Final data from 2 phase I expansion studies confirmed the efficacy of frontline osimertinib (Tagrisso) in patients with <em>EGFR</em>-positive non­–small cell lung cancer, investigators reported during the 2019 European Lung Cancer Congress.
James Chih-Hsin Yang, MD, PhD
Final data from 2 phase I expansion studies confirmed the efficacy of frontline osimertinib (Tagrisso) in patients withEGFR-positive non­small cell lung cancer (NSCLC), investigators reported during the 2019 European Lung Cancer Congress. 1
In expansion cohort data from the phase I AURA trial, at a median follow-up of 19.1 months, the objective response rate (ORR) was 67% (95% CI, 47-83) in patients receiving osimertinib at an 80 mg dose, and the ORR was 87% (95% CI, 69-96) in patients receiving an elevated dose of 160 mg of osimertinib. The ORR was 77% (95% CI, 64- 87) in the overall patient cohort with both doses.
The median best percentage change overall in target lesion size was -48% (range, -100% to +32%); the median change in the low-dose cohort was -46% (range, -81% to +32%), and the median change was -59% (range, -100% to -16%) in the higher dose cohort.
“Osimertinib is a third-generation, CNS-active EGFR-tyrosine kinase inhibitor that potently and selectively inhibits bothEGFR-TKI sensitizing (EGFRm) andEGFRT790M resistance mutations,” explained lead author James Chih-Hsin Yang MD, director and professor of the Graduate Institute of Oncology at the National Taiwan University in Taipei city, Taiwan.
“Final efficacy and safety data from the first-line cohorts of the AURA study support the use of osimertinib for patients withEGFRmutationpositive NSCLC,” added Yang.
The FDA approved frontline osimertinib in April 2018 for the treatment of patients with NSCLC whose tumors harborEGFRmutations (exon 19 deletions or exon 21 L858R substitution mutations). The approval was primarily based on the phase III FLAURA study, in which frontline osimertinib reduced the risk of progression or death by 54% versus standard therapy with either erlotinib (Tarceva) or gefitinib (Iressa).2The median progression-free survival (PFS) was 18.9 months with osimertinib compared with 10.2 months for standard treatment (HR, 0.46; 95% CI, 0.37-0.57;P<.0001).
The expansion cohorts in the AURA study enrolled 60 treatment-naïve patients with locally advanced/metastaticEGFRmutation-positive NSCLC. Key eligibility criteria included measurable disease and WHO performance status 0/1. Patients with stable asymptomatic CNS metastases were eligible. The primary endpoint was ORR, with secondary endpoints including PFS and safety.
Thirty patients were treated with osimertinib at a dose of 80 mg once daily and 30 patients received osimertinib at 160 mg once daily. Seventy-five percent of patients were female, and 72% were Asian. At study entry,EGFRex19del mutation was detected in 43% of patients, with 48% of patients havingEGFRL858R mutations. Five patients wereEGFRT790M mutationpositive by central test.
At the data cutoff of May 1, 2018, 11 patients remained on osimertinib; of these 13% and 23% of patients were in the 80 mg and 160 mg cohorts, respectively. The median duration of response (DOR) was 19.3 months (95% CI, 12.2-24.7) in the lower dose cohort, compared to 16.7 months (95% CI, 9.7-29.0) in the higher dose cohort and 18.0 months (95% CI, 12.5-24.7) in the overall cohort. Forty-eight patients overall experienced disease progression or died at this time point.
The estimated proportion of overall patients remaining in response at 36 months was 25% (95% CI, 14-38) and 18% (95% CI, 7-32) at 48 months.
At 78% data maturity, the median PFS in the 80 mg, 160 mg, and overall cohorts was 22.1 months (95% CI, 12.3-30.2), 19.3 months (95% CI, 11.1-26.0), and 20.5 months (95% CI, 13.7-26.1). respectively.
Dose reductions were mostly due to adverse events (AEs) and were required in 27% and 60% of patients receiving osimertinib at 80 mg and 160 mg, respectively.
Any grade AEs occurred in all patients in the overall population. Serious AEs occurred in 45% of patients and grade ≥3 AEs were reported in 68% of patients overall.
Diarrhea (3%) was the most commonly reported grade ≥3 AE among patients receiving osimertinib at 80 mg. In the 160-mg cohort, the most common grade ≥3 AEs included diarrhea in 7% of patients, stomatitis in 3%, and paronychia in 10%.
AEs led to treatment discontinuation in 13%, 10%, and 12% of patients in the 80-mg cohort , 160-mg cohort, and overall, respectively. One patient in the osimertinib 160-mg group died due to an AE.
“Our findings are consistent with previous reports that demonstrate first-line osimertinib efficacy in patients withEGFRmutationpositive advanced NSCLC. PFS was prolonged at both doses; however, better tolerability was observed at the 80-mg dose,” Yang summarized.