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Director, Thoracic Oncology Program
Division of Hematology/Oncology
David Geffen School of Medicine at UCLA
Director, Signal Transduction and Therapeutics
Division of Hematology/Oncology
Department of Medicine
Jonsson Comprehensive Cancer Center at UCLA
Los Angeles, California
Edward B. Garon, MD, MS: consultant: ABL Bio, Boehringer Ingelheim, Bristol-Myers Squibb, Dracen, Eisai, EMD Serono, GlaxoSmithKline, Lilly, Merck, Natera, Novartis, Regeneron, Sanofi, Shionogi, Xilio; researcher: ABL Bio, AstraZeneca, Bristol-Myers Squibb, Dynavax, EMD Serono, Genentech, Iovance, Lilly, Merck, Mirati, Neon, Novartis.
In December 2020, the FDA approved osimertinib as adjuvant therapy for treatment of patients with resectable stage IB-IIIA non-small-cell lung cancer (NSCLC) harboring an EGFR exon 19 deletion or exon 21 L858R mutation based on the phase III ADAURA trial, which reported a significant disease-free survival (DFS) benefit with adjuvant osimertinib compared with placebo (HR: 0.20; P <.001). Adjuvant osimertinib since has been approved in China and Europe. In this commentary, I discuss important considerations when using adjuvant osimertinib in clinical practice.
Are Patients Being Cured With Adjuvant Osimertinib?
We continue to await a key piece of data from ADAURA: overall survival (OS). OS has not been reported yet because not enough patients in the study have died to meet the minimum number of survival events for an OS analysis. These data will be particularly important because previous studies of adjuvant EGFR inhibition in early-stage NSCLC have not shown a survival benefit, despite initially improving DFS.
Given the magnitude of DFS benefit in ADAURA at the time of the original report, there was great enthusiasm about the possibility of adjuvant osimertinib achieving an OS benefit in resectable early-stage NSCLC where earlier trials of adjuvant EGFR tyrosine kinase inhibitor therapy had failed. At that time, however, the impact of osimertinib withdrawal had yet to be seen, as very few patients had completed 3 years of treatment. More recently, in an update of ADAURA with 3.7 years of follow-up presented at the 2022 European Society for Medical Oncology Congress, we saw that although the DFS benefit is maintained over time (HR: 0.27), the tails of the curves are beginning to converge, revealing a population of patients who have developed recurrent disease after stopping osimertinib.
Some may argue that the ADAURA update suggests we should be giving adjuvant osimertinib longer than 3 years. To me, the fundamental question remains: Are patients being cured with adjuvant osimertinib, or is inevitable progression simply being delayed?
Adjuvant Osimertinib in the Clinic
Talking With Patients About Adjuvant Osimertinib
In my clinic, I have a frank discussion with any patient who has resected NSCLC and is eligible to receive adjuvant osimertinib about the fact that, although we know this therapy is likely to delay recurrence of their disease, we do not yet know if it will lead to them living longer. In these conversations, I do not make a big distinction between stage IB and stage II-IIIA disease, as the DFS benefit with adjuvant osimertinib in ADAURA was consistent across stages. However, if data do emerge showing a difference in OS by disease stage, that would then become an important point to discuss with patients.
I also discuss potential toxicities associated with taking adjuvant osimertinib daily for 3 years. Although osimertinib is a well-tolerated drug, even a low-grade toxicity (eg, grade 1 rash) experienced for extended periods of time can become irritating. Because there are fewer follow-up visits and far less monitoring for patients who receive adjuvant osimertinib than for those receiving osimertinib for metastatic disease, it is important to make sure your patients feel comfortable discussing all aspects of their ongoing treatment with you and that lines of communication are open. Patient education should include how to recognize potential osimertinib-related toxicities and knowing when and how to contact you and the oncology care team if a toxicity should arise.
I have had patients stop adjuvant osimertinib because of tolerability concerns. I had a patient come to clinic with a pleural effusion more than 1 year into their course of adjuvant osimertinib. The patient admitted they had stopped taking osimertinib approximately 6 weeks earlier due to what seemed to me to be fairly vague complaints—ones that I think could have been mitigated with minor modifications to make taking the drug easier on the patient. Although making the decision to stop therapy is a reasonable option considering the absence of OS data at this time, I think this was a missed opportunity for the patient to make an informed decision with my input.
Adjuvant Osimertinib vs Other Adjuvant Therapies
Prior to the advent of adjuvant osimertinib, patients with resected EGFR-mutated NSCLC received adjuvant cisplatin-based chemotherapy as standard of care based on a relatively small but proven OS benefit. Furthermore, the design of the ADAURA trial allowed (but did not require) adjuvant chemotherapy to precede adjuvant osimertinib. As such, it is important that healthcare professionals do not substitute adjuvant osimertinib for adjuvant chemotherapy in a setting where adjuvant chemotherapy is appropriate.
A more difficult question to answer is whether to incorporate immune checkpoint inhibitors into adjuvant and neoadjuvant treatment of patients with resectable EGFR-mutated NSCLC. The same patients with resected stage II-IIIA NSCLC who are eligible for adjuvant osimertinib should they carry a sensitizing EGFR mutation also would be eligible for adjuvant atezolizumab should they be positive for tumor PD-L1 expression. Although it remains an open question for which we do not have much data, I typically try to avoid adjuvant immunotherapy in patients with EGFR mutations.
The utility of immunotherapy is even less clear in the neoadjuvant setting, where many patients receive chemotherapy plus nivolumab before resection, a time at which we often do not have molecular testing results and therefore do not know their EGFR mutation status. The extent to which neoadjuvant nivolumab would increase risk of toxicity with adjuvant osimertinib is an area of some concern based on data from the metastatic setting and is a question that we hope will be clarified in the coming years.
Oncology healthcare professionals are becoming increasingly comfortable with using osimertinib as adjuvant therapy for patients with resectable EGFR-mutated NSCLC. In fact, in a survey on all aspects of managing EGFR-mutated NSCLC that we conducted as part of this educational program, the percentage of learners who use adjuvant osimertinib in this setting rose from 25% in October 2021 to 41% in October 2022.
In my practice—which tends to include an aggressive group of patients who are seeking care at an academic medical center—there has been a strong tendency for patients with resectable EGFR-mutated NSCLC to select osimertinib as adjuvant therapy when presented with the data and the option. However, my guess is that there are still many patients who, when presented with the same data, will choose not to take a medicine for 3 years without knowing whether it is going to increase their life span. We anxiously await the crucial data point—OS—which will tell us whether adjuvant osimertinib is an essential part of patient management that is impacting the disease course.
How are you approaching management of early-stage EGFR-mutated NSCLC? Leave a comment in the discussion box below.
For further information concerning Lilly grant funding, visit www.lillygrantoffice.com.