The treatment of early-stage, resectable EGFR-mutated non–small cell lung cancer (NSCLC) has undergone a profound transformation, moving away from a “one size fits all” approach toward a personalized, biomarker-driven strategy. The phase 3 ADAURA trial (NCT02511106) established a new standard of care by demonstrating that adjuvant osimertinib (Tagrisso) significantly improved overall survival.
As the field shifts toward perioperative management, data from the phase 3 NeoADAURA trial (NCT04351555) highlighted the efficacy of neoadjuvant osimertinib, either as monotherapy or combined with chemotherapy, in achieving major pathologic responses and successful R0 resections. These advancements underscore a critical clinical mandate: the necessity of comprehensive biomarker testing at the time of initial diagnosis. Identifying driver mutations like EGFR or ALK is no longer just about selecting the right drug; it is essential for avoiding less effective chemo-immunotherapy combinations that carry higher risks of toxicity in these specific patient populations.
A panel of experts led by Alexander I. Spira, MD, PhD, FACP, FASCO, co-director of Virginia Cancer Specialists (VCS) Research Institute, director of VCS Thoracic and Phase I Program, chief scientific officer of NEXT Oncology, and clinical assistant professor at Johns Hopkins, discussed the implementation of these results into clinical practice.
He was joined by Edward Sanghyun Kim, MD, MBA, physician-in-chief at City of Hope Orange County, vice physician-in-chief at City of Hope National Medical Center, professor in the Department of Medical Oncology and Therapeutics Research, and Construction Industries Alliance City of Hope Orange County Physician-in-Chief Chair; Natalie Vokes, MD, assistant professor in the Department of Thoracic/Head and Neck Medical Oncology of the Division of Cancer Medicine, and assistant professor in the Department of Genomic Medicine at The University of Texas MD Anderson Cancer Center; and Ticiana Leal, MD, professor and director of the Thoracic Medical Oncology Program in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and medical director of the Clinical Trials Office at Winship Cancer Institute.
ADAURA/NeoADAURA Trial Relevance
Spira: From your perspective, what were the most practice-changing findings from the ADAURA trial, and how have longer-term follow-up data influenced your confidence in the use of adjuvant osimertinib for patients with resected stage Ib to IIIA, EGFR-mutated NSCLC?
Kim: It’s been a long journey for EGFR-directed therapies. I still remember when we were using gefitinib [Iressa] in the late 1990s and early 2000s, and we were using it in an undefined population. We struggled with how to incorporate them because we didn’t have a biomarker identified or used in practice until probably 10 years later, and that changed things. As far as lung cancer, we weren’t stacking therapies on top of each other; we were finally personalizing therapy based on an individual’s specific tumor. This was all occurring in the metastatic [and] advanced stages. I was glad we weren’t trying to do triplet chemotherapy regimens or anything funny like that. We knew eventually it would get to the early stage as even during that period, early-stage adjuvant therapy wasn’t recommended until we saw the data.
We have finally gotten to the point where we’re smarter now. ADAURA was the first step in personalizing therapy in our early-stage resected patient population, and the fact that we can migrate our concepts from the late stage to the earlier stage is exactly what we should be doing. As a research and treatment endeavor, we know that’s best for the patient. ADAURA set this stage. Even when they first reported the PFS [progression-free survival] values, I was a little disheartened with some of those people in our specialty field, because they said, “Well, I wouldn’t treat based on PFS”, and it was so striking. We were validated a couple years later when we saw the overall survival data [was] outstanding—I think it was an 88% five-year survival rate. In addition, there was also less subsequent therapy by half when [patients] were treated with the adjuvant osimertinib, and then more even brain and CNS protection, so I think it served as the first validated paradigm shift in early-stage resected patients. Now we’re seeing this with other driver mutation targets that are being integrated into this setting.
Spira: Looking at NeoADAURA, how has your thinking evolved regarding the timing of biomarker testing and treatment planning in resectable EGFR-mutated NSCLC? Should we be checking molecular status in everybody? How are you approaching that for neoadjuvant patients?
