Research Efforts Focus on Reducing Recurrence in Early-Stage EGFR-Mutant NSCLC

The EGFR TKI osimertinib (Tagrisso) has shaken up the treatment paradigm of advanced non–small cell lung cancer (NSCLC), and now the agent is under exploration in earlier-stage settings in an effort to further prevent recurrence and prolong survival, according to Edward S. Kim, MD, who added that the key to reaching patients earlier is to test for biomarkers earlier.

“In the early-stage setting, it is devastating when [patients experience] recurrence. Hopefully, [with osimertinib,] we can do something about it and treat them. Too many times, because of the nihilism that has built up over the years, we are just waiting for the recurrence to occur,” Kim said. “I hope we get to a point where recurrence is less common, and we are treating more patients with earlier-stage disease. Our paradigm has changed. We will continue to study other drugs and targets in these settings, as well.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on lung cancer, Kim, physician-in-chief of City of Hope Orange County and vice physician-in-chief of City of Hope National Medical Center, highlighted the impact of osimertinib in the treatment of patients with EGFR-mutant NSCLC, next steps with the agent, and the importance of early genetic testing to provide personalized care.

OncLive®: How has the emergence of osimertinib impacted the management of patients with EGFR-mutant lung cancer?

Kim: EGFR has really been one of the pioneering biomarker pathways in lung cancer. Osimertinib is the preferred drug because it has very strong efficacy and a [favorable] safety profile. The newer-generation drugs penetrate the brain and the central nervous system much more predictably than older-generation agents; this has changed the paradigm of how we approach patients who have initially been diagnosed with brain metastases. If they are stable, then we do not jump right to radiation. Instead, we treat them [with these drugs] if they have a mutation and watch them in case we need the radiation. [However,] it is great to see even our radiation colleagues embrace these data.

What are some areas of focus in the realm of EGFR research?

Throughout our investigations, we have also found other mutations in EGFR; some are sensitizing, some are resistant, and some we are not sure about yet. We are developing drugs [to target] these specific mutations, which is exciting. That is what we dream [to do with] cancer [treatment]: identify a marker in the tumor that is unique to an individual and finding a [targeted] therapy that [that is efficacious and] will not cause many adverse effects [AEs].

We are also seeing EGFR moving into the earlier-stage setting; this [development,] indeed, follows what we have seen in the breast cancer paradigm. You have drugs that [are initially used in the] metastatic [setting], like tamoxifen, that are now moving into the earlier-stage setting. [Patients] can take [these agents] for several years and [they are effective]. We are seeing that now with osimertinib, [which is under examination] in the early-stage setting, in patients who have stage IB through IIIA [disease].

As such, we want to test for EGFR mutations. If you find one, then after you finish the surgery and/or give chemotherapy, [you can] then treat the patient with osimertinib for 3 years; this has been shown to greatly improve disease-free survival [DFS]. We are still waiting for overall survival [OS] data [with this approach]. However, the trial [that examined this strategy] was unblinded early because of its effectiveness, and patients are still being treated.

[Treatment has] really cascaded in the direction [where] we want to reach patients earlier—especially those who have curable disease or curative intent disease. [We want to] try to keep disease away as long as possible. I am really happy that biomarkers have made it into the clinic. I urge everyone out there to test [for] biomarkers. Ensure that you are testing for these before you initiate any treatment. It does not matter if you are using smaller panels or larger panels; just ensure that you are getting that information and utilizing it to inform decisions.

Looking more closely at the use of osimertinib in the adjuvant setting, how did the agent perform in the phase 3 ADAURA trial (NCT02511106)? What does this information mean for practice?

The primary end point of ADAURA was DFS, specifically in [patients with] stage II and IIIA [disease], although the trial did enroll [those with] IB through IIIA [disease]. DFS was the first reported outcome because you get those outcomes earlier. Data were revealed early because of the effectiveness [of the agent]; this [runs] parallel to what happened with tamoxifen.

The hazard ratios for DFS were unprecedented. We had not seen that magnitude [of benefit] in lung cancer [previously], although we should; this is a curative intent population. We are asking patients to take a drug for up to 3 years and need to show that there is some benefit. Some would say we need to wait for OS and, of course, our due diligence has to be to wait for [those data].

However, you have to ask yourself, if this was a friend or family member, and they had gone through lung cancer resection, would you prescribe them osimertinib if they have an EGFR mutation? My answer is a very clear yes. I do believe that DFS is an important end point, and it is one that we use quite often in earlier stages [of disease]. If you consider any patient who has had early-stage breast cancer and they get a recurrence, it is just devastating.

How are the AEs associated with osimertinib being managed? Are there any challenges to using this agent in the clinic?

What has been really helpful is that osimertinib was first approved [for use] in the advanced metastatic setting. Clinicians gathered quite a bit of experience with not only this drug, but also with drugs that were similar in class. We all remember using gefitinib [Iressa], erlotinib [Tarceva], afatinib [Gilotrif], and now, we have osimertinib. There is a comfort level [with these agents]. Again, the parallels [to what has been seen in the] breast cancer [paradigm] are there. Tamoxifen was first used in the metastatic setting and [people felt comfortable] dealing with those AEs.

On the whole, osimertinib has a very [safe] toxicity profile, when considering other classes of drugs [that are used] in the metastatic setting. Upon conducting the study and reporting out, we really did not see any new safety [signals]. As we consider primary end points and focus on the [patients with] stage II and IIIA disease, even in the total analysis of [those with] IB through IIIA [disease], we saw a benefit across the board. [Osimertinib] is [an agent] that people are comfortable with and we [have] quite a bit of experience [with its use].