“Neoadjuvant treatment with osimertinib, with or without chemotherapy, should be considered when planning treatment for patients with resectable, EGFR-mutated, stage II to IIIB non–small cell lung cancer [NSCLC],” according to Jamie E. Chaft, MD, FASCO, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York. This recommendation is based on the primary results of the global phase III NeoADAURA trial, which were presented during the 2025 ASCO Annual Meeting1 and simultaneously published in the Journal of Clinical Oncology.2 (Osimertinib is a third-generation EGFR tyrosine kinase inhibitor.)
In a discussion with The ASCO Post, Dr. Chaft shared these comments: “The study fills an unmet need. Currently, our standard of care for patients with lung cancer who are appropriate for neoadjuvant treatment is chemoimmunotherapy; however, those with EGFR-driven lung cancer are not appropriate for this approach….” Her presentation further underscored the potential impact: “Effective neoadjuvant treatment allows patients to complete surgery, often down-staged, and get to the adjuvant phase of treatment, which has demonstrated an overall survival benefit in ADAURA.”
Study Details
Patients with completely resectable, stage II to IIIB, EGFR-mutated, nonsquamous NSCLC who had a World Health Organization performance score of up to 1 were stratified (stage II vs III; non‑Asian vs Chinese vs other Asian; exon 19 deletion vs L858R mutation). They were randomly assigned in a 1:1:1 ratio to receive one of the following neoadjuvant treatments:
- Osimertinib (80 mg) once daily for at least 9 weeks plus three cycles of chemotherapy with pemetrexed and either cisplatin or carboplatin every 3 weeks (n = 121);
- Osimertinib (80 mg) alone once daily for at least 9 weeks (n = 117);
- Placebo once daily for at least 9 weeks plus three cycles of chemotherapy with pemetrexed and either cisplatin or carboplatin every 3 weeks (n = 120).
Baseline characteristics were found to be well balanced between the arms. The population was predominantly female, and overall approximately 25% of patients were enrolled from regions outside of Asia. Dr. Chaft reported that the population was evenly balanced in terms of EGFR mutation types (exon 19 deletion vs L858R mutation) and disease stage (stage II vs III). More than one-third of patients in each arm had N2 disease at baseline.
Surgery was performed in 92% of patients treated with osimertinib plus chemotherapy, 97% of those treated with osimertinib alone, and 89% of those treated with placebo plus chemotherapy, with R0 resection rates of 91%, 95%, and 93%, respectively. “These numbers compare very favorably with the perioperative chemoimmunotherapy studies,” stated Dr. Chaft. Of note, with both osimertinib-containing regimens, fewer patients were found to experience progressive disease that precluded definitive surgery (2% vs 8%). A total of 91% of those who completed surgery received sponsor-supplied adjuvant osimertinib.
The primary endpoint of major pathologic response (≤ 10% viable tumor cells in the resection specimen) was evaluated by blinded central pathology review. Secondary endpoints included pathologic complete response, nodal downstaging, event-free survival, and safety.
Key Efficacy Outcomes
The major pathologic response rates appeared to be significantly lower with placebo plus chemotherapy (2%; pathologic complete response rate: 0%) than with osimertinib plus chemotherapy (26% [odds ratio = 19.8, P < .0001]; pathologic complete response rate: 4%) and osimertinib monotherapy (25% [odds ratio = 19.3, P < .0001]; pathologic complete response rate: 9%). Describing the major pathologic response rate in the control arm as “shocking,” Dr. Chaft stated: “For patients who need induction therapy, chemotherapy has been our historic standard of care, and I think we all believed it was better than this.”
The major pathologic response benefit with the osimertinib-containing regimens was found to be consistent across predefined subgroups, including those defined by EGFR mutation type, disease stage, and preoperative circulating tumor DNA status.
Nodal downstaging was observed at surgery in 53% of patients with baseline N2 disease treated with either osimertinib plus chemotherapy or osimertinib alone, compared with 21% of those who received placebo plus chemotherapy. Respectively, the osimertinib-containing regimens were found to be associated with a 4.8- and 4.2-fold increase in the odds of achieving such a lymph node response.
Regarding event-free survival, Dr. Chaft shared these comments: “The interim data are immature. At 15% maturity and a median follow-up between 14 and 18 months per arm, there is an early separation of the curves. Much of this is attributed to preoperative [disease] progression precluding definitive resection. However, in the control arm, we also saw early relapses after surgery. The crossing of the curves later is largely due to censoring.” Hazard ratios compared with placebo plus chemotherapy were 0.50 (P = .0382) for osimertinib plus chemotherapy and 0.73 for osimertinib monotherapy.
Given potential skepticism surrounding major pathologic response as an endpoint, Dr. Chaft discussed its performance and association with clinical outcomes. A single relapse was reported among patients whose tumors exhibited this response, corresponding to an event rate of 2%, compared with an 18% event rate in those whose tumors did not.
