ADAURA Fuels Hope for Ongoing Research With EGFR TKIs in NSCLC

Missak Haigentz Jr, MD

Research regarding how best to integrate osimertinib (Tagrisso) as treatment for patients with EGFR-mutant non–small cell lung cancer (NSCLC) in the neoadjuvant, locally advanced, and metastatic acquired resistance settings has the potential to alter the natural history of the disease beyond current prognoses, with the hope of one day delaying the onset of cancer altogether, said Missak Haigentz Jr, MD.

“We’ve changed the trajectory for patients with EGFR-mutant metastatic and historically incurable disease, offering them a median survival expectancy on the order of 40 months, and for some even longer than that,” said Haigentz. “[In the adjuvant setting], the ADAURA study demonstrated that osimertinib clearly improves disease-free survival [DFS] for patients [treated] with curative intent, [indicating that] we’re [also] moving the field forward by changing the trajectory of [our] high-risk patients treated with curative intent.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on lung cancer,Haigentz, the Section Chief of Hematology and Oncology at Morristown Medical Center, and Medical Director of Hematology and Oncology for Atlantic Health System, discussed the movement of osimertinib from the metastatic to adjuvant settings and ongoing research poised to improve outcomes for patients with EGFR-mutant NSCLC.

OncLive^®: Has osimertinib shown that EGFR TKIs can be used with curative intent? What has the continued study of osimertinib revealed about targeting EGFR in NSCLC?

Haigentz: Osimertinib has impacted treatment in a tremendous way. The FDA approval last year was in the adjuvant setting, but the drug has been FDA approved for quite some time. In 2015, it had its first FDA approval in the post-progression space for individuals who had EGFR T790M mutations, which was the gatekeeper mutation and most common reason for resistance to early-generation, EGFR TKIs. In 2018, the FLAURA study led to the FDA approval [of osimertinib] in the first-line setting for patients with EGFR-mutated, advanced NSCLC. Last year’s approval really took it a step further.

The approval in the adjuvant or curative-intent space was really the first agent of its kind to do so. This is [a testament to] our understanding of EGFR and how to target it. Twenty years ago, going back to how EGFR TKIs were being used in unselected patients with few patients benefiting, to now identifying the EGFR sensitizing mutations as the ones for which patients are going to benefit the greatest, to the advances where now targeted therapy can be used in place of standard chemotherapy, and now comparing head-to-head targeted therapies for incurable disease management.

Medical oncologists have gotten used to now wonderful responses of patients that have advanced disease, including central nervous system [CNS] involvement and the quality of life that the patients are experiencing on these on EGFR-targeted therapies is just tremendous.

Last year, there was a presentation in the New England Journal of Medicine that showed that the median survival of patients with EGFR-mutated NSCLC treated on the FLAURA study was approximately 40 months. Now, our patients are living longer and better lives. This [adjuvant indication for] osimertinib is the dream of medical oncologists, and that is taking a drug that works so well and is well tolerated in metastatic disease, and we’re now trying to move the agent earlier in the management of patients in a curative-intent setting. The adjuvant use of osimertinib has really moved the field forward in that regard.

What are the next steps for research following the read out of the primary analysis of the ADAURA trial?

The ADAURA study randomized nearly 700 patients who had curative-intent surgical resection, namely stage IB, II, and IIIA lung cancer, with EGFR mutations, namely EGFR exon 19 deletion mutations or EGFR L858R mutations, to postoperative osimertinib or placebo. Patients took osimertinib or placebo for up to 3 years after surgical resection. The study allowed for patients to have had prior chemotherapy. Adjuvant chemotherapy has been the standard for these patients for the past 15 years, having shown a small but very real impact on 5-year survival rates.

The ADAURA study demonstrated quite convincingly that the primary end point, DFS, was markedly improved in patients who received adjuvant osimertinib over placebo. There was an 83% [reduction in the] risk of recurrence or death in this patient population. The benefit extended not just to individuals who had postoperative chemotherapy, but also to individuals who were not treated with postoperative chemotherapy.

The study was a tremendous advance, and yet, there are several questions that arise. Namely, because the primary end point of the study was DFS, and not overall survival, one appropriate criticism is that osimertinib may only be extending DFS and may be delaying recurrence as opposed to curing more patients. That’s an important consideration when we’re exposing patients to these kind of therapies in a postoperative setting as far as extra adverse effects [(AEs) are concerned]. We also have to think about the financial toxicity that the patients may be experiencing as a result of taking osimertinib for up to 3 years. These are some of the challenges that are associated with the study.

On the flip side, the benefits were very clear in terms of extending DFS in this patient population. The drug clearly has CNS activity in the metastatic setting and was able to reduce CNS metastatic recurrence, which is impactful for quality of life [QOL] in this patient population.

