to keep that in mind. Look at the data and look at the final crossing over, meaning the potential confusion that is given by receiving the drug later on. It’s very important, too, to look at all these parameters to evaluate OS [overall survival]. But the PFS [progression-free survival] is convincing.

You have to keep in mind that we like to add the PFS of frontline erlotinib, gefitinib, and second-line osimertinib. But we don’t think about the same patients. We have been giving—and I agree—osimertinib only to patients with T790M mutations in the second line. Half of these patients, if you don’t give it to them frontline, will never be exposed to osimertinib. Osimertinib, by the way, in establishing a new standard, is extremely well tolerated. We still have some patients with difficulty tolerating erlotinib, gefitinib, or, even worse, afatinib; don’t even speak about dacomitinib. It’s really a drug that allows for a good quality of life and a very decent restart of a normal life for some months, right?

Benjamin P. Levy, MD: There’s big discrepancy in toxicities for first-generation TKIs.

Solange Peters, MD, PhD: Yes.

Benjamin P. Levy, MD: What’s the United Kingdom perspective, Sanjay, on these data?

Sanjay Popat, PhD, FRCP: The data speak for themselves. To us, this is a great standard of care now. The challenge we have in the United Kingdom is that the discussions between the NHS [National Health Service] reimbursement agency, NICE [National Institute for Health and Care Excellence], and the industry partner, AstraZeneca, are still ongoing. We look forward to a resolution of these in the next few months. At the moment, first-line osimertinib is not a standard of care in the United Kingdom and we’re still sequencing. But I think when we’re in position in a few months’ time, hopefully, that will become available, and there will be a pretty rapid uptake for frontline osimertinib for the reasons that we’ve discussed.

Benjamin P. Levy, MD: Is it similar in France?

David Planchard, MD, PhD: It is similar in France, but we don’t have first-line access currently. It’s not reimbursed, so it’s ongoing now. We still use it systematically for the patients who are T790M-positive beyond first-generation or second-generation agents. We will still have the discussion about the sequence of using the best drug first now. We just should keep in mind that we never know what the tumor evolution will be when we start a treatment, and this is a major issue. The main difference is if we compare it to the ALK population, in which you can expose all the patients to different generation agents regardless of their type of resistance mutation, this not the case for EGFR, in which for osimertinib you need to prove—if you want to keep it as second-line therapy—the patient is T790M-positive. As it has been said, only 50% of patients—and I would say in clinical practice, sometimes it’s much closer to 40% than 50% or 60%—are T790M-positive.

We know that in older trials and in the FLAURA trial, around 20% to 30% of the population never gets a reasonable line of treatment. This is something really important. I would say we never know the evolution of T790M positivity. It’s unpredictable, and we never know if we are able to capture this mutation, particularly if you have a brain evolution. Generally, in this population of circulating tumor DNA-negative patients, you cannot perform any tumor tissue biopsy. You’re not supposed to expose this population to osimertinib.

You can have some bone evolution as well. We know it is a challenge to have any molecular testing on this type of tumor and disease evolution. That’s why—this is always what I say, particularly for this population and for osimertinib—you cannot rewrite the script of the patient at baseline.

We are not playing a game now. On paper, it might be nice to say, “OK, you will have 10 months if I keep osimertinib; it will be nice.” But you never know this when you start the treatment. You have the patient in front of you, and you will ask if we play this game where in 50% of patients, we will use the sequence. Or, in 50% of patients, the story will stop after the third generation. It’s a short story, because after that, it’s chemotherapy.

After osimertinib, I have nothing, so I don’t want to use it in the first-line setting. But if you use osimertinib in the second line, it will be the same thing. After osimertinib in the second line, you have nothing beyond. Currently, we all are in favor of osimertinib. You have the PFS response rate and brain efficiency—you even cover the brain evolution—and for me this is probably one of the most important things seen also with alectinib. When you see that the probability to develop brain metastases at 1 year is 8% with osimertinib and 25% in standard of care with gefitinib or erlotinib, it’s something major for the patient.

Lastly, we also looked at the time to discontinuation of any EGFR TKI. We looked at the PFS, too, for which, in this case, you take into account 2 lines of treatment. Even for the PFS in the FLAURA trial, we maintained the magnitude of benefit in favor of osimertinib, despite all the harm the patient received in the sequence of treatment. That means you will do better to start with osimertinib than to keep osimertinib in the second line of treatment in 50% of your population.

Benjamin P. Levy, MD: You raise very good points. I think that you can’t ensure that a patient’s going to get the active drug. You have to identify the T790M mutation, which is only in 50% of patients, and you can’t ensure that patient’s actually going to get any second-line drug. I think that you’ve got progression that happens in the brain and systemically that unfortunately precludes a lot of patients from getting any additional therapy. I think using your best drug first in this instance is important. It ensures that every patient gets the right drug.

Some questions have come up. As you mentioned, David, people have, at least in the United States, liked the sequencing story initially. It was a first-generation TKI, identifying T790M in the plasma, and then patients went on to osimertinib. Of course, that’s being supplanted by first-line osimertinib. Now the question is, and I’ve asked this question before, what do we do after osimertinib? What is the common practice if we’re using osimertinib frontline? Do we know anything? Ram, maybe you can comment first about mechanisms of resistance to osimertinib. Does that inform treatment decisions? Do we just use chemotherapy for these patients afterwards?

Suresh S. Ramalingam, MD: Right now, the standard of care for those patients after osimertinib is platinum-based chemotherapy. But we know that will change in upcoming years because we will understand more about what the mechanisms of resistance are behind osimertinib. It’s public knowledge now on the ESMO [European Society for Medical Oncology] Congress website that next month, we will have a presentation in Munich about resistance mechanisms in the blood for patients treated with osimertinib on the FLAURA study.

I think those types of data will lead us to develop approaches that can overcome resistance, just like we had erlotinib and gefitinib and learned about T790M and developed a new drug to overcome T790M. We will have approaches to overcome resistance to osimertinib. I think this is a dynamic field. We’re by no means where we want to be, but we’re in a much better place with osimertinib as frontline therapy than we were a few years ago.

Solange Peters, MD, PhD: A good example is how there’s a lot of ongoing research about one of these mechanisms. Again, we will learn at ESMO a little bit more about its presence, but one of the resistant mutations, the C797S mutation, is potentially giving rise to a new sensitivity to first or second-generation TKIs. In the lab, there are also new developments of drugs targeting this mutation but also in some patients anecdotally.

I think we will gain this portfolio basket approach to resistance that will help us maybe to distinguish other options than platinum-based chemotherapy. But I think the most expensive price you have to pay if you start with an old generation is not so much a calculation of PFS. I think we always underestimate the psychological cost, the internal expense of having brain metastases, and, socially, how handicapped and debilitated you can be. People need to support you, and it is really something that is the worst scenario for patients. Having a drug able to delay that is probably very good.

Benjamin P. Levy, MD: And not only delay it, but circumvent the need for radiation up front. It’s been a huge alteration in what we used to do for these patients.

Transcript Edited for Clarity