EGFR-Mutated NSCLC: Looking Ahead

Edgardo S. Santos Castillero, MD, FACP: John, take us to the future in the EGFR-mutant population. By the way, you mentioned something that I want to know your opinion on, because we haven’t talked about what happens once you become resistant to osimertinib. I will leave that for the end. No one wants chemotherapy; it seems that chemotherapy has a bad reputation. Once you start a patient on targeted therapy, everyone wants to remain on targeted therapy. It’s easy: It’s an oral pill, and there are fewer visits to the clinic, specifically at this time with the pandemic. It is the same thing with immunotherapy. You start with immunotherapy, and the patient is doing well, so no one wants to get the chemotherapy. How do we improve on what we have right now? From now on with first-generation and ahead, what do you think as we’re moving forward?

John V. Heymach, MD, PhD: There are a lot of exciting possibilities. The first and most obvious is that if VEGF inhibitors like bevacizumab and ramucirumab improve outcomes with erlotinib, why not move the patient to a better drug, osimertinib? ECOG is doing a study by Helena Yu of osimertinib plus bevacizumab; that’s a phase 3 trial. Based on what we’ve seen with erlotinib and bevacizumab, I would expect that this trial has a good likelihood of success. We [at The University of Texas MD Anderson Cancer Center] are doing a randomized phase 2 study, and a Japanese group is doing a randomized phase 2 study as well of osimertinib plus ramucirumab. They’re taking the RELAY regimen and swapping osimertinib in for erlotinib. That’s a regimen that we’re excited about as well. There’s a study, the FLAURA2 study. Based on what we saw from the Tata [Memorial Centre in Mumbai, India,] study that you discussed before with the gefitinib combinations, there’s good reason to believe that this would be a positive study.

I’ll mention 1 other approach I’m enthusiastic about. We have a study called NORTHSTAR, and the idea behind the study is this: When patients are initially treated with the tyrosine kinase inhibitor [TKI], even when they have widespread metastatic disease, almost everybody has a good response, and they’re down to just a bit of residual disease. We know that if you didn’t kill it after 3 months, the TKI is never going to kill it, right? Why not use something different to kill it at that point? At the end of 3 months, if they haven’t progressed, we then radiate or resect all the residual disease. It’s a brute force approach, but just because it’s brute force doesn’t mean it’s wrong sometimes. We’re doing the randomization to either continue osimertinib or give osimertinib with this consolidative therapy while continuing the osimertinib. There are 4 different possibilities: adding VEGF, adding chemotherapy, and adding consolidation.

There are other possibilities that are emerging. People are looking at other drugs that they might be able to add with it as well. The early results of trying to add immunotherapy, which is another obvious choice, haven’t been very successful. We know PD-1 inhibitors don’t work great for patients with EGFR mutations, and there were some unexpected toxicities when osimertinib was combined with immunotherapy. That’s 1 that doesn’t look so promising to start with, but we have a number of good options that are in process right now, and I would be surprised if 1 or more of those don’t turn out to be positive. I expect that these are going to be positive studies. This may mean that, a few years from now, we would start with osimertinib, and the patient would get either chemotherapy, a VEGF inhibitor, or a consolidation or some combination of those as well.

We’re going to keep pushing back the PFS [progression-free survival] in that first-line setting. A VEGF inhibitor may add 4 to 6 months, chemotherapy may add 4 to 6 months, and consolidation may add something. I’d love to see us get PFS north of 30 months or longer. That’s where we can start having a big impact, even before we hit resistant disease.

Edgardo S. Santos Castillero, MD, FACP: In your opinion, it is chemotherapy, immunotherapy, plus bevacizumab, that is the therapy right now for osimertinib-resistant disease.

John V. Heymach, MD, PhD: Yeah, that’s right. That’s my preference; that is what I recommend. I’ll have to acknowledge this here: We have limited data. We don’t have comparative data.

Edgardo S. Santos Castillero, MD, FACP: Absolutely.

John V. Heymach, MD, PhD: With the data we have and what we know, we know that VEGF inhibitors are active in EGFR-mutant tumors, so I prefer the IMpower150 regimen because that was the first-line study that included patients with EGFR mutations. If you look at the KEYNOTE-189 study, it did not include EGFR or ALK. If you look at the CheckMate 227 study, it didn’t include those as well. But the IMpower150 study did include EGFR and ALK mutations. The benefit for the 4-drug regimen with the IMpower150 in the EGFR-mutant subgroup is not huge, but it looked like it had a benefit similar to the other groups. In my hands, acknowledging the limitations of the data set, I recommend the IMpower150 regimen, but this is clearly an area where we need improvement. The questions we raised before are important: Maybe you should keep the EGFR inhibitor going during that time, and maybe we need a different EGFR inhibitor. There are a lot of different things that we could consider there.

Edgardo S. Santos Castillero, MD, FACP: To back up what you said, in the initial presentation by Mark Socinski on the IMpower150 study, which was positive for overall survival, I’m going to start with that. In a subsequent update this year, that particular group, the EGFR-mutant population, continued having the same impact on the overall survival in the control arm.

John V. Heymach, MD, PhD: Yeah, that’s right. My personal approach is to treat with the TKIs for as long as you can, and I tend to be pretty aggressive. If the patient has oligoprogression, and if they develop bone metastases, I radiate it. If they develop a solitary metastasis, I radiate it, resect it, or do whatever I need to. When they are clearly progressing, and you’ve lost control of it with the EGFR inhibitors, if the patient is suitable for the more aggressive regimen, IMpower150 is what I’ve been favoring so far.

Edgardo S. Santos Castillero, MD, FACP: There are many things, John, on the EGFR pathway. When you mentioned that you treated your first patient in 1999, that was also when I treated my first patient. I remember that, in May 2019, the patient was still alive. Having a stage IV patient live for 11, close to 12 years already is amazing. We’re looking forward. The only way is through research, and we’re advancing the field specifically. This particular topic has been amazing for all our patients everywhere.

John V. Heymach, MD, PhD: Yeah, absolutely.

Transcript edited for clarity.