Future Efforts Focused on Optimizing TKI Use Across the Continuum of Care for EGFR+ NSCLC

Kristen A. Marrone, MD, discusses research efforts with osimertinib in EGFR-mutated lung cancer, overcoming resistance to the agent, and optimizing sequential molecular testing.

Following the establishment of the third-generation TKI osimertinib (Tagrisso) as a standard-of--care treatment in patients with EGFR-mutated non–small cell lung cancer (NSCLC), research efforts have been focused on how to build on the success achieved with this approach, how to overcome resistance to the agent, and how to individualize care decisions with TKIs to optimize outcomes.

The phase 3 ADAURA trial (NCT02511106), which evaluated the safety and efficacy of adjuvant osimertinib in patients with stage IB-IIIA EGFR-mutated NSCLC, has been a frequently discussed trial since data read out during the 2020 ASCO Virtual Scientific Program.

“ADAURA really brings to the forefront of our minds how to best use targeted therapies in the early-stage lung cancer treatment paradigm,” said Kristen A. Marrone, MD. “Ongoing studies are looking at using TKIs in the neoadjuvant setting. It's really going to be a very rapidly-evolving field over the next few years when we look at how to best use targeted therapies for these patients either before or after surgery.”

Results from the trial demonstrated that the disease-free survival (DFS) had not been reached with osimertinib (95% CI, 38.8–not calculated [NC]) versus 20.4 months (95% CI, 16.6-24.5) with placebo (HR, 0.17; 95% CI, 0.12-0.23; P <.0001) in patients with stage II/IIA disease. Moreover, in the overall population, the DFS still was not reached with the targeted agent (95% CI, NC-NC) versus 28.1 months (95% CI, 22.1-35.8) with placebo (HR, 0.21; 95% CI, 0.16-0.28; P <.0001).

“The future directions in lung cancer that has EGFR mutations is really exciting and promising. We're really thinking about how to personalize these treatments and optimize how these patients are going to do with using medications that have less toxicity and more efficacy, said Marrone. “Thinking about how best to use TKIs along the entire continuum of disease is really where we are right now. The future steps of using molecular testing sequentially for patients throughout their disease course and thinking about how to combine therapies to improve outcomes is where we should be going at the end of 2020 and into 2021.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Marrone, a thoracic medical oncology specialist and associate program director of the Hematology/Medical Oncology Fellowship Program at the Johns Hopkins School of Medicine, highlighted research efforts examining osimertinib in EGFR-mutated lung cancer, overcoming resistance to the agent, and optimizing sequential molecular testing.

OncLive®: Could you start off by speaking to the significance of the FLAURA trial and how this established osimertinib as a standard-of-care approach?

Marrone: FLAURA, which was published in the New England Journal of Medicine, established osimertinib as our new standard of care for the first-line treatment of patients whose NSCLC harbored an EGFR mutation in either exon 19 or exon 21. It was a really exciting day for our patients because we could now offer this therapy to them in the frontline setting.

This year, we had the exciting update that [the drug] improves overall survival for these patients, which is really a great step forward for them. We're happy that we can offer them a medication that works well and has less toxicities than drugs we were previously using in that scenario.

What are the objectives of the FLAURA2 trial? How will this research provide additional clarity?

FLAURA2 is an ongoing study looking at the combination of osimertinib with standard-of-care first-line, platinum-based doublet chemotherapy in a similar population to FLAURA. [This research is] exciting because it's looking to see whether we can deepen or prolong the response to osimertinib that we had seen in FLAURA. It's an important thought for us in terms of thinking [about whether] we [should] use our most well-known therapies up front or consider sequencing as the right option for these patients in the frontline setting.

Resistance to osimertinib is a key challenge faced in the field. What is your approach to overcoming this resistance in practice?

Unfortunately, patients who are treated with osimertinib, regardless of the line of therapy that it is being used, will eventually develop resistance. We're learning a lot about the mechanisms of resistance that different patients are experiencing. My current practice is to evaluate for these mechanisms of resistance, either with a plasma- or tissue–based test. [We need to use] next-generation sequencing of some kind, because we know that this is needed to identify which mechanism has [emerged. With this information] we can best consider how to treat the patient. We know, and are learning more about, how to best target those molecular changes to optimize outcomes for patients.

What are some of the molecularly-defined approaches that are under exploration for patients who progress?

