Osimertinib After Definitive Chemoradiation Is New SOC for Unresectable Stage III EGFR+ NSCLC

Lung Cancer | Image Credit: © Katsyarina
– stock.adobe.com

A trend toward improved overall survival (OS) was seen with osimertinib (Tagrisso) following definitive chemoradiation vs placebo in patients with unresectable stage III non–small cell lung cancer (NSCLC) harboring EGFR mutations, according to updated data from the phase 3 LAURA trial (NCT03521153) presented during the 2025 European Lung Cancer Congress.1

At the time of the primary analysis of the trial, which had a data cutoff date of January 5, 2024, and 20% maturity, the median OS in the osimertinib arm (n = 143) was 54.0 months (95% CI, 46.5-not calculable [NC]) vs not reached (95% CI, 42.1-NC) in the placebo arm (n = 73; HR, 0.81; 95% CI, 0.42-1.56).2

The updated OS analysis had a data cutoff date of November 29, 2024, and 31% maturity, and continued to showcase an improved trend toward OS benefit with osimertinib (median follow-up: 30.4 months) vs placebo (median follow-up: 35.2 months).1 The median OS in the respective arms was 58.8 months (95% CI, 54.1-NC) and 54.0 months (95% CI, 42.1-NC; HR, 0.67; 95% CI, 0.40-1.14; P = .140). The estimated 36-month OS rate in the osimertinib arm was 82% vs 73% in the placebo arm; the 48-month OS rates were 70% and 52%, respectively. Notably, 80% of patients who discontinued study treatment in the placebo arm subsequently received a third-generation EGFR TKI.

“Osimertinib after definitive chemoradiotherapy is the new standard of care for patients with unresectable stage III EGFR-mutated NSCLC,” Suresh S. Ramalingam, MD, FACP, FASCO, of Emory University School of Medicine, Winship Cancer Institute, in Atlanta, GA, said in a late-breaking presentation of the data.

Taking a Closer Look at LAURA

The randomized, double-blind, placebo-controlled, international phase 3 study enrolled 216 adult patients with locally advanced, unresectable, stage III, NSCLC who had not experienced disease progression during or following chemoradiation and who had EGFR exon 19 deletions or exon L858R mutations, a World Health Organization performance status score of 0 or 1, and a maximum interval of 6 weeks between last dose of chemoradiation and randomization. Patients were at least 18 years of age or at least 20 years of age if enrolled in Japan.

Study participants were randomly assigned 2:1 to receive oral osimertinib at 80 mg or placebo once daily until disease progression by blinded independent central review (BICR) or RECIST 1.1, intolerable toxicity, or other discontinuation criteria were met. Notably, open-label osimertinib was offered to both arms following disease progression.

The primary end point of the trial was BICR-assessed progression-free survival (PFS) by RECIST 1.1, and secondary end points comprised OS and central nervous system PFS. Secondary post-progression end points included time to first subsequent treatment (TFST), second PFS (PFS2), and time to second subsequent treatment (TSST).

Previous data from the study showed that osimertinib significantly improved PFS vs placebo in this population.2 The median PFS with osimertinib was 39.1 months (95% CI, 31.5-not estimable) vs 5.6 months (95% CI, 3.7-7.4) with placebo, translating to an 84% reduction in the risk of disease progression or death (HR, 0.16; 95% CI, 0.10-0.24; P < .001). The data supported the FDA’s decision to approve osimertinib in September 2024 for use in adult patients with locally advanced, unresectable, stage III NSCLC whose disease had not progressed during or after concurrent or sequential platinum-based chemoradiation and whose tumors harbored EGFR exon 19 deletions or exon 21 L858R mutations.3 PFS by investigator assessment also proved consistent with the primary end point, with a hazard ratio of 0.19 (95% CI, 0.12-0.29; nominal P < .001) in favor of osimertinib over placebo.1

Baseline characteristics were noted to be well balanced between the treatment arms. Most patients in the osimertinib and placebo arms were female (63%; 58%), never smokers (71%; 67%), Asian (81%; 85%), had stage IIIB disease per American Joint Committee on Cancer eighth edition staging criteria (47%; 52%), had adenocarcinoma histology (97%; 95%), and had received concurrent chemoradiation (92%; 85%).

