The importance of long-term safety, tolerability, and health-related quality of life: lessons from the ADAURA trial

Introduction

Epidermal growth factor receptor (EGFR) activating mutations are identified in approximately 15% of patients with non-small cell lung cancer (NSCLC), and this prevalence is as high as 40% in patients with Asian ancestry (1,2). Several EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed over the last 20 years, leading to a radical change in the treatment paradigm of patients with EGFR-mutated NSCLC. Although first and second-generation EGFR-TKIs improved patients’ outcomes vs. standard chemotherapies, acquired resistance to these therapies invariably developed, due to an acquired EGFR mutation at exon 20 (p.T790M) in approximately 60% of cases (3-5). Osimertinib is a mutant specific, irreversible, third-generation EGFR inhibitor designed to overcome T790M mediated acquired resistance. In the phase III, randomized, FLAURA trial, osimertinib has shown to improve progression-free survival and overall survival (OS) compared to first-generation inhibitors, making osimertinib the current standard first-line option for patients with advanced NSCLC and EGFR exon 19 deletions or exon 21 L858R mutations (6). Until recently, the use of EGFR inhibitors was limited to patients with locally advanced or metastatic tumors, as previous generation EGFR-TKIs failed to demonstrate meaningful survival improvement in the early-stage NSCLC. More recently, the ADAURA trial assessed the efficacy and safety of adjuvant osimertinib in patients with resected stage IB to IIIA NSCLC harboring EGFR exon 21 L858R point mutation and exon 19 deletion (7). In this study, adjuvant osimertinib demonstrated significant improvement in disease-free survival (DFS), and OS compared to placebo in resected early-stage NSCLC with common EGFR sensitizing mutations.

Although the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved osimertinib as an adjuvant treatment based on this study, it is still crucial to carefully analyze the safety and quality of life in an adjuvant setting, especially when considering the risk of overtreating patients, and exposing them to adverse events (AEs), and financial toxicity. Specifically, it is imperative to consider both acute and chronic toxicities to correctly interpret and understand health-related quality of life (HRQoL) analyses. Here, we provide a comment on the recently published article by John et al. on the 3-year update of safety, tolerability, and HRQoL outcomes of patients enrolled in the ADAURA trial at 3 years of follow-up (8).

The ADAURA trial

ADAURA is a phase 3, randomized, double-blind trial comparing the efficacy of adjuvant osimertinib vs. placebo in patients affected by stage IB–IIIA [7th edition American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC)] NSCLC with common EGFR sensitizing mutation (L858R, del 19) (7). The ADAURA trial randomized 682 patients to receive either osimertinib 80 mg (n=339) or placebo (n=343) once daily for up to 3 years in a 1:1 ratio. The primary endpoint was DFS in stage II–IIIA patients, while the secondary endpoints were DFS among patients with stage IB–IIIA, OS, safety, and quality of life analysis. The trial met its primary endpoint with a hazard ratio (HR) for DFS of 0.23 [95% confidence interval (CI): 0.18–0.30], and a longer median DFS in the osimertinib group (65.8 vs. 21.9 months) (7). The DFS benefit was confirmed across all pre-specified subgroups, including age, sex, stage, type of mutation, and adjuvant chemotherapy administration (7). The magnitude of benefit from adjuvant osimertinib vs. placebo was higher for patients with stage IIIA (DFS: HR =0.20; 95% CI: 0.14–0.29) compared to patients with stage II (DFS: HR =0.34; 95% CI: 0.23–0.52) and stage IB (DFS: HR =0.41; 95% CI: 0.23–0.69) NSCLC (7). The HR for central nervous system (CNS) DFS in the entire population was 0.36 (95% CI: 0.23–0.57), suggesting that adjuvant osimertinib has the potential of delaying the development of brain metastasis (2). More recently, results from the pre-planned OS analysis were also presented. At a median follow-up time of 59.9 months (6), patients who received adjuvant osimertinib experienced a significant OS benefit (HR =0.49; 95% CI: 0.34–0.70) (9). Again, the benefit of adjuvant osimertinib was observed across all subgroups, with a greater effect seen among patients with stage IIIA NSCLCs.

