Novel Strategies Explored to Optimize Osimertinib Treatment and Beyond in EGFR+ NSCLC

Mark G. Kris, MD

The emergence of osimertinib (Tagrisso) in the EGFR-positive non—small cell lung cancer (NSCLC) treatment paradigm has led to unprecedented progression-free survival (PFS) in patients, said Mark G. Kris, MD. Now, researchers are channeling their efforts into optimizing patient selection for and outcomes with the targeted therapy.

Data from the phase III FLAURA trial brought forth a new standard of care in the form of osimertinib to the frontline setting of EGFR-positive NSCLC. Results showed that the third-generation EGFR TKI not only significantly improved survival, but also decreased the risk of central nervous system (CNS) progression compared with erlotinib (Tarceva) or gefitinib (Iressa).

In FLAURA, treatment-naïve patients with EGFR-positive NSCLC were randomized 1:1 to receive osimertinib at 80 mg once daily or comparator EGFR TKIs gefitinib or erlotinib at standard doses. In an analysis of the study, results of which were presented at the 2019 ASCO Annual Meeting, researchers found that clearance of plasma EGFR mutations after 3 to 6 weeks of therapy was associated with a statistically significant improvement in PFS.

Plasma EGFR mutation analysis was conducted at baseline, week 3, and week 6 via droplet digital PCR. Clearance was defined as undetectable levels of EGFR in circulating tumor DNA at weeks 3 and 6, when they were initially detectable at baseline.

At week 3 of osimertinib treatment, patients with nondetectable EGFR mutations (clearance) experienced a median PFS of 19.8 months compared with 11.3 months in those with detectable mutations in the plasma. After 6 weeks of osimertinib therapy, the median PFS in those achieving clearance of plasma EGFR mutations remained the same, while it fell to 11.1 months in those with detectable mutations.

Researchers are hopeful these data can be used to help identify which patients will thrive on osimertinib, and which patients are at high risk of early progression and would greatly benefit from a proactive early-intervention strategy.

In an interview with OncLive, Kris, a medical oncologist and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center, discussed the latest data with osimertinib and shared unanswered questions that remain in EGFR-positive NSCLC.

OncLive: Could you discuss the importance of the FLAURA trial? What were the key takeaways from the analysis presented at the 2019 ASCO Annual Meeting?

Kris: The FLAURA trial has been a tremendous resource both in giving us new therapy with osimertinib and helping us understand ways to treat patients with EGFR-mutant NSCLC. We all know osimertinib induced better responses, less CNS progression, and better PFS than the comparators. However, there's more information from the FLAURA trial [that can be useful]. One thing we have tried very hard to do is find ways to risk-stratify patients. We want to find the patients who will have the best response to osimertinib as well as the ones who will relapse sooner. Is there a way to do that? One way that people have tried to answer that question is through tumor DNA in the bloodstream.

In an analysis of the FLAURA data, we have found that if you are able to clear the plasma DNA, to lower the amount of DNA that comes from the bloodstream in the cancer, it would predict a better outcome. We were able to do that. This is important because it gives us a strategy to go after those patients who are destined to have a short benefit and are fated to ultimately relapse. We are very happy to have this kind of information because it allows us to take the next step here.

The FLAURA trial gave us osimertinib, but it also gave us so much more. There will be many trials going forward that will look at the clearance of plasma DNA and use that [data] to risk-stratify people and select them for other treatments. The goal is to not wait until they progress. We want to be able to find someone before they relapse, so they don't have to suffer through that; these data give us a chance to do that.

What is the biggest unanswered question with osimertinib?

The biggest question is, “Why doesn't osimertinib cure patients? Why do patients eventually have their cancer persist?” Those are the main questions, and there are some strategies [under investigation that are] to try to [answer] them. The other thing is, when these patients do relapse, we are seeing that the pattern of their relapse is entirely different than what it was after erlotinib and gefitinib. How do we take a good drug and turn it into a drug that might increase chance for cure? Also, [we need to determine] when the patients do relapse, what will our strategy be?

Despite the progress made with EGFR TKIs in this space, relapse is still an important challenge. Could you discuss the RELAY trial and how it set out to address that issue?

The discovery that EGFR TKIs could uniformly cause cancers to shrink and lengthen patients' lives has dramatically changed the care of all patients with lung cancer. The problem with all of these TKIs, including our newest one, osimertinib, is that they still do not cure patients. Virtually every patient with stage IV disease is destined to have the cancer come back. As such, we are looking for ways to further delay or prevent the time to relapse. A relapse is a very devastating thing for a patient both physically and emotionally, so preventing relapse is a very important goal.

We have previous data suggesting that by adding bevacizumab (Avastin) to erlotinib, you could lengthen the time to relapse by 6 months compared with erlotinib alone. What has been shown in this study is that if you use a different drug targeting angiogenesis, in this case ramucirumab (Cyramza), you could still see a delay in time to relapse. That was the goal of this study, and we delayed relapse by about 7 months. This is good news, and ramucirumab is widely available in virtually every institution already. However, the difficulty that people will have with this trial is that it was done with erlotinib, a drug that is not commonly used today.

Now, many people, myself included, make the easy switch from erlotinib to osimertinib. We know osimertinib is a better drug, but I feel that we could substitute this for erlotinib; not everybody agrees with that. We are working on a trial [evaluating the use of] bevacizumab with osimertinib and we have had no trouble in doing that, just like [we know that] bevacizumab can be given with erlotinib. We are very confident in giving the best EGFR TKI with the best VEGF inhibitor upfront, but not everyone is comfortable doing that. This will be worked out in the years to come.

Is there anything else you would like to add?

With the EGFR TKIs, we have been both excited and frustrated. We are frustrated in that we are not curing patients. The hope was that these drugs would be the breakthrough we needed for cure. What's interesting about these trials is that one of them, looking at cell-free DNA, is a way of intensifying therapy but only does so in those high-risk patients. The hope is that if you intensify treatment in those patients, you could lengthen relapse-free survival. With ramucirumab, the hope is that by adding the drug, you could lengthen that time and maybe even cure someone. Whether these trials will get us to that goal is still unknown.

Zhou C, Imamura F, Cheng Y, et al. Early clearance of plasma EGFR mutations as a predictor of response to osimertinib and comparator EGFR-TKIs in the FLAURA trial. J Clin Oncol. 2019;37(suppl 15; abstr 9020). doi: 10.1200/JCO.2019.37.15_suppl.9020.