Background
Lung cancer is the leading cause of cancer-related deaths in the United States, accounting for about 1 in 5 of all cancer deaths.1 According to The American Cancer Society's estimates for lung cancer in the U.S. for 2025, an estimated 226,650 new cases of lung and bronchial cancer will be diagnosed, and 124,730 will die because of the disease.1 Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, and about 10-30% of NSCLC tumors harbor an actionable epidermal growth factor receptor (EGFR) mutation, most commonly exon 19 deletions and L858R point mutations, which drive tumor growth and confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs).2
In metastatic EGFR-mutated NSCLC, the third-generation TKI, osimertinib (Tagrisso), improved progression-free and overall survival compared with earlier TKIs, both as monotherapy and in combination with chemotherapy.3 In the adjuvant setting, osimertinib improves disease-free survival after resection and is standard of care for EGFR-mutated (Stage IB to IIIA) NSCLC.3 Despite these advances, outcomes after surgery remain suboptimal, and the role of neoadjuvant therapy – to reduce tumor burden and micrometastatic disease – continues to evolve. Platinum-based chemotherapy has historically provided modest benefit, and immunotherapy shows limited efficacy in EGFR-mutated disease.4
NeoADAURA
The NeoADAURA (NCT04351555) trial is a global, randomized, controlled, phase III, three-arm study evaluating neoadjuvant osimertinib, with or without platinum-based chemotherapy, versus standard chemotherapy alone in patients with resectable, stage II–IIIB EGFR-mutated NSCLC.2 Enrollment began in December 2020 and ended in October 2024, with 358 patients enrolled across 25 countries. Eligible participants were adults ≥18 years with histologically or cytologically confirmed NSCLC deemed resectable (Stage II-IIIB N2 NSCLC). Complete surgical resection must be considered achievable based on multidisciplinary team assessment, including a thoracic oncologic surgeon. Patients must have an ECOG performance status of 0-1 at enrollment, with no deterioration in the 2 weeks prior to baseline or the first dose, and tumors must harbor a common activating EGFR mutation associated with EGFR-TKI sensitivity (exon 19 deletion or L858R), either alone or in combination with other EGFR mutations. Key exclusion criteria included prior systemic therapy for NSCLC, unresectable or metastatic disease, clinically significant interstitial lung disease (ILD), or other active malignancies that could interfere with study outcomes. This randomized, three-arm study assigned patients in a 1:1:1 ratio to receive either osimertinib 80 mg once daily for more than nine weeks combined with platinum-based chemotherapy every three weeks for three cycles (n=121), osimertinib 80 mg once daily for more than nine weeks as monotherapy (n=117), or placebo plus platinum-doublet chemotherapy (n=120), prior to resection. The primary endpoint is major pathologic response (MPR), defined as ≤10% residual viable cancer cells in the primary tumor based on centralized pathology assessment following surgical resection. Secondary endpoints include pathologic complete response (pCR), nodal downstaging, event-free survival (EFS), disease-free survival (DFS), and overall survival (OS).2,5
Discussion
NeoADAURA demonstrates that neoadjuvant osimertinib, either alone or in combination with chemotherapy, substantially improves pathological response rates in resectable EGFR-mutated NSCLC. Across all treatment arms, baseline characteristics were balanced, with a predominance of female patients, a higher proportion of never-smokers than current or former smokers, and an even distribution between exon 19 deletions and L858R mutations. Following neoadjuvant therapy, most patients proceeded to curative-intent surgery, with fewer than 10 patients per arm not undergoing resection, and over 90% resected patients achieving an R0 resection. Major pathologic response rates were markedly higher with osimertinib plus chemotherapy (26%) and osimertinib monotherapy (25%) compared with chemotherapy alone (2%), accompanied by higher rates of nodal downstaging in the osimertinib-containing arms. These pathological improvements translated into favorable early clinical outcomes, with 12-month event-free survival of approximately 93-95% in the osimertinib arms compared with 83% with chemotherapy alone.3,5 No new safety signals were identified, and surgical complication rates were comparable across all arms. Given prior evidence linking MPR and nodal response to survival, these findings suggest that neoadjuvant osimertinib may offer meaningful long-term benefits by reducing recurrence risk and improving survival.
Unlike traditional neoadjuvant chemotherapy, targeted therapy in the preoperative setting provides a tumor biology–driven approach that is particularly relevant in EGFR-mutated NSCLC, a population in which immunotherapy has shown limited benefit.6 By intervening earlier with a highly active, mutation-specific agent, neoadjuvant osimertinib has the potential to achieve deeper tumor responses and more favorable nodal downstaging prior to surgery. Notably, osimertinib monotherapy demonstrated pathologic and early clinical outcomes comparable to those observed with osimertinib combined with chemotherapy, raising important questions regarding the incremental benefit of adding cytotoxic therapy in this setting as well as whether select patients may be able to safely avoid chemotherapy altogether. However, given established perioperative treatment paradigms and the absence of mature overall survival data, uncertainty remains, and clinicians may be cautious about omitting chemotherapy from multimodal strategies. Furthermore, because all eligible patients who underwent surgery in NeoADAURA were offered adjuvant osimertinib, any incremental survival advantage attributable solely to neoadjuvant osimertinib may be attenuated. As such, long-term follow-up data are needed to confirm the durability and clinical significance of this strategy.
If confirmed with longer follow-up, NeoADAURA has the potential to establish neoadjuvant osimertinib, with or without chemotherapy, as a new standard of care for resectable EGFR-mutated NSCLC, signaling a paradigm shift toward personalized, targeted perioperative therapy and shaping future treatment guideline recommendations, which currently emphasize molecular testing prior to perioperative therapy selection and generally favor chemotherapy-based approaches without considering neoadjuvant immunotherapy in EGFR-mutated disease.
References
1.American Cancer Society. Cancer Facts & Figures 2025. American Cancer Society; 2025.
2.National Library of Medicine (U.S.). A study of osimertinib with or without chemotherapy versus chemotherapy alone as neoadjuvant therapy for patients with EGFRm-positive resectable non-small cell lung cancer (NeoADAURA) (NCT04351555). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04351555. Published May 23, 2025. Accessed December 14, 2025.
3.He J, Tsuboi M, Weder W, Chen KN, Hochmair MJ, Shih JY, Lee SY, Lee KY, Nhung NV, Saeteng S, Liu L, Xing L, Gia NH, Murakami S, Han Y, Saavedra MP, Yoon SH, Teixeira CHA, Escriu C, Martinez-Marti A, Blakely CM, et al.; NeoADAURA Investigators. Neoadjuvant osimertinib for resectable EGFR-mutated non-small cell lung cancer. J Clin Oncol. 2025;43(26):2875-2887. doi:10.1200/JCO-25-00883
4.Chaft JE, He J, Tsuboi M, et al. Neoadjuvant osimertinib ± chemotherapy versus chemotherapy alone in resectable EGFR-mutated NSCLC: NeoADAURA. J Clin Oncol. 2025;43(16_suppl):8001. doi:10.1200/JCO.2025.43.16_suppl.8001
5.Marabella C. NeoADAURA trial launches with plans to assess neoadjuvant osimertinib in resectable EGFR-positive NSCLC. Targeted Oncology. 2021. https://www.targetedonc.com/view/neoadaura-trial-launches-with-plans-to-assess-neoadjuvant-osimertinib-in-resectable-egfr-nsclc. Accessed December 14, 2025.
6.Wang L, Xian X, Ke H, et al. Immunotherapy in EGFR-mutant non–small cell lung cancer. Clin Exp Med. 2025;26:10. doi:10.1007/s10238-025-01927-1