The ADAURA trial study design raises several critical points that warrant scrutiny.

While this study met its primary endpoint of DFS, it should be highlighted that only a fraction of patients in the placebo group received osimertinib at the moment of recurrence, which makes the OS data harder to interpret since the lack of access to osimertinib at the time of recurrence may have contributed to reduce the generalizability in a real-world context. Furthermore, the distinct resistance mechanisms to osimertinib compared to other EGFR-TKIs introduce uncertainties, especially without established treatment options after osimertinib progression.

In addition, patients with stage III N2 disease enrolled in ADAURA did not undergo, per protocol, extensive mediastinal staging through positron emission tomography (PET)-fluorodeoxyglucose (FDG), mediastinoscopy, or endobronchial ultrasound (EBUS). Also, cerebral magnetic resonance imaging (MRI) at baseline was not required, increasing the risk of unrecognized brain metastasis. Proper staging is instead necessary to ensure that the observed outcomes are attributable to the treatment rather than disease severity or stage variations. A standardized staging protocol would have improved trial validity and clarified the impact of adjuvant osimertinib on patients with different disease stages.

Finally, less than two-thirds of patients received adjuvant chemotherapy that was not considered mandatory per protocol. The subgroup analysis did not evidence a significant increase in progression or death risk according to chemotherapy administration. However, these data do not support the omission of adjuvant chemotherapy, which should remain a standard treatment for these patients if clinically indicated.

Safety and quality of life with adjuvant osimertinib

The safety and HRQoL were important secondary endpoints of the ADAURA trial. The primary analysis of this study did not identify any new safety concerns, and the rates of dose reduction and discontinuations were low (7). The safety and HRQoL analysis included 337 patients on osimertinib and 343 patients on placebo (7,8). Safety assessments were conducted at various time points throughout the treatment period, and the Short Form-36 (SF-36) survey was used to measure HRQoL at specific intervals. The baseline SF-36 scores were similar between the two groups, and similar patterns of variation were assessed during the time (8). The ADAURA study initially found no significant differences in SF-36 scores between the experimental and control arms (7). Consistently, the 3-year follow-up analysis of this study confirmed that most patients in both groups either remained stable or improved in their HRQoL for up to 156 weeks compared to baseline (8). Of note, the SF-36 questionnaire consists of 36 questions divided into eight health categories (8,10). It is intended to assess the overall health of individuals who are not impacted explicitly by cancer, and it was specifically chosen assuming that patients undergoing postoperative treatments were hypothetically cancer-free. Conversely, the CTONG study (11) assessed the HRQoL via the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument (11,12), while the RADIANT (13) and IMPACT (14) studies did not provide detailed patient-reported-outcome data. The employment of patient-reported outcomes (PROs) is certainly recommended within the context of clinical trials to improve the transversal evaluation of a certain intervention and should be implemented in clinical trials (15). There are multiple reasons why there may be differences between the symptoms that clinicians record and the symptoms that patients report (15). However, these discrepancies may potentially impact the proper assessment of patients’ quality of life while they are on active treatment (15). Choosing a questionnaire that is comprehensive and easy to understand is essential for gathering correct safety information. In the ADAURA trial, the use of the SF-36 survey allowed for the collection of reliable safety data. By contrast, other scales that have been validated in patients with active cancer may produce less informative results.

In the ADAURA, patients treated with osimertinib had a longer median total drug exposure (35.8 months) than those who received placebo (25.1 months). Most AEs were reported within the first 12 months of starting treatment, with a higher incidence in the osimertinib group (97%) than in the placebo group (86%). AEs leading to dose reduction, interruption, or discontinuation were more frequent in the osimertinib group, with 12%, 27%, and 13% of patients experiencing these events, respectively. In contrast, the placebo group had lower rates of 1%, 13%, and 3%, respectively, for these outcomes. Stomatitis and diarrhea were the most common AEs leading to osimertinib dose reduction or interruption, while interstitial lung disease (ILD) was the most common reason for osimertinib discontinuation (2%, 8 patients), and 1 patient died of respiratory failure classified as treatment unrelated. Cardiac events (as a general category) were all of grade 1–2, and ejection fraction impairment was the most frequent among these. The study suggests thorough baseline cardiological and pneumological evaluations for patients treated with postoperative osimertinib to minimize the risk of cardiac events and respiratory failure, especially in patients with multiple comorbidities. The safety profile observed in a phase 3 trial may not be representative of real-world contexts, primarily due to the selective inclusion of patients in good clinical condition and without significant past medical history.