Leal: NeoADAURA, in my mind, is a perioperative strategy. The trial was investigating the neoadjuvant component of the therapy. This is a randomized phase 3 study in patients with a resectable EGFR mutation, stages II to III, who were randomly assigned to 3 arms: neoadjuvant osimertinib plus chemotherapy, osimertinib monotherapy, or placebo plus chemotherapy. In this study, we saw that the trial did meet its primary end point of major pathologic response, with a major pathologic response of about 25% in the osimertinib-containing arms vs 2% in the placebo plus chemotherapy arm. We also saw that there was significant nodal into downstaging compared with the chemotherapy plus placebo. In addition to that, what was remarkable to see was that greater than 90% of the patients went to surgery, and that greater than 90% of the patients had R0 resection. In this study, they did allow the adjuvant osimertinib to be offered to patients who are eligible. That’s why I said that I think about it as a perioperative strategy to employ, but the study was a neoadjuvant study. Because of the benefits of this strategy, I certainly think that reinforces my practice of making sure that we do NGS [next generation sequencing] testing before the decision of choosing the appropriate preoperative strategy, for a patient, was already the practice. Considering that we were already using adjuvant osimertinib was important to know upfront. Do patients have EGFR/ALK alternation? Because with this, those patients would not be well served with pre-operative chemo-immunotherapy. This data with neoadjuvant NeoADAURA reinforces the practice that all our patients with early-stage, resectable NSCLC should be receiving biomarker testing before we make the decision to do pre-operative strategies.
EGFR-Mutated NSCLC Treatment Options
Spira: How do you explain the rationale for selecting EGFR-targeted therapy, regardless of PD-L1 expression in the adjuvant setting…especially compared with how we’re thinking about immunotherapy? How do you explain that to patients? How do you get everybody tested for that as well? That’s something that may differ between academic and community settings.
Vokes: As chemo-immunotherapy has become an option, both in stage IV, irrespective of PD-L1, and now perioperatively, there is this tendency to feel like it’s a one-size-fits-all solution for all of our patients. The key thing here is to remember that mutations like EGFR, ALK, RET, and ROS1, are not only positive biomarkers for targeted therapy, but they are also negative biomarkers for immunotherapy. Not only are they telling us, “Hey, something like osimertinib is going to be the best drug for these patients”, but it’s also telling us immunotherapy is not the best drug for these patients. We have many years of data now in the metastatic setting, including some subgroup analyses of early perioperative studies that [show] the patients who don’t benefit from immunotherapy are those with these driver mutations—EGFR, ALK and some of the others. Importantly, these are patients, not only who don’t benefit from immunotherapy, but there are also risks of toxicity if you move from immunotherapy to the preferred targeted therapy. In the metastatic setting, where we don’t want to give immunotherapy before we have the results of our biomarker testing, it is now incumbent to do that biomarker testing in the early-stage setting. If you’re considering neoadjuvant therapy or even adjuvant immunotherapy, you need to know EGFR, ALK, and ideally those others. How do we, practically, head towards this? It’s streamlining the testing system so that we don’t introduce delays, so that patients can get biomarker testing and then move on to appropriately-timed neoadjuvant therapy or surgery. There’s a lot we can do on the systems level, but from a knowledge standpoint, it’s clear that PD-L1is not a predictive biomarker in the context of EGFR-mutant lung cancer and should not be used to guide immunotherapy selection.
Spira: When clinicians review EGFR TKI [tyrosine kinase inhibitor] data generated across different regions and study designs, what factors determine whether results are applicable to early-stage clinical practice in your own patient populations? Do we think about this differently depending on your patient selection and where you live?
Leal: It’s important that, as you consider these new treatments that from the get-go, these trials are thinking about including a broader patient population because there could be regional differences in the patients included in the trial that can impact the results of the trial, and perhaps then put into question whether this is applicable to different regions of the world. A classic example of that in EGFR is thinking about studies that are mainly including Chinese and a broader East Asian population of patients with EGFR NSCLC. They have higher rates of EGFR mutation compared with the western population. They have higher prevalence of being never smokers. In addition to that, they have consistently shown better outcomes, better responses, and better PFS, so [this broadens] that patient population so that when you look at trial outcomes, it really will be applicable to all of the patients that we see in clinical practice.
Practical Considerations of NSCLC Treatment
Spira: In resectable NSCLC, how important is obtaining comprehensive biomarker testing at the time of initial diagnostic biopsy rather than waiting for surgical specimens, particularly considering emerging neoadjuvant strategies?
