Future Outlook of EGFR Mutant NSCLC

Solange Peters, MD, PhD: In advanced stage EGFR-mutating non-small cell lung cancer, we are waiting for data to offer options, specifically targeted and personalized options for resistance. This is moving with, for example, the ADAURA trial, but there are others. Once you manage to establish what the mechanism of resistance is, then what are the subsequent options, still excluding chemotherapy? Is it offering additional months of survival? It can be 5 to 19 months possibly but delaying the use of chemotherapy will offer more survival. I think going into this precision oncology field, which of course is small numbers of more small numbers, is what we need to do in order to make a further prolongation of overall survival [OS] of these patients. We might also define here, options like patritumab deruxtecan or maybe at the time being, lazertinib [Leclaza] and amivantamab [Rybrevant]. We might also offer options which are valid for all comers at resistance towards the osimertinib [Tagrisso]. So this panel is very important. The second challenge is to know what to do exactly with chemotherapy. Whether to combine it with IO [immuno-oncology], or IO/antiangiogenic. The third challenge is what to do in the third line, and whether that is targeted therapy and what type. All of these remain very interesting questions. In early disease, what we will need to know for EGFR, of course, is the OS data. But we need to wait 3 or 5 more years. So do we want to deprive a patient from adjuvant osimertinib for all these years knowing such a magnitude of DFS [disease-free survival] improvement? I would not, particularly because osimertinib protects the brain and there’s nothing worse than the patients having the diagnosis of relapse at the brain level. I think we have to continue to deliver it while waiting for OS data. Waiting to see what other data can be collected in stage 1 to try to define if it is needed or not. I think that that’s the challenge. The most important challenge is to know what we do with EGFR. Is it true for ALK, ROS1, RET, NTRK, BRAF, HER2, MET? So, is this option of giving chemotherapy followed by TKI [tyrosine kinase inhibitor], is this a general consent or is it just for EGFR? As you will understand, it will take way more time to define the establishment of the rule of targeted therapy. It’s a matter of debate. Do we improvise to date on whether it is the same or not? We still don’t know.

Tony S.K. Mok, MD: In the early stage, as we probably know, the immunotherapy, using the aducanumab [Aduhelm], have been established, and there is the CheckMate 816. The early data was presented of using chemotherapy plus nivolumab [Opdivo] as the so-called new adjuvant treatment. The complete pathological response rate was about 24%. Now, just this month, they announced that the progression-free survival, or the event-free survival, will be positive. We don’t have the number yet, but certainly by next year I look forward to hearing the result. That gives us an extra option whether we want to treat the patient with preoperative chemotherapy plus the immunotherapy. So, I think this is an exciting development in this regard.

In the first-line situation, the third generation TKI had definitely taken a dominant space, but I think the trick now is to personalize the management or resistance to osimertinib. We started personalized medicine, but now I think we are taking on a step to personalize the personalized medicine. This means that we use the personalized approach to identify the cause of resistance. For example, if the patient is MET amplification, then we give the treatment with the associated MET inhibitor. With the patients in the future, hopefully we have the fourth-generation EGFR-TKI. We may have to decide whether we want to do chemotherapy or chemotherapy/IO. We are likely to use a different criterion to decide what will be the best. I think I’m looking forward to it in that personalized approach of management in EGFR mutation-positive lung cancer.

Solange Peters, MD, PhD: The main points I’d like to stress discussing the ADAURA trial, is first of all, this trial establishes a benefit in term of disease-free survival, which was very rarely met in non-small cell lung cancer. Of course, this is not overall survival, but this is an amazing benefit for the patient who can stay without disease under a very tolerable drug. Waiting for the OS data, if we can or argue for that, and then make this drug available and propose to the patient after standard of care resection and adjuvant chemotherapy. I think that’s a political move that we should do waiting for OS final data. But, as I said before, only in 3 to 5 years from now. So that’s quite important to argue for that. The second thing is in adjuvant osimertinib, with those in adjuvant atezolizumab [Tecentriq], we have reached the point where we have to take the time and have educated discussion with the patients about the pros and contra. What we know and what we don’t know. What might happen if we do? What might happen if we don’t do? All of this is important because I think everything we do now can be researched by patients on Google. They know what happens in terms of science. We should have this discussion to make sure that we understand the pro and contra of everything we propose, and we agree. Consensually, we have an informed consent of our patients in everything we do. But to my opinion and following my recent experience about osimertinib in the adjuvant setting, we should discuss it with the patient who has undergone resection, which is chemotherapy usually. Trying at least to see how osimertinib is tolerated in order to prevent relapse, especially brain relapse is more important than anything. Most of the patients would buy it, try it, and go through that to try and see how it goes with the osimertinib in the adjuvant setting. Now it is time to learn how to discuss things with patients.

This transcript has been edited for clarity.