Frontline Treatment Options for Patients With EGFR-Mutated NSCLC

At the 2023 Great Debates and Updates in Lung Cancer, Heather Wakelee, MD, Stanford University, Palo Alto, California, covers updates in first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC).

Dr Wakelee discussed the combination options with EGFR tyrosine kinase inhibitors (TKIs), such as with VEGF inhibitors, chemotherapy, or other EGFR TKIs, as well as the use of ctDNA.

Transcript

Hi, I'm Heather Wakelee, Professor of Medicine, and Chief of the Division of Oncology at Stanford University, Deputy Director of the Stanford Cancer Institute, and I'm here in Chicago, Illinois at the 2023 Great Debates and Updates in Lung Cancer meeting. I was excited to have an opportunity to talk about updates in first-line treatment of EGFR mutant non-small cell lung cancer.

As I was preparing this talk, I really wanted to reflect on how we got to where we are. I reviewed the history, starting with the IPASS trial, that looked at chemotherapy versus first generation EGFR tyrosine kinase inhibitor, and showed that when an EGFR mutation was identified in the tumor, patients did much better when starting off with an EGFR TKI versus chemo. But if the mutation wasn't there, chemotherapy was the better option. That was really the dawn of targeted therapy for non-small cell lung cancer.

Other developments have included development of the third-generation drugs. That is predominantly, osimertinib in this part of the world, though, there are others in development in other parts of the world and utilized there.

We have had osimertinib as our first-line treatment now for several years, and there have been studies trying to improve upon that. In my talk, I focused on what are the major categories and what progress have we made? We have been looking at adding vascular endothelial growth factor (VEGF) inhibitors to EGFR TKIs for quite some time. The BeTa trial takes us back in time, which was positive, and we've had a series of trials since then, and have shown disease-free or progression-free survival, adding bevacizumab to EGFR TKIs, adding ramucirumab to VEGFR TKIs, adding VEGFR TKIs to EGFR TKIs. But we really haven't broken that overall survival barrier. We haven't seen overall survival benefit with those approaches, though many have had progression-free survival benefits. We have approvals for the combination of erlotinib and ramucirumab in Asia. There's afatinib with gefitinib, but others haven't really panned out so far.

There is an ongoing study with an ECOG-ACRIN Cancer Research Group, looking at osimertinib plus or minus bevacizumab in the first line. That study's being run with Helena Yu [MD, Memorial Sloan Kettering, New York, NY] and Balazs Halmos [MD, Albert Einstein College of Medicine, New York, NY] as the two PIs. We are hoping to see positive outcomes from that, but it's still enrolling.

The next big category is looking at EGFR TKIs with chemotherapy. Again, this goes back a long time. We had the FASTACT-2 trial, which was very positive, looking at intercalated chemotherapy with gefitinib. Despite the overall survival benefit in that trial, it hasn't been adopted. We had two trials, 3, 4, 5 years ago, looking at chemotherapy plus EGFR TKI, a big study in Japan, gefitinib plus chemotherapy, together or sequentially with the gefitinib, and then the chemo at time of progression. That study did not show any difference in progression-free survival with giving everything together or doing it sequentially. But there was an overall survival benefit to the group that got everything concurrently, so gefitinib plus chemotherapy together.

There are ongoing trials studying that approach further. There is a study with osimertinib. There are other ongoing trials. Perhaps we'll start to use that approach, but we've had other positive trails that didn't change practice, so kind of waiting to see how that all pans out.

An interesting twist on that is using ctDNA, and looking at patients to see if they have a robust initial response to osimertinib and completely clear ctDNA. Maybe osimertinib is enough, but if you don't get a robust enough response, then going along and adding the chemotherapy at that time to the EGFR TKI. That's an ongoing study, the SHEDDER study, so we'll see how that pans out.

The third big category that's being worked on are looking at EGFR combinations. Studies looking at combining first generation and third generation, with the acknowledgement that there are different resistance pathways. If you have a third-generation drug, you might develop C797S, first generation drugs work there. If you're on a first-generation drug, you develop T790M. EGFR, third-generation drugs work there. If you combine them together, is that a better approach? Lots of work happening with that strategy also. It looks encouraging. Then we have other EGFR strategies like the bispecific drug, amivantamab, a lot of work being done with that and some similar approaches.

Another topic I mentioned was with immune therapy, and we talked about that a lot in the discussion. Unfortunately, immune therapy strategies that we have today don't seem to work very well in patients who have EGFR mutated disease. We know that combinations of osimertinib plus the checkpoint inhibitors have been toxic, so we avoid that. Other EGFR drugs plus checkpoint inhibitors may be less toxic, but not clearly additive or effective either. That's a huge untapped area we've been exploring. There's more research that needs to happen.

In the setting for first-line EGFR mutated lung cancer, first-line osimertinib is still the standard. We've done a lot of work at what we can add to make that better. VEGF, chemotherapy, EGFR/EGFR combos, looking at immune therapy, but it's still been slow progress. We're still with osimertinib, but there are many ongoing trials that might allow us to change that in the future.

Source:

Wakelee, H. “Upfront Treatment in Sensitizing EGFR Mutation.” Presented at Great Debates & Updates in Lung Cancers. May 4-6, 2023; Chicago, IL