What has not been fully addressed is the impact these kinds of therapies have on a patient-specific level. QOL has been studied in the ADAURA trial, and those data were presented at the 2020 World Conference on Lung Cancer, and osimertinib did not lead to a detriment in QOL. I’m hoping to see a study that shows what the end result of having an improvement in DFS is on a patient-level because that matters tremendously.

The questions regarding overall survival [OS] remain outstanding. Another question is: Who are the patients who are going to benefit the most from osimertinib-based therapy? What is the role of adjuvant chemotherapy for these patients? It is the one treatment that has been demonstrated to have an impact on OS. It’s not ready to be left out of the treatment armamentarium. Clearly adjuvant chemotherapy remains a standard treatment option, but for individuals who are not able to tolerate adjuvant chemotherapy, osimertinib in the adjuvant setting remains a very viable option.

In what other settings is osimertinib being evaluated?

How can osimertinib impact the management of individuals with locally advanced or regional disease in a curative-intent setting? Ongoing international studies are testing this question. Specifically, the NeoADAURA study, which is studying the role of osimertinib with or without chemotherapy in a neoadjuvant setting. That’s one area that remains an open question, and a great amount of information will be understood from that kind of a study.

Another excellent question is how to consider EGFR-targeted therapy in a patient who may have been treated with chemotherapy or radiotherapy. There are ongoing studies of that, namely the LAURA study, or locally advanced AURA study that are exploring that particular question. I would encourage my colleagues to enroll patients in studies asking those specific questions regarding how best to integrate EGFR-targeted therapies for patients with EGFR mutations in other curative-intent settings.

In the advanced-disease setting, although osimertinib as well as other EGFR TKIs have yielded tremendous benefit over chemotherapy in patients with newly diagnosed advanced metastatic lung cancer, clearly there’s a need for management of resistance mechanisms that develop so that we can come up with new therapies for the patients who have had disease progression on treatment already.

The most common resistance mechanisms to osimertinib are MET amplification or point mutation at EGFR C797S, and a number of targeted therapies are in clinical development that are evaluating MET TKIs. MET can be targeted with TKIs, antibodies, or antibody-drug conjugates that are in clinical development. There are novel, third-generation EGFR inhibitors that are also in clinical development to target acquired immune resistance mechanisms.

There are EGFR-mutated patients [with uncommon] EGFR mutations. There is an FDA-approved indication for afatinib [Gilotrif] for uncommon EGFR mutations, but we need to do better. Also, the EGFR exon 20 insertion mutations are a group of patients who have historically had challenging outcomes with EGFR TKIs, and new agents that are in clinical development may help to advance the care of these patients as well.

Could you highlight the importance of reflex tumor testing for these patients?

The only way we know how to utilize our targeted therapies is with molecular testing of our patients’ tumors. Medical oncologists have been well educated to recognize the importance of molecularly guided therapy for patients with advanced NSCLC and have been routinely doing this in their clinical practice.

Most institutions have adopted a reflexive, almost a deliberate plan to test patients’ tumors in the advanced-stage setting for molecularly guided mutations. That’s been in practice or is getting to be accepted as standard medical practice increasingly and not just on an individual targeted mutation testing.

Broad panel testing is generally becoming more common because of the different types of treatments that we have available, not just the EGFR TKIs, but other molecularly targeted therapies. The ADAURA study demonstrated, for the first time, that osimertinib can be utilized in a curative-intent setting. [As such], we must be testing our patients not just when they have metastatic disease, but really, after their curative-intent surgical resection, to not deny them the opportunity of benefit from osimertinib.

My hope is that institutions will develop a policy to reflexively test their patients’ resected tumors for EGFR, certainly, for screening for use of osimertinib. My hope is that the ADAURA study will be the beginning of other targeted therapies to be utilized in the curative-intent setting. It’s really critical to not just have broad panel-based testing for patients with metastatic disease, but also to do this going forward for patients with curative-intent management.

What is on the horizon in EGFR-mutant NSCLC within the next few years?

Addressing acquired resistance mechanisms to EGFR TKIs in the first-line setting, extending the survival outlook for patients with this disease with the novel therapies, looking for uses of novel therapies—not just for the patients with the common sensitizing EGFR mutations, but also with the tough to treat EGFR mutations, like the exon 20 insertion mutations—with an effort towards moving the [needle] not just [for] select individuals with EGFR mutations, but [those with] EGFR mutations that are not deriving as much of a great benefit with these agents to really push the progression-free survival and, ultimately, OS of this patient population forward.

How have the aforementioned advances affected the natural history of NSCLC?

We have improved QOL and survival outcomes for patients with metastatic disease. We have [also] improved the trajectory of patients with curatively managed lung cancer. My hope is that during my career, we’ll see a time where we’re able to change the trajectory of patients who are at risk for lung cancer, and it’s these kinds of efforts that may move the field forward, both in terms of patients with existing metastatic disease to patients with existing disease that was managed with surgical treatment, but maybe, with the hope that one day, we may be able to delay and defer the onset of cancer in the first place.