ADAURA, a Bridge Connecting Disease Control with Long-term Survival

To the editor,

The ADAURA study aims to explore the optimal adjuvant strategy in patients with resectable stage IB-IIIA non-small cell lung cancer (NSCLC) harboring sensitive epidermal growth factor receptor (EGFR) mutations. The improved disease-free survival (DFS) observed in the osimertinib group was rather impressive with HR as low as 0.20. ¹ Very recently, an exploratory analysis of adjuvant chemotherapy use and outcomes have been reported, the HR of DFS in patients with adjuvant chemotherapy was further improved to 0.16. ² We thus have pretty high expectations for the survival data. Notably, previous studies, such as SELECT ³ and ADJUVANT ⁴ trails, assessing adjuvant first-generation EGFR-TKI in NSCLC, only showed delayed recurrence without altering the disease prognosis. In the ADAURA study, whether dramatic DFS advantage would be translated into survival benefit would be determined by some key points.

First, to figure out the contribution of adjuvant chemotherapy in the osimertinib group. Current evidence has demonstrated the value of the adjuvant osimertinib compared to placebo, at least in terms of DFS, no matter in the adjuvant chemotherapy group or no adjuvant chemotherapy group (Table 1). The HR of DFS in patients with adjuvant chemotherapy was lower than that in the overall population. To deeply affect clinical practice, it is of great importance to make a direct comparison between the patients with and without chemotherapy within the osimertinib group, however, the set of data remains premature by now. This evidence is the crucial complement to explain the negative survival benefit observed in the ADJUVANT trial. ⁴

Table 1.

Disease free survival and 24 months disease free survival rate in ADAURA trial.

	Osimertinib (n = 203)	Placebo (n = 207)	HR(95% CI)
Overall population
mDFS	NR(NC,NC)	27.5 (22.0, 35.0)	0.20 (99.12% CI, 0.14–0.30)
Patients with adjuvant chemotherapy
mDFS	NR(38.8,NC)	22.1 (17.4, 32.9)	0.16 (0.10,0.26)
24 months DFS rate	89%	49%
Patients without adjuvant chemotherapy
mDFS	NR(NC,NC)	33.1(22.6,NC)	0.23(0.13,0.40)
24 months DFS rate	89%	58%

Second, to understand the resistant patterns. In ADAURA, the patients were assigned to receive osimertinib for 3 years or until disease recurrence. For if recurrence happens before osimertinib discontinuation, we need to understand whether the resistant mechanisms are comparable to those observed in the FLAURA study. For those demonstrating recurrence after discontinuation, whether the relapsed clone still bears the identical sensitive mutation profiles as naive treatment should be carefully estimated. Novel acquired resistance patterns and the early emergence of resistance under selective pressures both affect the prognosis.

Third, to depict the efficacy of treatment after disease relapse, especially in patients who present a recurrence after osimertinib discontinuation. Since more than 70% of individuals didn't progress after 3 years, ¹ we ought to answer whether the adjuvant osimertinib would diminish the efficacy of TKI in the recurrent setting. SELECT trial ³ has brought some hints: 26 patients were retreated with erlotinib after recurrence, yielding a median duration of treatment of 13.1 months, which was close to the median progression-free survival of first-line erlotinib in advanced NSCLC. ⁵

The ADAURA study has provided significant evidence for the use of TKIs in a postoperative setting. We look forward to the analysis of disease recurrence data to expand the understanding of the tumor evolution during the adjuvant TKI.

Author biographies

Jing Zhao, is a medical oncologist of Second Affiliated Hospital of Zhejiang University School of Medicine. She is interested in Immuno-oncology of lung and breast cancer.

Rui Jin, is completing her residency in pulmonary Medicine in Second Affiliated Hospital of Zhejiang University School of Medicine. She is a junior doctor with great enthusiasm in clinical translational research.

Lingxiao Zhou, is a pulmonary physician of Second Affiliated Hospital of Zhejiang University School of Medicine, who focus on research of lung cancer.

Yang Xia, is a pulmonary physician of Second Affiliated Hospital of Zhejiang University School of Medicine. He has been dedicated in management of lung cancer, with special interests on clinical translational research.

Wen Li, is the vice chair of the Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, where she is the chief physician, doctoral supervisor of medicine. She has long been committed to the study of the molecular mechanism of the occurrence and development of chronic airway inflammatory disease and lung cancer.