Key Safety Outcomes
According to Dr. Chaft, treatment-related adverse events of grade 3 or higher were uncommon during the neoadjuvant period (osimertinib plus chemotherapy: 29%; osimertinib alone: 4%; placebo plus chemotherapy: 23%), with most attributed to chemotherapy (vs osimertinib or placebo: 28% vs 17%, not applicable vs 4%, and 23% vs 10%, respectively). She furthermore reported a low incidence of adverse events leading to treatment discontinuation, as well as serious adverse events attributable to the study drugs.
The most common adverse events were “exactly what we expect from each individual drug and the drugs in combination,” Dr. Chaft remarked. The adverse events of special interest of wound complications and cardiac effects were reported in two and one of the patients treated with osimertinib plus chemotherapy, one and three of those who received osimertinib monotherapy, and zero and two of those who received placebo plus chemotherapy. Two cases of interstitial lung disease or pneumonitis were reported, both occurring with osimertinib monotherapy, neither of which precluded definitive resection.
Expert Point of View
In evaluating “whether earlier is indeed better,” invited discussant Lizza Hendriks, MD, PhD, of Maastricht University Medical Center, the Netherlands, offered a critical perspective on the phase III NeoADAURA trial of neoadjuvant osimertinib for resectable, EGFR-mutated non–small cell lung cancer (NSCLC).
Preoperative treatment with this third-generation EGFR tyrosine kinase inhibitor, with or without chemotherapy, was found to improve the major pathologic response rate compared with chemotherapy alone. However, according to Dr. Hendriks, “the additive benefit of neoadjuvant therapy on top of adjuvant osimertinib remains undefined.”
Dr. Hendriks shared these thoughts on the study design: “For the stratification factors, I would have liked to see TP53 [mutation status], because we know these [mutant] tumors respond less to tyrosine kinase inhibitors.” She furthermore questioned whether osimertinib monotherapy was sufficient for a treatment arm, especially considering the “disappointing” results of three single-arm phase II studies of perioperative or neoadjuvant osimertinib (NORA, NEOS, and ClinicalTrials.gov identifier NCT03433469).
Dr. Hendriks noted that the trial was not limited to early-stage cases, with approximately half of patients having stage III disease and one-third having N2 disease—tumors that may benefit from downstaging before surgery. Yet, “surprisingly,” adding chemotherapy to osimertinib did not appear to improve surgical rates, and all groups were found to perform well.
The major pathologic response rates appeared to be similar between the osimertinib arms, leading Dr. Hendriks to pose these questions: “Is it [because of] an imbalance for TP53 or other co-mutations? Does chemotherapy not work? Is major pathologic response the right endpoint for this clinical trial?”
Dr. Hendriks also acknowledged the trend toward improved event-free survival in patients who received osimertinib, particularly in combination with chemotherapy. However, she cautioned, the low use of adjuvant chemotherapy in the monotherapy arm (11%) may be a confounding factor. “We need longer follow-up data for the true effect of the neoadjuvant part,” she remarked.
To further improve outcomes in this patient population, multiple trials are currently ongoing, including those investigating amivantamab-vmjw, antibody-drug conjugates, and other novel therapies. “The real effort should be in the translational part,” Dr. Hendriks noted, “because only if we can truly understand the biology of the disease can we improve our treatment.”
DISCLOSURE: Dr. Chaft has served as a consultant or advisor to Arcus Biosciences, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Oncology, Lilly, Merck, and Sanofi/Regeneron; has received research funding from AstraZeneca/MedImmune, BeOne Medicines (formerly BeiGene), Bristol Myers Squibb, Genentech/Roche, Merck, and Novartis; and has an uncompensated relationship with AstraZeneca. For full disclosures of the other study authors, visit coi.asco.org. Dr. Hendriks has served as a consultant or advisor to AbbVie, Amgen, AnHeart Therapeutics, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, GlaxoSmithKline, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Sanofi, Summit Therapeutics, and Takeda; has participated in a speakers bureau for AstraZeneca, Bayer, Benecke, GlaxoSmithKline, High5Oncology, Lilly, Medimix, MEDtalks, MSD, Pfizer, Sanofi, Takeda Pharmaceuticals, and VJOncology; has received research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Gilead Sciences, Merck, Novartis, Pfizer, Roche/Genentech, Summit Therapeutics, and Takeda Pharmaceuticals; has other relationships with AbbVie, Amgen, AstraZeneca, BluPrint Oncology, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Merck, Merck Serono, Mirati Therapeutics, MSD, Novartis, Pfizer, Roche/Genentech, and Takeda Pharmaceuticals; and has uncompensated relationships with the Dutch Thoracic Group, the European Society for Medical Oncology, the European Organisation for Research and Treatment of Cancer, and NVALT (the Dutch Pulmonary Diseases Association).
REFERENCES
1. Chaft JE, Weder W, He J, et al: Neoadjuvant osimertinib ± chemotherapy (CT) vs CT alone in resectable epidermal growth factor receptor–mutated NSCLC: NeoADAURA. 2025 ASCO Annual Meeting. Abstract 8001. Presented June 2, 2025.
2. He J, Tsuboi M, Weder W, et al: Neoadjuvant osimertinib for resectable EGFR-mutated non–small cell lung cancer. J Clin Oncol. June 2, 2025 (early release online).
