Unanswered Questions About Adjuvant Osimertinib in Resectable NSCLC

Balazs Halmos, MD

Associate Director

Professor of Medicine

Clinical Science Montefiore Einstein Comprehensive Cancer Center

New York, NY

DISCUSSION QUESTIONS

• What are your reactions to the ADAURA trial (NCT02511106) data?​
• What are the strengths and weaknesses of the clinical trial, and the pros vs cons of this treatment strategy?​
• ​How often do you typically prescribe osimertinib (Tagrisso) to your patients and what is the duration of that therapy?​
• What are some of the barriers to continuing therapy over time?​

ISOSCELES GARBES, MD: Do we need [adjuvant] chemotherapy for all patients prior to osimertinib?

BALAZS HALMOS, MD: That is an excellent question. That’s why I highlight the stage IB [patients on the trial], where for 3 cm to 4 cm tumors, generally speaking, medical oncologists would not ask for chemotherapy, but you can offer adjuvant osimertinib based on these data.¹ For tumors that are larger in size, you might potentially consider the same way. In the subset analysis, 40% of the patients did not receive adjuvant chemotherapy, and 60% did receive adjuvant chemotherapy.2 The benefit of osimertinib was identical between the 2 cohorts. A patient who is older might be frailer, so if you do not think that the patient could benefit from adjuvant chemotherapy, you could still make a very nuanced decision as to use adjuvant osimertinib irrespective and independent of your prior decision to use adjuvant chemotherapy. Does that help?

GARBES: Yes, it certainly does. But it doesn’t answer the question whether patients really need adjuvant chemotherapy.

HALMOS: It definitely does not. The current recommendation is, for high-risk patients, yes, we should still offer adjuvant chemotherapy. I personally have revisited as to where I think the risk cutoff is, but the overall survival [Kaplan-Meier] curve on adjuvant osimertinib [showed] these patients have a very high chance of surviving for 5 years.² How much added benefit they get from chemotherapy—maybe the patients with node-negative disease will get too small of a benefit to justify the risk of chemotherapy, but it also depends on how healthy your patient is. For a patient who is 45 years old and has no comorbidities, adjuvant chemotherapy carries a lot less risk. So you have to look at a lot of different factors here.

But yes, in some patients, it’s appropriate to have adjuvant osimertinib without chemotherapy. [We could also] talk about the ALINA trial [NCT03456076]. The randomization was between [adjuvant] targeted therapy vs chemotherapy, with alectinib [Alecensa] for patients with ALK translocation. This study was positive, and the regimen is already in the guidelines.³ At the same time, it will leave our medical oncologists including myself in limbo. Do we follow the study and not offer adjuvant chemotherapy? Or do we follow the traditional path and give chemotherapy and then give alectinib afterwards? We will probably not have clear answers on this very good question for quite a few years.

Does anyone else wants to say how they have incorporated osimertinib?

KIN LAM, MD: Yes, I have engaged this regimen in my practice. It’s a pretty large clinical study. If you want to [discuss] any weakness, I would say it’s that they didn’t include patients with uncommon EGFR mutations.¹ Once in a while you get a patient like this. I don’t know what to do, maybe [hold] the chemotherapy and wait, then maybe use afatinib [Gilotrif], which is indicated for uncommon mutations. But this study is not covering this aspect.

HALMOS: Yes, you’re absolutely right. This study answered some questions and opened up doors for precision medicine in the adjuvant setting. But it leaves some dilemmas behind, and the uncommon mutation subset is one where we don’t know how to use these data to help that patient population. There are ongoing studies helping get some answers for uncommon mutations, but they are not randomized pivotal studies that will provide high level of evidence, so we’ll be sitting with this dilemma for some more time. Let me ask you, in your practice…do you see many of these patients?

LAM: Yes, I have a lot of patients with EGFR-mutated disease; the majority of my patients are Asian. I would say my testing for EGFR for them is more than 70% positive, although studies say it has 30% to 45% [prevalence in Asian patients].⁴ I think a barrier to this treatment is the financial toxicity, because you’re using the drug for 3 years, and this drug is not cheap.

HALMOS: Yes, of course. For most patients, there’s appropriate co-payment support, but each company will need to pay attention to make sure that these drugs can be available for the largest patient population at need.

LAN MO, MD, PHD: I have some patients on the ADAURA regimen, and some are almost at 3 years. A few patients are progressing on adjuvant osimertinib, so I have a question for you. What do we do next if the adjuvant osimertinib leads to progressive disease?

HALMOS: That’s a great question…. Fortunately, it’s not very common to see progression on adjuvant osimertinib. It’s much more common to see it soon afterwards; you stop the drug and within the next 6 to 12 months, a recurrence event takes place. I think retesting them first—proving the recurrence and retesting is appropriate. But if they have the actionable mutation, rechallenge with osimertinib is probably perfectly appropriate in that case. Patients who progress on osimertinib pose a lot bigger challenge.

YIWU HUANG, MD, PHD: For the patients who already received 3 years…I test the circulating tumor DNA [ctDNA]. If they’re positive [for EGFR mutation], I will continue treatment. If it is negative after 3 years, I may just stop it at that time.

HALMOS: Yes, I’ve heard that some physicians are starting to use some biomarkers as to how to decide whether to stop or to continue. ctDNA, like a minimal residual disease test, is definitely the most relevant to use. It’s hard to know what the right time point for it is, because when the patient is still on osimertinib, most likely those tumor clones are suppressed enough that you might not be able to see them. I’m wondering whether a month after stopping is the time to check if somebody has some residual disease or not. We don’t have any answers as to how to manage this.

Also, when do we reimage over 3 years of adjuvant osimertinib? How about afterwards? Afterwards is the biggest risk period the next couple of months. Do we get a brain MRI a few months after stopping? These are not clear. All of us have to figure out how to manage our patients in the best possible way. They need a lot of attention at the time that you’re stopping the adjuvant osimertinib. Whether that’s at year 1, 3, or 5, whatever you decide, that’s the risk period of recurrence.

_References:

_{1. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071}

_{2. Herbst RS, Wu YL, John T, et al. Adjuvant osimertinib for resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer: updated results from the phase III randomized ADAURA trial. J Clin Oncol. 2023;41(10):1830-1840. doi:10.1200/JCO.22.02186}

_{3. Solomon BJ, Ahn JS, Dziadziuszko R, et al. LBA2 ALINA: Efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl_2):S1295-1296. doi:10.1016/j.annonc.2023.10.051}

_{4. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9(2):154-162. doi:10.1097/JTO.0000000000000033}