Neoadjuvant Osimertinib Enhances Responses in Resectable EGFR-Mutated NSCLC

Patients who received osimertinib plus chemotherapy achieved an MPR rate of 26% and those treated with osimertinib monotherapy experienced an MPR rate of 25% compared with 2% in the placebo plus chemotherapy arm.

Osimertinib (Tagrisso) monotherapy or with chemotherapy in the neoadjuvant setting displayed an major pathological response (MPR) rate advantage vs chemotherapy in patients with resectable EGFR-mutated non–small cell lung cancer (NSCLC), according to findings from the phase 3 NeoADAURA trial (NCT04351555) presented at the2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Patients who received osimertinib plus chemotherapy (n = 121) achieved an MPR rate of 26% (95% CI, 18%-34%) and those treated with osimertinib monotherapy (n = 117) experienced an MPR rate of 25% (95% CI, 17%-34%) compared with 2% (95% CI, 0%-6%) in the placebo plus chemotherapy arm (n = 120). The pathological complete response (pCR) rates were 4%, 9%, and 0%, respectively. Notably, the MPR benefit with the osimertinib-containing regimens was consistent across predefined patient subgroups. Using the chemotherapy-only arm as the reference, the odds ratios (ORs) for the combination and monotherapy arms were 19.8 (95.002% CI, 4.6-85.3; P < .0001) and 19.3 (99.9% CI, 1.7-217.4; P < .0001), respectively.

“The key takeaway [from this presentation] is that neoadjuvant osimertinib, with or without chemotherapy, should be considered for patients with resectable EGFR-mutated NSCLC for whom neoadjuvant therapy is recommended,” Jamie E. Chaft, MD, thoracic medical oncologist and attending physician, Memorial Sloan Kettering Cancer Center, in New York, New York, said during the presentation.

Examining the Study Design and Baseline Characteristics

NeoADAURA enrolled adult patients with completely resectable EGFR-mutated stage II to IIIB NSCLC. Patients were required to have histologically or cytologically confirmed nonsquamous disease, a World Health Organization (WHO) performance status of 0 or 1, and exon 19 deletions or mutations in L858R. After enrollment, patients were stratified by disease stage (II vs III), race (Chinese vs other Asian vs non-Asian), and EGFR mutation type (exon 19 deletion vs L858R mutation).

Patients were randomly assigned 1:1:1 to receive osimertinib plus chemotherapy, osimertinib monotherapy, or placebo plus chemotherapy. Osimertinib was administered at a dose of 80 mg daily for at least 9 weeks. The chemotherapy regimen consisted of carboplatin for a target area under the curve of 5 or 75 mg/m² of cisplatin, plus pemetrexed at a dose of 500 mg/m², every 3 weeks for 3 cycles. All patients proceeded to surgery after treatment and received investigator’s choice of adjuvant therapy.

The primary end point was MPR per blinded central pathology review. Secondary end points included event-free survival (EFS), pCR rate, nodal downstaging, and safety.

Chaft noted that the baseline patient characteristics were well balanced between the combination, monotherapy, and chemotherapy-only arms; the median ages were 63 years (range, 31-82), 66 years (range, 42-83), and 65 years (range, 36-86), respectively. Most patients in each arm were female (60% vs 65% vs 75%), were never smokers (68% vs 66% vs 78%), had a WHO performance status of 0 (80% vs 79% vs 83%), and had adenocarcinoma (98% vs 100% vs 100%). Patients in each arm also had exon 19 deletions (50% vs 51% vs 51%) and stage III disease by American Joint Committee on Cancer 8th edition criteria (51% vs 50% vs 49%). The mean baseline tumor sizes were 4.2 cm (SD,1.4), 4.0 cm (SD, 1.5), and 4.3 cm (SD, 1.6), respectively.