This emphasizes the need for a personalized assessment of risks and benefits and a collaborative patient-centered approach to treatment to improve outcomes and prevent potential negative effects. In this context, pharmacovigilance studies, or observational multicenter collaborations will help clarify the possible impact on HRQoL in a more heterogeneous population for this treatment setting.

Globally, no safety signals were found in comparison to the ADAURA primary analysis and the first-line FLAURA study (16). In addition, safety data relative to osimertinib treatment that emerged from prospective trials have been confirmed within a large real-world analysis of pharmacovigilance (17).

Interestingly, the ADAURA safety analysis did not evidence significant sex-driven differences (8). However, it was observed that the occurrence of grade ≥3 AEs was numerically greater in males (27% vs. 22%), while females were more likely to need dose reductions (15% vs. 6%). Even though differences seem minor, an increased propensity for developing AEs has already been documented among women receiving targeted therapies (17,18). Consistently with the FLAURA and AURA studies (11), patients with ≥70 years were more likely to experience serious AEs or those leading to dose reduction or discontinuation also in the ADAURA (8).

Given the limited improvement in OS rates at 5 years with the use of adjuvant chemotherapy (about 5%), and the paucity of elderly (≥70 years) patients enrolled in adjuvant randomized clinical trials, using adjuvant chemotherapy among elderly with EGFR mutations should be carefully discussed with patients, as using only adjuvant osimertinib could represent a safer option. In such cases, a thorough review of each patient comorbidities and comedications will be essential to optimize patient selection for adjuvant therapies. Using comprehensive geriatric assessment may also help improving clinical adherence and the management of osimertinib side effects.

Interestingly, there were no significant differences in terms of time to deterioration for HRQoL as measured by SF-36 physical and mental component summaries between the osimertinib and placebo groups (8). This evidence suggests that while some AEs occurred more frequently in the osimertinib arm, they did not negatively impact their overall quality of life compared to the placebo group.

Conclusions

The 3-year safety data from the ADAURA trial confirm the favorable safety profile of adjuvant osimertinib in patients with resected stage IB to IIIA EGFR-mutated NSCLC. Most AEs occurred within the first year of treatment and were manageable with dose adjustments or treatment discontinuation. Importantly, no new safety signals were identified during the extended follow-up period, and no specific patient populations were determined to be more likely to develop osimertinib-related AEs. Overall, an accurate preliminary education of patients and caregivers may improve the prevention and management of serious AEs. The implementation of PROs within clinical practice may also contribute to optimal safety monitoring (15). In this context it is important to highlight that the HRQoL metrics in the osimertinib arm of the ADAURA study were overall similar to placebo, suggesting that the benefits of this therapy extend beyond survival outcomes. Together with the significant benefit in term of DFS and OS reported in this study, this 3-year follow-up safety analysis of the ADAURA trial provides additional evidence supporting the use of adjuvant osimertinib in this patient population. However, it will be essential to continue monitoring long-term safety and HRQoL data in larger cohorts of patients to obtain additional insights on the impact of osimertinib treatment in the real-world setting. Additionally, studies dedicated to specific subgroups that may experience different safety or HRQoL outcomes will be valuable in refining treatment decisions and optimizing patient care. Overall, the ADAURA trial has provided strong evidence for the use of adjuvant osimertinib, offering a new standard of care for the adjuvant treatment of patients with resected stage IB–IIIA, EGFR-mutated NSCLC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-15/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-15/coif). B.R. has received consulting fees from Regeneron, AstraZeneca, and Amgen, and payment or honoraria from Targeted Oncology. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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