ADAURA update: only the end of the beginning

The treatment of early-stage epidermal growth factor receptor (EGFR) mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) finally began to change for the better after the first ADAURA results were published in October 2020. Until then, chemotherapy was the only perioperative, systemic tool available albeit with a meager 5-year overall survival (OS) improvement of 4–5% (1,2). By comparison, the initial results of ADAURA showed that 3 years of adjuvant osimertinib improved 24-month disease-free survival (DFS) by 37% in patients with EGFRm+, stage IB–IIIA NSCLC. Moreover, there was an improved 24-month central nervous system (CNS) DFS of 13% compared to placebo (3). A little over a month after ADAURA was presented to the world, adjuvant osimertinib was approved by the Food and Drug Administration and added to National Comprehensive Cancer Network guidelines soon after (4).

One concern about these initial results was that the analysis was premature and done during an unplanned interim analysis at 24 months of follow up. Most patients were still in the midst of their 3 years of treatment at that time, leaving open the possibility that the DFS improvement seen at that time point would disappear after patients stopped osimertinib. However, the final DFS data recently published by Herbst and colleagues confirmed the benefit from adjuvant osimertinib (5). At 48 months and thus at least a year after stopping osimertinib, 73% of patients in the osimertinib arm were disease-free and alive compared to 38% in the placebo arm. Hazard ratios (HRs) for both the intention-to-treat (ITT) (stage II–IIIA) and overall (stage IB–IIIA) populations continued to be low at 0.23 and 0.27 along with a CNS DFS HR of 0.24 in the ITT group (5). Between the persistent and clinically significant DFS improvement in the final analysis, and perhaps more significantly the March 2023 announcement from AstraZeneca that OS was also significantly improved in the tyrosine kinase inhibitor (TKI) arm, osimertinib has solidified its place in the adjuvant space (6). Despite the positive news, however, there are still important questions that still need to be answered.

The first unanswered question is how long should patients be treated with adjuvant osimertinib? Three years was arbitrarily chosen for the ADAURA trial but may not be long enough for certain patients. The DFS curve for the osimertinib arm has a sharper decline after 3 years, most noticeable in the curve for stage IIIA patients in the previous update presented at the European Society of Medical Oncology Congress 2022, suggesting that in some of these patients their disease may have been suppressed by the TKI. The stage IB curve, meanwhile, was relatively stable (7). Also, 15/18 CNS recurrences occurred while off of osimertinib compared to only 3/32 in the placebo group (3). These results could signify that certain subgroups may benefit from a longer duration of adjuvant osimertinib, although who that should be is currently unknown. Presently, the TARGET trial is ongoing to evaluate 5-year of osimertinib for patients with resected stage II–IIIB disease (NCT05526755).

Other important questions include whether TKI treatment is best given before resection, after resection or both? And how should chemotherapy, with its small but proven OS benefit, be sequenced? The NEOADAURA trial is currently evaluating neoadjuvant osimertinib with or without chemotherapy vs. chemotherapy alone for stage II–IIIB (N2) disease (NCT04351555). After resection any adjuvant therapy is left up to investigator choice, which can also include osimertinib (8). It will be interesting to see if the use of adjuvant osimertinib will be balanced between the arms, because if NEOADAURA also has positive results, there may be confusion between using a neoadjuvant and/or adjuvant osimertinib. Ideally, there would be a study directly comparing preoperative vs. postoperative treatment, but we might first see a combination of neoadjuvant plus adjuvant vs. either neoadjuvant or adjuvant alone.

While we as a field work to answer the above questions, we can confidently say that some manner of perioperative osimertinib will be widely used to prevent recurrence and prolong survival for patients with early-stage EGFRm+ NSCLC, exposing many to potential long term side effects. While health-related quality of life does not seem to be drastically affected with adjuvant osimertinib, this does not mean that it is not without negative clinical and financial effects (9,10). While it is critical to continue investigations into perioperative osimertinib combinations and timing, we need to be just as diligent on making osimertinib regimens as patient-specific as possible to reduce the clinical and financial risks to those who may not benefit. For example, a patient with stage IIA disease may not need as long a course of adjuvant treatment as someone with stage IIIA. Ideally, we would have better markers of risk than stage, and this is where research on biomarkers such as using circulating tumor DNA to detect minimal residual disease (MRD), and risk scores similar to Oncotype DX in breast cancer, can help define those who may benefit the most from adjuvant osimertinib and perhaps spare those who don’t need it. Some ongoing trials like NEOADAURA are incorporating MRD testing into their exploratory analyses (8). The next step would be to see if such results can be applied clinically for patient selection or treatment de-escalation.

While we wait for more information on the best way to utilize perioperative osimertinib, we at least now know that adjuvant osimertinib improves DFS (and OS of an unknown magnitude) in stage IB–IIIA, EGFRm+ NSCLC. And although this is certainly not the end of the question, to paraphrase Winston Churchill, it may be the end of the beginning. We owe it to our patients to continue to be comprehensive in our investigations and continue to find ways to improve survival for early-stage NSCLC while limiting overtreatment.

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