As we learn more and more about these molecularly targetable mechanisms of resistance, clinical trials have been developed to look at this. Some trials are being done for the most common changes, as well as some off-label use of certain medications. We're excited about these trials because they’re going to help us answer the question of what the best next line of therapy will be for patients whose tumors develop osimertinib resistance.

Early data have recently read out for the ADAURA trial examining osimertinib in the adjuvant setting. Could you speak to the significance of this research?

We saw really exciting recent data from ADAURA, which looked at the use of osimertinib in earlier-stage lung cancer, specifically following resection with or without adjuvant chemotherapy. In the trial, osimertinib [is administered] for up to 3 years and the treatment would will continued until disease recurrence or treatment completion. The primary outcome of the study that was shared in the New England Journal of Medicine was looking at DFS [benefit]. We saw an encouraging trend, and a statistically significant hazard ratio of 0.17, favoring osimertinib; this is pretty impressive as an outcome, especially when we look at the primary population of [patients with] stage II/III [disease]. These are really encouraging findings and it'll be great to learn more as the survival data mature.

How are you navigating the conversations that are currently ongoing regarding this trial?

These data are exciting, but they definitely lead to having to think about how to have the most correct and nuanced conversation for each individual patient in this scenario. Unfortunately, this patient population is at a high risk for relapse, so we do want to optimize their potential treatment options, but this medication is not without potential toxicity.

We also aren't sure what's going to happen after the data mature past this 3-year point. In terms of talking with our patients [about this option] right now, it's really an individualized discussion. In my clinic, in this scenario, we do have the conversation with our patients who [may be appropriate candidates]. We go through the trial outcomes and talk about the potential toxicity. I think it [adjuvant osimertinib is] a reasonable option, especially for patients who are otherwise healthy and seem to really understand what the study's main outcome is along with its limitations.

What are some questions that are raised by this research?

We're going to see—similar to FLAURA and FLAURA2—the concept of: [Would it be] best to use these [approaches] sequentially? Should we be thinking about combining them? How does this play into the [treatment of] patients who have stage III disease that is not resectable? This study is bringing many questions to the forefront.

Even within this study, thinking about times of therapy [will also be important]: Is 3 years enough? Is 3 years too much? A lot of data [will be analyzed]. Really important patient-relevant clinical data are going to be gleaned from the results of this study in the coming years.

How might sequential molecular testing be optimized in this space in the future?

How to best test patients for molecular alterations is something that we struggle with in the clinic every day. What testing platform is best for each individual patient? Which tissue type is best for each individual time point? We think about [these questions] a lot. Do we always need to use tumor-based testing? In many scenarios, we can think about using plasma; [this approach] is more convenient and it's less risky because we're not talking about an interventional procedure. However, we also need to—especially in the context of some mechanisms of resistance where we see histological transformation that wouldn’t be picked up in plasma—ensure that we're still considering the use of tissue-based testing when necessary.

I think ‘optimizing’ is a good word, but also personalization of how to best use molecular testing is something that we're going to learn more about [in the coming years]. As we become more comfortable with each platform, we're going to be able to make these decisions for patients more quickly and accurately in the future.

Incorporating TKIs into earlier stage disease is a big area of interest. How might this drive progress for this population?

Using TKIs in early-stage lung cancer is something we need to consider because we see in the metastatic space that TKIs have superior outcomes to chemotherapy. As such, the natural thought process is: How do we think about using TKIs in earlier-stage lung cancer?

I think we're going to get a lot of great data out of ADAURA, as well as NeoADAURA, which is a study looking at using it in the neoadjuvant space. As we become more comfortable with doing so and thinking about how they are equally effective, if not more effective, at disease control even in the early-stage setting, we're going to [start] using these drugs in a more precise way moving forward.

What is the potential of immunotherapy in these patients with actionable mutations?

Definitely using immunotherapy for patients with oncogene-driven lung cancer is something that we desperately need to learn more about so that we can figure out how to optimize [this approach]. The data that we have available in 2020 indicate that single-agent PD-1 therapy is not the right therapy for our patients with oncogene-driven lung cancer, but certainly I think we can learn a lot more about the tumor microenvironment. We can look at how combination therapies might improve outcomes.

Even though clearly TKIs are the right first-line choice for these patients, thinking about how to optimize the antitumor immune response, either in subsequent lines of therapy or in other ways, is going to be the wave of the future. Learning more about both the tumor and molecular characteristics and how we can use those contexts to personalize immunotherapeutic approaches is probably where we will be moving next.


Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non–small-cell lung cancer. N Engl J Med. 2020;383:1711-1723. doi:10.1056/NEJMoa2027071