Identifying, Treating Resistance to TKIs Are Next Step in EGFR+ NSCLC

Christina Baik, MD, MPH

Identifying how to best treat patients who develop resistance to EGFR-targeted therapy, especially frontline osimertinib (Tagrisso), is part of the next chapter of research in this molecularly driven non–small cell lung cancer (NSCLC) arena, explained Christina Baik, MD, MPH.​

“It’s important to understand that there is now another option in the space [with frontline osimertinib],” said Baik. “There is also some debate in terms of adding EGFR inhibitors to TKIs. People should be familiar with some of the work that is being done for patients at the time of progression, as well as some of the therapies that are being developed after osimertinib.”

One such research effort is the platform phase 2 ORCHARD trial (NCT03944772), in which at time of progression on frontline osimertinib, patients with EGFR-mutant NSCLC are then segmented into different study arms of various combination regimens with osimertinib, based on biomarker-positive status.

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Baik, a physician at Seattle Cancer Care Alliance, an associate professor of medicine at the University of Washington School of Medicine, who is also an associate professor in the Clinical Research Division at Fred Hutchinson Cancer Research Center highlighted the evolving role of EGFR inhibition in the NSCLC space.

OncLive®: How did the FLAURA findings significantly propel EGFR-targeted treatment forward?

Baik: The FLAURA study has certainly changed the NSCLC landscape. There are many drugs that were studied prior to this trial, including first- and second-generation TKIs. Now that osimertinib (Tagrisso) was found to be superior when compared with first-generation TKIs, the discussion around these agents [in the frontline setting has] quieted down.

Some still argue that, when administering sequential therapy, the time on treatment is probably going to be similar with upfront osimertinib and other TKIs. [Osimertinib] also easier for patients to tolerate, which makes it easy for physicians to change practice.

While this is true for oncologists in the United States, there are parts of the world that still use first- and second-generation TKIs. Even so, FLAURA truly established the role of osimertinib in the first-line setting.

When compared with chemotherapy or immunotherapy, we know that EGFR-targeted therapies are better treatment options in the first-line setting. I try to point this out to patients because they often ask if they can receive immunotherapy or chemo-immunotherapy first.

Ultimately, if a patient has an EGFR mutation, they should start with targeted therapy, Baik explained.

Although more research is still needed, could you expand on the challenge with resistance to osimertinib with these patients?

A number of studies have reported on resistance to first- and second-generation TKIs, so we know that MET amplification is [identified] after treatment with earlier-generation TKIs.

Now we must determine what the landscape of resistance looks like after osimertinib. We have data from FLAURA using circulating tumor DNA (ctDNA) and, with these data, we must keep in mind that the numbers may not truly reflect the actual prevalence of resistance. Although, it does give us some insight on what happens [with resistance to osimertinib]. We know that MET amplification is an important alteration, and C797S mutations are also important in this space. Additionally, we understand that many patients will develop a secondary genetic alteration.

What was the rationale behind the ORCHARD trial? What question does this research hope to address?

It makes intuitive sense that, if a patient has a second genetic alteration, we might be able to add a drug [to target that alteration]. However, additional research is needed.

This is exactly what the ORCHARD trial is focusing on. The idea is that patients undergo a biopsy at the time of progression on osimertinib, and this is based on tissue testing. If they are found to have a prespecified actionable alteration, patients will get assigned to a particular targeted therapy that matches to the alteration.

Osimertinib is now continued throughout the entire treatment, [and the second targeted therapy is added on at time of progression]. The idea [to continue with osimertinib] is that there are still EGFR mutations in the clones. Ultimately, the study is evaluating the safety and efficacy of this therapy.

What is unique about U3-1402 as a lung cancer therapy? When can we expect more data to read-out?

Preliminary data were presented during the 2019 ASCO Annual Meeting so we do have some idea of the early results and toxicities [with U3-1402]. There will certainly be more data coming out in the upcoming months or years. Based on the data currently available, we know that there is a subset of patients who do respond. The idea is that EGFR-mutated patients have a high prevalence of HER3 expression. Although the degree of expression can vary, it is there.

Based on what we know, there are a subset of patients who respond nicely to this therapy and others who achieve disease control. They may not be meeting that RECIST criteria, but there is some degree of tumor shrinkage.

Switching over to the adjuvant setting, the ADAURA trial garnered lots of excited this year. What do you find most interesting about this research?

The role of adjuvant EGFR inhibitors in EGFR-positive patients has been addressed for many years, and we’ve been awaiting results from randomized studies. In the ADAURA trial, EGFR-positive patients with stage IB to IIIA disease were randomized to osimertinib versus placebo. For those of us who follow this space very closely, we were all anticipating this was going to be a positive study, with disease-free survival being the primary end point. There was really no question about that. The real question was: How much will these patients benefit?

Now, it was surprising how dramatic the DFS benefit was. Many of us were anticipating a hazard ratio around 0.5 or 0.6, so the fact that it was in the 0.1 range was very impressive. Even for those of us who had been fairly conservative [with data], this was compelling enough where we felt obligated to talk to patients [about it]. We have to ask patients if delaying their cancer recurrence by few years is meaningful to them, especially since there is a chance they may be cured without this medicine. However, we do not know how to identify those patients right now.

What other unanswered questions remain following ADAURA?

I don't believe we'll ever see a survival benefit from the ADAURA trial. It's now unblinded and many patients may withdraw and end up receiving osimertinib [over placebo]. As such, I suspect that there will be crossover. With that knowledge, I don't believe we're going to get an answer on whether this therapy is curative.

As a doctor, I still say that, for stage I patients, there is a group of patients who can be cured with surgery alone. Chemotherapy adds to this a little bit, but not by a whole lot. I also believe there will be a large group of people who [will receive more treatment] after receiving adjuvant osimertinib.

There are financial costs, too. Oftentimes, patients will have a high copay, even when it’s covered by insurance. I do worry about over-treating stage I patients. In stage III, since most patients will eventually relapse, I think of [osimertinib] as early treatment rather than late treatment.

From the perspective of an academic oncologist, there is a lot of room for further evaluation. Even if we use ctDNA, and patients have no molecular residual disease, maybe we could follow them. When patients do have molecular disease, we can administer TKIs. In my mind, there's still enough equipoise, thus, we should be conducting biomarker-driven studies.

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