Adjuvant osimertinib significantly prolongs the overall survival of patients with EGFR-mutant, early-stage non-small cell lung cancer

Three years ago, results of the phase III ADAURA trial demonstrated that adjuvant osimertinib significantly improved the disease-free survival (DFS) of patients with early-stage, EGFR-mutant non-small cell lung cancer (NSCLC). During the 2023 annual ASCO meeting, long-awaited overall survival (OS) data of this trial were presented, showing that this delayed disease recurrence indeed translates into a statistically significant and clinically relevant OS benefit for patients treated with adjuvant osimertinib vs. placebo. As such, these data underscore that adjuvant osimertinib should be considered the new standard of care in this setting.

Background

At the time when ADAURA was designed, the only adjuvant treatment option for patients with high-risk, stage IB to IIIA NSCLC following surgery consisted of cisplatin-based chemotherapy. However, even when adjuvant chemotherapy was used, still 45% to 76% of patients experienced a recurrence within 5 years. To address the unmet need in this setting, the ADAURA trial aimed to determine whether osimertinib could meaningfully influence clinical outcomes for patients with stage IB to IIIA NSCLC harboring a sensitizing EGFR mutation. Previously, results of ADAURA showed that adjuvant osimertinib more than doubled the median DFS compared to placebo among patients with stage IB-IIIA, EGFR-mutant NSCLC (median DFS: 65.8 vs. 28.1 months; HR[95%CI]: 0.27[0.21-0.34]). As part of the plenary session at ASCO 2023, the long-awaited OS results of this study were presented.

Study design

ADAURA was a global endeavor conducted in 26 countries across Europe, the Asia-Pacific, North America, and South America. The study included a total of 682 patients with completely resected stage IB, II, or IIIA non-squamous NSCLC harboring either an exon 19 deletion or a L858R mutation in EGFR. All patients in the study received up to 3 years of treatment with osimertinib or placebo. Of note, standard postoperative platinum-based chemotherapy was allowed but was not mandatory and had to be completed before patients were randomized. In total, approximately 60% of patients in the trial received adjuvant chemotherapy. Overall, 66% of patients in the osimertinib arm and 41% of patients in the placebo arm completed the planned treatment duration of 3 years. Consistent with the DFS findings, markedly fewer patients in the osimertinib arm went on to receive subsequent anticancer treatment compared to the placebo arm (22% vs. 54%).

Results

After a median follow-up for OS of 61.5 months for osimertinib and 61.5 months for placebo, adjuvant osimertinib proved to be associated with a statistically significant and clinically meaningful improvement in OS compared to placebo in patients with stage IB-IIIA patients (i.e., the overall study population) (medians not reached, HR[95%CI]: 0.49[0.34-0.70); p< 0.0001). Five years after randomization, this translated into an OS rate of 88% in the osimertinib arm, which is 10% higher than the 78% 5-year OS rate observed with placebo. This OS benefit was seen across all investigated subgroups, irrespective of age, sex, smoking history, race, disease stage, the type of EGFR mutation and the use of adjuvant chemotherapy. The hazard ratio for OS was reported at 0.44, 0.63 and 0.37 for patients with stage IB, II and IIIA, respectively.

The clinical benefit obtained with adjuvant osimertinib did come at the cost of a slightly higher rate of grade ≥3 adverse events (23% vs. 14%). AEs led to treatment discontinuation in 13% of patients on osimertinib as compared to 3% in the placebo arm. There were no treatment-related deaths in any of the treatment arms.

Conclusions

The significant DFS benefit obtained with adjuvant osimertinib vs. placebo in the phase III ADAURA trial translates into a significant and clinically relevant OS benefit for patients with EGFR-mutant, early-stage NSCLC. This benefit was seen in the primary study population (stage II-IIIA; HR[95.03%CI]: 0.49[0.33-0.73]; p= 0.0004) and in the overall study population (stage IB-III; HR[95.03%CI]: 0.49[0.34-0.70]; p< 0.0001). This OS benefit was consistent across the different disease stages and was seen regardless of whether the patient received adjuvant chemotherapy or not. As such, these findings mark ADAURA as the first global phase III study to demonstrate a significant and clinically meaningful OS benefit with a targeted agent in this patient population. These results therefore reinforce adjuvant osimertinib as the preferred treatment strategy for patients with resected, EGFR-mutant, stage IB-IIIA NSCLC.

Reference

Herbst R, 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. Presented at ASCO 2023; Abstract LBA3.