Real-World Study Expands Benefit-Risk Assessment Data for Osimertinib in EGFR+ NSCLC

The benefits and risks of osimertinib as second- or later-line treatment of patients with EGFR-positive non–small cell lung cancer that were reported when the agent was first approved, have now been confirmed, according to data from a real-world study conducted in Japan.

The benefits and risks of osimertinib (Tagrisso) as second- or later-line treatment of patients with epidermal growth factor receptor (EGFR)-positive non–small cell lung cancer (NSCLC) that were reported when the agent was first approved, have now been confirmed, according to data from a real-world study conducted in Japan.

“In this large post-marketing investigation in greater than 3500 Japanese patients with EGFR T790M-positive NSCLC, osimertinib 80 mg once daily provided clinical benefit to patients with no new safety concerns. These results were compared with clinical trial data and other real-world analyses of osimertinib in this patient population and support the currently established benefit-risk assessment of this important therapeutic agent,” wrote the study authors led by Yuichiro Ohe, MD.

Before the FDA approval of osimertinib as treatment of EGFR-positive NSCLC, the agent was approved by the Japanese regulatory authorities in 2016 in the second- or later-line settings for patients who progressed on prior EGFR tyrosine kinase inhibitors (TKIs). In 2018, Japan also approved osimertinib in the frontline setting. After the drug was approved and marketed in Japan, the Japan-local all-patient Clinical Experience Investigation (CEI) was launched to assess the adverse events (AEs), efficacy, and the occurrence of interstitial lung disease (ILD) in real-world patients with EGFR-positive NSCLC treated with osimertinib.

The post-marketing study of 3578 patients (NCT02756039) was conducted at 718 sites between the time of the first approval of osimertinib in Japan through August 31, 2018. The study was designed to observe patients for 12 months and use case report forms to obtain formal data on osimertinib outcomes in this patient population. Patients enrolled in the study were required to have EGFR T790M mutation-positive inoperable or recurrent NSCLC that is resistant to EGFR TKI, which slightly differed from the label indication for osimertinib in Japan.

Demographics and disease characteristics obtained at baseline showed that the majority of the patient population (71.9%) was 65 years old or above, and male (66.3%). Body mass index (BMI) was measured at baseline and patients mostly ranged from ≥ 18.5 kg/m2 to < 2.5 kg/m2. Just over 70% of patients in the study were not smokers, but 29.7% were smokers.

In terms of the World Health Organization (WHO) performance status, 81.2% of patients scored at ≤ 1, while the remaining 18.8% scored at ≥ 2. Most patients were beyond the second-line setting, including 50.1% who were in the third-line and 49.2% who were in the fourth-line. The treatment setting was unknown for the 24 remaining patients. The EGFR mutation status was T790M for 96.9% of the study population, but 49.2% had an EGFR exon 19 deletion, 34.7% had an EGFR L858R mutation, and 2.5% had other mutations. Additionally, the majority of patients were stage IV (86.2%) and had adenocarcinoma histology (98.5%).

The safety analysis went on for a median period of 343.0 days (range, 1-764). AEs were reported in 2079 (58.1%) patients. In total, there were 42 AEs reported. A large number of patients (624, 30.0%) recovered from the AEs, 825 (39.7%) were improving, and 547 (26.3%) still had present AEs. Fifty-two patients (2.5%) died during the study and the status of 22 patients (1.1%) was reported as unknown.

The most frequently reported AEs were diarrhea (10.9%) and paronychia (10.3%). Any-grade ILD occurred in 245 patients (6.8%), and grade ≥ 3 ILD was observed in 104 patients (2.9%). Twenty-nine (11.8%) of the patients with ILD died during the study.

A total of 3563 patients were included in the efficacy analysis. The objective response rate (ORR) achieved with osimertinib was 69.9% (95% CI, 68.4%-71.4%). Of the patients who responded to treatment, complete responses (CRs) were reported in 119 patients (3.3%), partial responses (PRs) were reported in 2373 patients (66.6%), and stable disease (SD) was reported in 598 patients (16.8%). The disease control rate (DCR) was 86.7% (95% CI, 85.6%-87.8%). Based on patient characteristics taken at baseline, patients with a WHO performance score of 0 to 1 had a higher ORR and DCR compared with those with a WHO performance score of 2 through 4. Patients with asymptomatic central nervous system (CNS) metastasis also fared better in terms of response compared with patients who symptomatic CNS metastasis. Differences were not observed in patients according to age or type of EGFR mutation.

Osimertinib led to a median progression-free survival (PFS) of 12.3 months (95% CI, 12.2-12.6), with PFS rates of 77.4% (95% CI, 75.9%-78.9%) at month 6 and 53.2% (95% CI, 51.3%-55.1%) at 1 year. Notably, patients who were ≥75 years had a longer PFS compared with younger patients, and patients with asymptomatic CNS metastasis had a longer PFS compared with patients who had symptomatic CNS metastasis.

The overall survival rate at 6 months in the overall population was 88.3% (95% CI, 87.2%-89.4%), and at 12 months, the OS rate was 75.4% (95% CI, 73.8%-77.0%).

“The results of this CEI confirm and expand the currently established benefit-risk assessment of osimertinib in patients with EGFR T790M-positive NSCLC and are expected to inform future therapeutic decision-making for patients who have traditionally had few available treatment options,” wrote Ohe et al.


Ohe Y, Kato T, Sakai F, et al. Real-world use of osimertinib for epidermal growth factor receptor T790M-positive non-small cell lung cancer in Japan. Jpn J Clin Oncol. 202; 50(8): 909-919. doi: 10.1093/jjco/hyaa067