FDA Grants Breakthrough Therapy Designation to Osimertinib in EGFR+ Lung Cancer

The FDA granted Breakthrough Therapy designation to osimertinib as adjuvant treatment of patients with stage IB-IIIA EGFR-mutated non–small cell lung cancer following complete tumor resection with curative intent.

The FDA has granted a Breakthrough Therapy designation to osimertinib (Tagrisso) as adjuvant treatment of patients with stage IB-IIIA EGFR-mutated non–small cell lung cancer (NSCLC) following complete tumor resection with curative intent, AstraZeneca announced in a press release.1

The Breakthrough Therapy designation for osimertinib was granted on the basis of positive results from the phase 3 ADAURA clinical trial (NCT02511106), which were presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. The trial showed a statistically significant and clinically meaningful improvement in disease-free survival (DFS) for this patient population.

“The historic magnitude of the DFS benefit seen in ADAURA speaks to the impact osimertinib has on the lives of patients with EGFR-mutated NSCLC after receiving surgery and appropriate adjuvant chemotherapy,” the study’ lead investigator, Roy Herbst, MD, PhD, Ensign Professor of Medicine, professor of Pharmacology, chief of Medical Oncology, and associate Director for Translational Research at Yale Comprehensive Cancer Center, told Targeted Oncology.

In the study, osimertinib was administered to 339 patients at a dose level of 80 mg, once daily and compared with placebo. A total of 343 patients were treated in the placebo arm. Both study arms continued treatment until disease recurrence, completion, or due to other discontinuation criteria being met. Follow-up was conducted on weeks 12 and 24, followed by every 24 weeks to 5 years and yearly, until disease recurrence. After recurrence, follow-up was every 24 weeks for 5 years, then yearly.1,2

The study population was stratified by stage of disease, type of EGFR mutation (Exon 19 deletion [Ex19del] vs. L858R), and race (Asian vs. non-Asian). According to the American Joint Committee on Cancer staging, 31 patients in the osimertinib arm were diagnosed as stage IB at baseline, while 35 were stage II, and 34 were stage IIIA. In the placebo group, 31 patients were stage IB, 34 were stage II, and 35 were stage IIIA. Most patients in the study had EGFR Ex19del mutations rather than EGFR L858R mutations, including 55 patients in the osimertinib arm and 56 in the placebo arm. This left 45 patients in the osimertinib arm with EGFR L858R mutations and 44 in the placebo arm. The majority of the patient population was Asian versus non-Asian, including 64 in each arm, while 36 in each arm were non-Asian.

The median DFS in patients with stage II/IIIA disease, the study’s primary end point, was not reached in the osimertinib arm (95% CI, 38.8-not calculated) compared with 20.4 months (95% CI, 16.0-24.5) in the placebo arms (HR, 0.17; 95% CI, 0.12-0.23; P <.0001). The data had reached 33% maturity at the time they were presented during ASCO. In the overall study population, the median DFS was also not reached in the osimertinib arm compared with 28.1 months (95% CI, 22.1-35.8) in the placebo arm (HR, 0.21; 95% CI, 0.16-0.28; P <.0001). The data were 29% mature at the time they were reported.

The subgroup analysis showed good DFS hazard ratios, which were consistent with the primary analysis. The hazard ratios ranged from 0.21 to 0.50. The clinical benefit favoring osimertinib was observed across the subgroup populations.

The 2-year DFS rate was also calculated by stage, showing a rate of 87% 95% CI, 77%-93%) in patients with stage IB disease who received osimertinib compared to 73% (95% CI, 62%-81%) in the placebo arm HR, 0.50; 95% CI, 0.25-0.96). For stage II patients, the DFS rate was 91% (95% CI, 82%-95%) in the osimertinib arm versus 56% (95%. CI, 45%-65%) in the placebo arm (HR, 0.17; 95% CI, 0.08-0.31). Finally, among patients with stage IIIA disease, the DFS rate was 88% (95% CI, 79%-94%) in the osimertinib arm versus 32% (95% CI, 23%-42%) in the placebo arm (HR, 0.12; 95% CI, 0.07-0.20).

Most patients in the study experienced an adverse event (AE), regardless of study treatment. Any-grade AEs specifically occurred in 97% of patients who received osimertinib compared with 89% who received placebo. Grade 3 or higher AEs were observed in 20% of the osimertinib group compared with 145 of the placebo group. Serious AEs were also seen in the study in 16% of the osimertinib-treated patients and 13% of those who received placebo.

AEs of any grade led to discontinuation of treatment in 11% of patients in the osimertinib arm versus 4% in the placebo arm. Dose reductions caused by any-grade AEs occurred in 7% of the osimertinib arm and 1% of the placebo arm.

The most common AEs observed in osimertinib group versus the placebo group were diarrhea (46% vs. 19%), paronychia (25% vs. 1%), dry skin (23% vs. 6%), and pruritis (19% vs. 9%), respectively. Overall osimertinib demonstrated a tolerable safety profile.

The Breakthrough Therapy Designation is another step towards osimertinib receiving FDA approval for this indication. Due to the high recurrence rate among these patient, the drug has the potential to fill a treatment gap in the landscape.

“The ADAURA trial has shown osimertinib to be a new practice changing therapy for patients with EGFR-positive stage I-III NSCLC- preventing recurrent in both local and metastatic sites.”


1. Tagrisso granted Breakthrough Therapy Designation in the US for the adjuvant treatment of patients with Stage IB-IIIA EGFR-mutated lung cancer. News release. AstraZeneca. July 30, 2020. Accessed July 30, 2020. https://bit.ly/3hTXurg

2. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020: 38 (suppl; abstr LBA5). doi: 10.1200/JCO.2020.38.18_suppl.LBA5