Secondary End Point Data and Safety Findings

Additional findings from the interim EFS analysis of NeoADAURA revealed that EFS events occurred in 2% (n = 1/62) of patients with an MPR compared with 18% (n = 52/296) of those without an MPR. The 12-month EFS rates in the combination, monotherapy, and chemotherapy-only arms were 93%, 95%, and 83%, respectively. Using the placebo plus chemotherapy arm as the reference, the EFS HRs were 0.50 (99.8% CI, 0.17-1.41; P = .0382) and 0.73 (95% CI, 0.40-1.35) for the combination and monotherapy arms, respectively. The median durations of follow-up in the combination, monotherapy, and chemotherapy-only arms were 14.3 months, 18.3 months, and 14.3 months, respectively.

At the time of surgery, 53% of patients with baseline N2 disease in both the combination (n = 47) and monotherapy (n = 38) arms were downstaged compared with 21% of patients in the chemotherapy-only arm (n = 34). Using the chemotherapy-only arm as the reference, the ORs for the combination and monotherapy arms were 4.8 (95% CI, 1.6-14.0) and 4.2 (95% CI, 1.4-12.1), respectively.

Most patients in the combination (90%), monotherapy (95%), and chemotherapy-only (88%) arms completed definitive surgery. Most patients in each arm underwent R0 resection (91% vs 95% vs 93%). Ninety-one percent of patients in each arm who completed surgery received adjuvant osimertinib. Notably, no patients died within 30 days after surgery.

In terms of safety, any-grade adverse effects (AEs) during the neoadjuvant period in the combination (n = 119), monotherapy (n = 117), and chemotherapy-only (n = 120) arms occurred at respective rates of 92%, 89%, and 93%. Patients in each arm experienced grade 3 or higher AEs (36% vs 13% vs 33%), serious AEs (20% vs 11% vs 20%), and AEs leading to discontinuation of study treatment (9% vs 3% vs 5%). No patients experienced AEs leading to death.

Any-grade AEs that were deemed to be possibly related to study treatment were reported in the combination, monotherapy, and chemotherapy-only arms at rates of 87%, 61%, and 82%, respectively. Grade 3 or higher AEs (29% vs 4% vs 23%) and serious AEs (8% vs 2% vs 8%) of this distinction were present in all arms. The median total durations of osimertinib or placebo exposure were 75.0 days (range, 5-110), 75.0 days (range, 42-103), and 74.5 days (range, 34-103), respectively.

In the combination arm, the most common any-grade AEs reported during the neoadjuvant period included nausea (28%), constipation (27%), and decreased neutrophil count (25%). In the monotherapy arm, common any-grade AEs included diarrhea (26%), constipation (15%), and cough (14%). Common any-grade AEs in the chemotherapy-only arm included constipation (34%), nausea (25%), and anemia (19%).

AEs of special interest in the combination arm included wound complications (2%) and cardiac effects (1%). In the chemotherapy-only arm, these AEs were reported at rates of 0% and 2%, respectively. Patients in the monotherapy arm experienced wound complications (1%), cardiac effects (3%), and interstitial lung disease/pneumonitis (2%).

“The interim EFS [results] trend favorably for each of the osimertinib-containing arms compared with chemotherapy alone [and] fewer patients with an MPR had an EFS event compared with patients without an MPR,” Chaft said in her conclusion. “Over 50% of patients with baseline N2 disease were downstaged at surgery contrasted to 21% with chemotherapy and the safety findings were consistent with the known profiles of the drugs.”

Disclosures: Chaft reported consulting or advisory roles with Arcus Biosciences, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech/Roche, Guardant Health, Janssen Oncology, Lilly, Merck, and Sanofi/Regeneron. She also received research funding from AstraZeneca/MedImmune, BeiGene, Bristol-Myers Squibb, Genentech/Roche, Merck, and Novartis. She also has an uncompensated relationship with AstraZeneca.

Reference

Chaft J, Weder W, He J, et al. Neoadjuvant (neoadj) osimertinib (osi) ± chemotherapy (CT) vs CT alone in resectable (R) epidermal growth factor receptor-mutated (EGFRm) NSCLC: NeoADAURA. J Clin Oncol. 2025;43(suppl 16):8001. doi:10.1200/JCO.2025.43.16_suppl.8001