Research Summary
In this randomized, controlled, Phase III study,1 patients with resectable, epidermal growth factor receptor (EGFR)–mutated, Stage II to IIIB non-small cell lung cancer (NSCLC) were assigned 1:1:1 to receive neoadjuvant osimertinib (80mg orally once daily for at least nine weeks) plus platinum-based chemotherapy for three three-week cycles, osimertinib monotherapy for at least nine weeks, or placebo plus platinum-based chemotherapy, followed by surgical resection. Adjuvant osimertinib was offered to eligible patients after surgery, and the primary endpoint was major pathologic response (MPR), with event-free survival (EFS) as a secondary endpoint. MPR was defined as no more than 10 percent residual viable tumor cells in the lung primary tumor at resection with an R0 margin.
A total of 358 patients were randomly assigned to osimertinib plus chemotherapy (121 patients), osimertinib monotherapy (117 patients), or placebo plus chemotherapy (120 patients). Median age was 65 years, with most patients being female (66%), having an Eastern Cooperative Oncology Group performance status of 0 (81%), and being never-smokers (71%). Approximately one-half of patients had Stage III disease, and over one-third had N2 disease.
The proportion of patients completing all neoadjuvant study treatments was 90, 98, and 93 percent in the osimertinib plus chemotherapy, osimertinib monotherapy, and placebo plus chemotherapy groups, respectively, and 91 and 93 percent completed all three chemotherapy cycles in the combination and control groups, respectively. After neoadjuvant therapy, most patients underwent curative-intent surgery (92% with osimertinib plus chemotherapy, 97% with osimertinib monotherapy, and 89% with placebo plus chemotherapy).
Among patients who underwent surgery, R0 resection was achieved in 91, 95, and 93 percent in the combination, monotherapy, and control groups, respectively. Across all groups, the median time from the last neoadjuvant dose of osimertinib or placebo to surgery was three days, and the median time from surgery to first dose of sponsor-supplied adjuvant osimertinib was 35 days.
In the primary analysis, osimertinib plus chemotherapy (MPR: 26%) and osimertinib monotherapy (25%) significantly improved MPR versus placebo plus chemotherapy (2%), with odds ratios (ORs) of 19.82 (95% confidence interval [CI]: 4.60–85.33; p<0.0001) and 19.28 (99.9% CI, 1.71–217.39; p<0.0001), respectively. Pathologic complete response (pCR) occurred in four, nine, and zero percent of patients in the combination, monotherapy, and control groups, respectively.
Among patients with baseline N2 disease who had surgical assessment, downstaging to N0 or N1 occurred in 53 percent with osimertinib plus chemotherapy, 53 percent with osimertinib monotherapy, and 21 percent with placebo plus chemotherapy, with ORs versus control of 4.77 (95% CI: 1.62–14.00) and 4.18 (95% CI, 1.44–12.14), respectively.
With 15-percent data maturity and median follow-up durations of 14.3, 18.3, and 14.3 months in the combination, monotherapy, and control groups, respectively, for event-free-survival (EFS), the hazard ratio (HR) for EFS comparing osimertinib plus chemotherapy with placebo plus chemotherapy was 0.50 (99.8% CI: 0.17–1.41; p=0.04). The HR for osimertinib monotherapy versus control was 0.73 (95% CI: 0.40–1.35). EFS favored osimertinib-containing regimens but did not meet the prespecified two-sided significance level of 0.002. At 12 months after random assignment, 93, 95, and 83 percent of patients in the combination, monotherapy, and control groups, respectively, had not experienced an EFS event. An exploratory analysis showed one EFS event among patients who achieved an MPR (1/62, 2%) versus 52 events among those without MPR (52/296, 18%).
Safety during the neoadjuvant period showed adverse events (AEs) of any cause in 89 to 93 percent of patients across groups, predominantly low grade and nonserious. Grade 3 or higher and serious AEs occurred in 36 and 20 percent of patients with osimertinib plus chemotherapy, 13 and 11 percent with osimertinib monotherapy, and 33 and 20 percent with placebo plus chemotherapy, respectively. AEs leading to discontinuation of osimertinib or placebo occurred in 2 to 3 percent of patients across groups, and discontinuation of chemotherapy occurred in eight percent with osimertinib and five percent with placebo. Hematologic toxicities were more frequent with osimertinib plus chemotherapy (52%), followed by placebo plus chemotherapy (40%) and osimertinib monotherapy (11%). Among those who underwent surgery, serious AEs causally related to surgery occurred in 10, five, and seven percent of patients in the combination, monotherapy, and control groups, respectively.
Neoadjuvant osimertinib, with or without chemotherapy, improved MPR compared to placebo plus chemotherapy, and more than half of patients with baseline N2 disease were downstaged at surgery with osimertinib-containing regimens compared to 21 percent with control. Neoadjuvant osimertinib did not adversely affect surgical feasibility or outcomes, no patients died within 30 days after surgery, and rates of surgery and R0 resection were high with osimertinib-containing regimens. At 15-percent data maturity, EFS favored osimertinib-containing regimens, and EFS curves separated early, coinciding with fewer cases of progressive disease that prevented surgery in the osimertinib groups. Final EFS outcomes will be reported at the protocol-specified later analyses.
Reference
- He J, Tsuboi M, Weder W, et al. Neoadjuvant osimertinib for resectable EGFR-mutated non-small cell lung cancer. J Clin Oncol. 2025:JCO2500883. Epub ahead of print.