Osimertinib After Chemoradiotherapy Shows Manageable Safety in NSCLC

New safety data from the phase 3 LAURA trial (NCT03521154) support osimertinib (Tagrisso) as a standard-of-care option after definitive chemoradiotherapy (CRT) in patients with unresectable stage III EGFR-mutated non–small cell lung cancer (NSCLC), according to an in-depth safety analysis published in Lung Cancer.¹

The analysis, which builds on previously reported efficacy results showing a median progression-free survival of 39.1 months with osimertinib vs 5.6 months with placebo (HR, 0.16; P <.001),² found that adverse events (AEs) with osimertinib were consistent with the drug's known safety profile and that of CRT, with no new safety signals identified.¹

Study Design

LAURA is a global, double-blind, randomized trial that enrolled patients aged 18 years or older (20 years or older in Japan) with unresectable stage III EGFR-mutated NSCLC (exon 19 deletion or L858R) who had not progressed during or after definitive concurrent or sequential CRT.

Between August 2018 and July 2022, 216 patients were randomized 2:1 to receive oral osimertinib 80 mg (n = 143) or placebo (n = 73) once daily, stratified by CRT strategy, disease stage, and inclusion in the China cohort. Treatment continued until radiologic progression confirmed by blinded independent central review or another discontinuation criterion was met; patients in both arms could receive open-label osimertinib after progression. Median total treatment exposure was 24.0 months with osimertinib and 8.3 months with placebo.¹

Safety Findings

AEs of any cause occurred in 98% of patients receiving osimertinib and 88% of those receiving placebo. The most frequently reported AEs with osimertinib vs placebo were radiation pneumonitis (48% vs 38%), diarrhea (36% vs 14%), and rash (24% vs 14%). Grade 3 or higher AEs occurred in 35% of patients on osimertinib compared with 12% on placebo, and serious AEs occurred in 38% vs 15%, respectively. Rates of AEs leading to death were similar between arms (2% vs 3%).

AEs led to treatment interruption in 56% of osimertinib-treated patients vs 25% of placebo-treated patients, and to discontinuation in 13% vs 5%.¹ After adjusting for the longer treatment exposure in the osimertinib arm, exposure-adjusted rates of grade 3 or higher AEs (18 vs 13 per 100 patient-years) and serious AEs (20 vs 15 per 100 patient-years) were similar between groups. AEs for which exposure-adjusted rates were notably higher with osimertinib included diarrhea, paronychia, stomatitis, and decreased white blood cell count—all previously identified adverse reactions associated with the drug.

Radiation pneumonitis, the most common AE overall, was predominantly grade 1 or 2, with no grade 4 or 5 events in either arm; nearly all cases occurred within the first 18 weeks of treatment. Under protocol-mandated toxicity management guidelines, most osimertinib-treated patients with radiation pneumonitis (n = 60/69; 87%) were able to continue or restart treatment without recurrence. Consistent with prior literature on radiation-related lung toxicity, radiation pneumonitis was more common among Asian patients (57% with osimertinib, 44% with placebo) than non-Asian patients (11% and 9%, respectively).

Interstitial lung disease occurred in 8% of osimertinib-treated patients and 1% of placebo-treated patients, was mainly grade 1 or 2, and was manageable with prespecified guidelines. Cardiac safety findings were reassuring: a single case of chronic cardiac failure, considered unrelated to treatment, was reported in the osimertinib arm, and left ventricular ejection fraction decreases were infrequent and similar between arms.¹

Clinical Implications

The authors concluded that osimertinib after definitive CRT has an acceptable and manageable safety and tolerability profile, with a positive benefit-risk balance, reinforcing its role as the standard of care for this patient population. They noted a limitation that the analysis was confined to the primary data cutoff and that longer-term safety data, particularly regarding cardiac toxicity that can result from CRT, would be of interest.

The findings align with safety data from other pivotal osimertinib trials, including FLAURA (NCT02296125) and ADAURA (NCT02511106), and with the phase 3 PACIFIC trial (NCT02125461) of durvalumab after CRT in unselected stage III NSCLC, which similarly reported higher rates of pneumonitis among Asian patients.^3-5

Learn more about the LAURA study.

REFERENCES

1. Kato T, Dong X, Takahashi T, Soparattanapaisarn N, et al. Osimertinib after definitive CRT in unresectable stage III EGFR-mutated NSCLC: safety outcomes from the phase III LAURA study. Lung Cancer. 2026 Jun 6;218:109486. doi: 10.1016/j.lungcan.2026.109486. Epub ahead of print. PMID: 42296617.

2. Lu S, Kato T, Dong X, Ahn MJ, et al. Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. N Engl J Med. 2024 Aug 15;391(7):585-597. doi: 10.1056/NEJMoa2402614. Epub 2024 Jun 2. PMID: 38828946.

3. Liu T, Li S, Ding S, Qiu J, et al. Comparison of post-chemoradiotherapy pneumonitis between Asian and non-Asian patients with locally advanced non-small cell lung cancer: a systematic review and meta-analysis. EClinicalMedicine. 2023 Sep 25;64:102246. doi: 10.1016/j.eclinm.2023.102246. PMID: 37781162; PMCID: PMC10539643.

4. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8. PMID: 28885881.

5. Vansteenkiste JF, Naidoo J, Faivre-Finn C, et al. Symptomatic Pneumonitis With Durvalumab After Concurrent Chemoradiotherapy in Unresectable Stage III NSCLC. JTO Clin Res Rep. 2024 Jan 18;5(3):100638. doi: 10.1016/j.jtocrr.2024.100638. PMID: 38455595; PMCID: PMC10918565.