Kim: Whether it’s patients within the metastatic, locally advanced, or early stage [setting], what we hear in that resectable aspect is, “Well, you’re going to get enough tissue once you have the surgical resection done and that way we’ll be able to test and you won’t miss out on whether you’re going to give the patient adjuvant osimertinib or not.” Well, that works great with the ADAURA study and others like it. We’ve all been pushing for better neoadjuvant strategies. We love the fact that if we can, we try to downstage cancers. I know that’s still a foreign concept in lung cancer, and [we’re] not sure if we can completely do that yet, but we know that in other tumors, we can, and this is the way to start. I don’t think it’s an excuse to say, “Oh, we took a tiny little scraping of a biopsy. We didn’t get the markers, and we’ll get it after surgery.” No. What’s wrong with putting in neoadjuvant or induction strategies to optimize surgery, optimize disease control? The sooner we get systemic therapy; you’ll reduce your chances of that metastatic leakage or recurrence. I’m all for that. We have to push that again. Are you going to cut someone’s tumor out who’s staged without biomarkers? Going back to my original comment, if we include it as part of the staging, we wouldn’t have to talk about this question anymore.
Spira: Once an EGFR mutation is identified from a biopsy specimen, how do you coordinate discussions between medical oncology and thoracic surgery to determine whether neoadjuvant therapy should be considered prior to resection?
Leal: It’s important to the appropriate pre-operative staging. This patient needs to see a medical oncologist, a surgeon, and perhaps even a radiation oncologist, to keep other options on the table. It’s important to do the biopsy testing for NGS, and to make the treatment decision on what is the best next step? The decision for neoadjuvant, again, is a multidisciplinary one but typically, for patients with stage II and above, a patient with stage I, a peripheral tumor, it may be appropriate to go straight to surgery, and again, using the best available evidence and multidisciplinary discussion with the patient.
For the patients who are considering a neoadjuvant approach or a perioperative approach, you do have to have that NGS. If the patient does have an EGFR mutation and you are automatically considering that this patient is an appropriate candidate for neoadjuvant chemotherapy—that is a patient that I would consider the NeoADAURA strategy, because I’m already thinking of giving neoadjuvant [therapy]—you could give osimertinib monotherapy. But if you already think that you’re going to need to give chemotherapy, another attractive strategy with the NeoADAURA is giving the chemotherapy together with osimertinib, because otherwise, in a post-operative setting, you have to do them sequentially. That’s one advantage.
Ultimately, it’s important for us to make sure that all of the patients have access to NGS testing, but also multidisciplinary care. If, unfortunately, there is not multidisciplinary care all in one place, it is important for the patient to see a surgeon at the nearest location. Medical oncologists alone should not be making the call for neoadjuvant strategy because we need to make sure that this patient will be sequenced with the appropriate surgery. Overall, [we need to educate] patients that this is the best approach, and this is the curative setting. We want to ensure that they get the optimal outcome.
Spira: Adverse event management is often critical to keeping patients on therapy long term. What strategies have you found most effective for monitoring and managing common EGFR TKI–associated toxicities to support adherence and minimize treatment interruptions?
Kim: With osimertinib’s profile, we saw the generations of EGFR drugs adding more [adverse] effects, finally reversed course. With this generation of drug, we were pleasantly surprised that it did not continue to stack on those [adverse] effects. I always like to remind people that adverse events were also found in the placebo arm as well. You’re going to have [adverse] effects regardless. [Creating a baseline for] the expectation is important, and that piece of data is important. What happens when we get to those grade 2 [adverse effects], which we underreport and underestimate because they do have functional disharmony in in someone’s life, as well as grade 3?
We know that there are superficial toxicities that occur with cutaneous and nail aspects. We’ve always believed, in the metastatic setting, to be proactive on these, not reactive. [We] instruct people that you can do things to mitigate this early on, that you can absolutely start with creams. When it’s early, don’t tolerate it. Try to get rid of it. I always tell [my patients] that it’s like a sunburn. The minute we start seeing it increasing in grade, start with some oral antibiotics or other aspects to try and mitigate this aspect. Diarrhea can be an uncomfortable aspect. Now, some people live with irritable bowel, and we can certainly help that. This is something that is frequently reported with TKIs. We can use things like loperamide or dietary modifications to help with that. It’s a proactive vs reactive [process]. We talk about interstitial lung disease, cardiac effects, etc. These are things that we have to continue to monitor and follow-up at regular intervals. People feel safe when they do have some follow up with their primary physicians. If these were the things that we had to worry about the most, that’s not a bad trade off vs having a recurrence or having to deal with primary therapy again. It’s educating our patient constituency.