In the osimertinib arm, the WHO performance score was 0 for 56% and 1 for 44% of patients; in the placebo arm, these respective percentages were 42% and 58%. In the osimertinib arm, 52% of patients had EGFR exon 19 deletion at the time of screening and 48% had L858R mutations; in the placebo arm, these respective percentages were 59% and 41%. The median target lesion size by BICR in the osimertinib arm was 33 mm and was 36 mm in the placebo arm.

Delving Deeper into the Updated Analysis: Subsequent Treatment and Additional Efficacy Data

Of the 143 patients randomized to the osimertinib arm, 48% of patients were still receiving treatment and 52% had discontinued. Thirty percent of patients received subsequent osimertinib after discontinuation of study treatment. Of the 73 patients randomized to the placebo arm, 5% were still receiving placebo and 95% had discontinued. Notably, 78% of these patients received subsequent osimertinib after study treatment discontinuation.

EGFR TKIs were the most common first subsequent treatment, according to Ramalingam. Seventy-three percent of patients on the osimertinib arm who discontinued randomized treatment (n = 74) began a first subsequent treatment (FST). FSTs included radiotherapy (31%), osimertinib (28%), cytotoxic chemotherapy (27%), another EGFR TKI (14%), a VEGF inhibitor (7%), immunotherapy (5%), or other (4%).

Of the patients who discontinued randomized treatment on the placebo arm (n = 69), 87% of patients began a FST. FSTs included osimertinib (77%), radiotherapy (10%), another EGFR TKI (9%), cytotoxic chemotherapy (4%), and a VEGF inhibitor (3%).

Cytotoxic chemotherapy was the most common second subsequent treatment, Ramalingam added.

Osimertinib was also found to lead to clinically meaningful improvements in TFST, PFS2, and TSST vs placebo. The median TFST was 43.8 months (95% CI, 39.9-NC) with osimertinib vs 9.5 months (95% CI, 6.6-11.5) with placebo (HR, 0.13; 95% CI, 0.08-0.21; P < .001). The median PFS2 with osimertinib was 48.2 months (95% CI, 44.4-NC) vs 47.4 months (95% CI, 28.2-NC) with placebo (HR, 0.62; 95% CI, 0.35-1.08; P = .088). The median TSST was not reached vs 47.4 months in the osimertinib and placebo arms, respectively HR, 0.51; 95% CI, 0.28-0.91; P = .022).

“Longer-term outcomes from LAURA further support the benefit of osimertinib over placebo for patients with unresectable stage III EGFR-mutated NSCLC without progression during or following chemoradiotherapy,” Ramalingam concluded.

Disclosures: Dr Ramalingam disclosed institutional research funding from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, and Pfizer, and travel/accomodations/expenses from AbbVie.

References

1. Ramalingam SS, Özgüroglu M, Ahn M-J, et al. Osimertinib after definitive chemoradiotherapy in patients with unresectable stage III EGFRm NSCLC: Updated overall survival analysis from the LAURA study. Presented at: 2025 European Lung Cancer Congress; March 26-29, 2025; Paris, France. Abstract LBA4.
2. Ramalingam SS, Kato T, Dong X, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: primary results of the phase 3 LAURA study. J Clin Oncol. 2024;42(suppl 17):LBA4. doi:10.1200/JCO.2024.42.17_suppl.LBA4
3. FDA approves osimertinib for locally advanced, unresectable (stage III) non-small cell lung cancer following chemoradiation therapy. FDA. September 25, 2024. Accessed March 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-locally-advanced-unresectable-stage-iii-non-small-cell-lung-cancer