Neoadjuvant Osimertinib in Resectable EGFR-Mutated NSCLC: Advancing Preoperative Therapeutics

Highlight

• Neoadjuvant osimertinib, with or without platinum-based chemotherapy, markedly enhances major pathologic response (MPR) rates compared to chemotherapy alone in resectable EGFR-mutated non-small cell lung cancer (NSCLC).
• Both combination and monotherapy regimens of osimertinib showed statistically significant improvements in MPR, indicating its efficacy as a neoadjuvant strategy.
• The safety profile of neoadjuvant osimertinib was manageable, with no new safety concerns or increased surgical delays observed.
• Event-free survival at 12 months favored osimertinib-containing regimens, suggesting potential long-term clinical benefit.

Study Background and Disease Burden

Non-small cell lung cancer (NSCLC) harbors activating mutations in the epidermal growth factor receptor (EGFR) in approximately 10–30% of cases, particularly in Asian populations. EGFR mutations, mainly exon 19 deletions and L858R point mutations, are associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite advances, surgical resection for early-stage and locally advanced resectable NSCLC remains the cornerstone of curative treatment; however, recurrence rates remain substantial. Adjuvant osimertinib, a third-generation EGFR-TKI, has become the standard of care following resection, markedly improving disease-free survival. Nonetheless, neoadjuvant approaches aiming to reduce tumor burden preoperatively and eradicate micrometastases may further enhance long-term outcomes and improve surgical feasibility. Osimertinib’s favorable central nervous system penetration and safety profile make it a promising candidate for neoadjuvant application, yet robust evidence has been limited and inconclusive until recently.

Study Design and Methods

Two pivotal clinical studies investigated neoadjuvant osimertinib’s safety and efficacy in patients with resectable EGFR-mutated NSCLC.

1. A Phase III Randomized Controlled Trial (NeoADAURA, NCT04351555)
– Population: 358 patients with resectable, EGFR-mutated NSCLC stage II–IIIB.
– Intervention arms: (a) Neoadjuvant osimertinib (80 mg orally once daily for ≥9 weeks) plus platinum-based chemotherapy (three cycles, every three weeks); (b) Neoadjuvant osimertinib monotherapy (≥9 weeks); (c) Placebo plus platinum-based chemotherapy.
– Postoperative: Adjuvant osimertinib offered to eligible patients.
– Primary endpoint: Major pathological response (MPR) assessed by blinded central pathology review.
– Secondary endpoint: Event-free survival (EFS), safety.

2. Phase II Multicenter Study (NCT03433469)
– Population: 27 patients with surgically resectable stage I–IIIA EGFR-mutated NSCLC.
– Intervention: Neoadjuvant osimertinib 80 mg orally once daily for up to two 28-day cycles.
– Primary endpoint: MPR rate.
– Secondary endpoints: Safety, response rate, disease-free survival (DFS).
– Exploratory: Tumor mutation profiling pre- and post-treatment.

Key Findings

NeoADAURA Phase III Trial Results
– MPR rates were significantly higher with osimertinib plus chemotherapy (26%) and osimertinib monotherapy (25%) compared to placebo plus chemotherapy (2%).
– Odds ratios for MPR: 19.82 (95.002% CI, 4.60–85.33; P < .0001) for combination and 19.28 (99.9% CI, 1.71–217.39; P < .0001) for monotherapy.
– Event-free survival at 12 months: 93% (combination), 95% (monotherapy), 83% (control).
– Safety: Grade ≥3 adverse events occurred in 36%, 13%, and 33% for combination, monotherapy, and control, respectively. No new safety signals were identified.

Phase II Study Outcomes
– MPR rate was 14.8% (95% CI, 4.2–33.7), lower than in the phase III trial but consistent with a smaller cohort.
– No pathological complete responses were observed.
– Overall response rate by imaging was 52%.
– Median DFS was 40.9 months.
– One treatment-related serious adverse event reported (3.7%).
– No surgical delays or unresectability due to adverse events.
– Frequent co-alterations included TP53 (42%) and RBM10 (21%) mutations.

Comparison of Studies:
While the larger phase III trial demonstrated robust improvement in pathological response and favorable EFS signals, the smaller phase II study showed modest MPR rates but confirmed safety and surgical feasibility of neoadjuvant osimertinib. Both studies reinforce osimertinib’s active role before surgery, with or without chemotherapy.

Expert Commentary

Neoadjuvant osimertinib represents a promising advance in managing resectable EGFR-mutated NSCLC, bridging targeted therapy with curative-intent surgery. The NeoADAURA trial’s statistically significant MPR improvements over chemotherapy alone underscore the potent preoperative activity of osimertinib. Additionally, the inclusion of a monotherapy arm suggests that osimertinib alone can be an effective neoadjuvant option, potentially sparing selected patients chemotherapy-associated toxicities.

Safety and surgical feasibility are paramount in neoadjuvant settings, and both studies affirm that osimertinib does not increase operative risk or delay, critical considerations for clinical applicability. Nonetheless, longer follow-up data are essential to confirm overall survival benefit and optimal sequencing with surgery and adjuvant therapy.

Study limitations include heterogeneity in staging between trials, modest data maturity for EFS in NeoADAURA, and the small sample size of the phase II study limiting statistical power. Future research should explore biomarker-driven selection and the integration of immunotherapy for resistant clones. Moreover, mechanistic insights into residual disease and resistance mutations such as TP53 co-alterations may inform personalized neoadjuvant therapies.

Conclusion

Neoadjuvant osimertinib—both as monotherapy and combined with platinum-based chemotherapy—achieves significant improvements in major pathological response and shows encouraging event-free survival trends in patients with resectable, EGFR-mutated NSCLC. The favorable safety profile and lack of surgical delay bolster its potential as a new standard neoadjuvant approach. These findings support the incorporation of osimertinib into perioperative management paradigms and invite further confirmatory research to define long-term survival impact and optimize treatment sequencing.

References

1. He J, Tsuboi M, Weder W, et al; NeoADAURA Investigators. Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small Cell Lung Cancer. J Clin Oncol. 2025 Sep 10;43(26):2875-2887. doi:10.1200/JCO-25-00883 IF: 41.9 Q1 B1. Epub 2025 Jun 2. PubMed PMID: 40454705 IF: 41.9 Q1 B1.

2. Blakely CM, Urisman A, Gubens MA, et al. Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: A Phase II Multicenter Study. J Clin Oncol. 2024 Sep 10;42(26):3105-3114. doi:10.1200/JCO.24.00071 IF: 41.9 Q1 B1. Epub 2024 Jul 19. PubMed PMID: 39028931 IF: 41.9 Q1 B1; PMCID: PMC11379363 IF: 41.9 Q1 B1.