Compared with placebo, adjuvant osimertinib significantly improved disease-free survival in patients with stage IB to IIIA EGFR-mutated non–small cell lung cancer (NSCLC) who underwent complete resection of primary tumor and received chemotherapy if indicated. Reported during the Plenary Program of the ASCO20 Virtual Scientific Program, these findings are from the first interim analysis of the phase III ADAURA trial.¹

In patients with stage II to IIIA NSCLC, osimertinib improved disease-free survival by 83% vs placebo (P < .0001). The 2-year disease-free survival rate in patients with stage II to IIIA disease was 90% with osimertinib vs 44% with placebo. When adding in earlier-stage disease, in the overall study population of stage IB to IIIA NSCLC, osimertinib improved disease-free survival by 79% vs placebo (P < .0001), and the 2-year disease-free survival rate was 89% vs 53%, respectively.

“This trial is a home run. It exceeded our already high expectations,” stated lead investigator Roy S. Herbst, MD, PhD, Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital and Associate Cancer Center Director for Translational Research at Yale Cancer Center, New Haven, Connecticut.

“The disease-free survival data suggest that osimertinib will be useful in patients with stage II and III disease and in those with stage IB disease as well.”

— Roy S. Herbst, MD, PhD

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“Adjuvant osimertinib is the first targeted agent in a global randomized trial to show a statistically significant and clinically meaningful improvement in disease-free survival in patients with stage IB/II/IIIA EGFR-mutated NSCLC after complete tumor resection and adjuvant chemotherapy, when indicated. Adjuvant osimertinib is a highly effective, practice-changing treatment for patients with stage IB to IIIA NSCLC after complete tumor resection,” Dr. Herbst said. Results were so positive in favor of osimertinib that the independent data monitoring committee recommended unblinding the trial early.

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor noted for its superior efficacy compared with the earlier-generation EGFR tyrosine kinase inhibitors gefitinib or erlotinib; it is distinct for its activity against the EGFR T790M mutation and against brain metastases. Patients who present with stage I to IIIA NSCLC represent 30% of lung cancers, and up to 20% of them are EGFR-positive. Surgery is the primary treatment, and adjuvant chemotherapy is standard of care for patients with resected stage II, III, and selected IB disease. However, even with the best treatments available, the improvement in 5-year survival is only about 5% with platinum-based chemotherapy, Dr. Herbst noted. In addition, recurrence rates are high. At 5 years, the recurrence rate ranges from 45% in stage I disease to 76% in stage III disease.

Osimertinib is currently approved by the U.S. Food and Drug Administration as first-line treatment of EGFR-mutated advanced NSCLC and second-line treatment of EGFR T790M mutation–positive advanced NSCLC. The ADAURA trial results will likely move osimertinib up from the front-line setting to earlier in the adjuvant setting in patients who have undergone complete resection.

Study Details

ADAURA is a phase III, randomized, double-blind, placebo-controlled trial conducted in the United States, China, Korea, Australia, and Europe. The study included patients with primary nonsquamous NSCLC stage IB, II, or IIIA with confirmed EGFR mutation. Patients had fully recovered from surgery. Postoperative chemotherapy was given if indicated.

Patients (n = 682) were randomly assigned in a 1:1 ratio to receive osimertinib at 80 mg/d or placebo and treated for up to 3 years until disease progression or unacceptable toxicity. Participants were stratified according to disease stage (IB, II, or III), mutation type (ex19 del or L858R), and race (Asian vs non-Asian).

Baseline demographic and disease characteristics were well balanced between the two treatment arms. Approximately 31% had stage IB disease, and 69% had stage II/IIIA disease; 72% were female; 56% had ex19 del, and 44% had L858R.

Key Results

The median disease-free survival was not reached in patients with stage II to IIIA treated with osimertinib vs 20.4 months with placebo (hazard ratio [HR] = 0.17; P < .0001). The 2-year disease-free survival rate was 90% with osimertinib vs 44% with placebo. When patients with stage IB disease were added into the analysis, the median disease-free survival in this overall population was not yet reached in the osimertinib-treated group vs 28.1 months in those who received placebo (HR = 0.21; P < .0001). The 2-year disease-free survival rate was 89% with osimertinib vs 53% with placebo.

“The disease-free survival results are extraordinary. The disease-free survival data suggest that osimertinib will be useful in patients with stage II and III disease and in those with stage IB disease as well,” Dr. Herbst commented. The subgroup analysis found that the disease-free survival benefit of osimertinib extended to every category, including sex, age, smoking status, race, stage of disease, EGFR mutation type, and prior chemotherapy. “You almost never see this in subgroup analysis of studies,” Dr. Herbst noted.

The median duration of exposure to osimertinib was 22 months, confirming the ability to give the drug for a long period of time. The safety profile was consistent with what is known about osimertinib. The main side effects of osimertinib, as well as other EGFR tyrosine kinase inhibitors, included diarrhea, dry skin, pruritus, cough, and stomatitis. They were mainly grade 1 and 2, and the incidence of grade 3 adverse events was extremely low in patients randomly assigned to osimertinib (maximum of 1%–2%). The rate of interstitial lung disease, which is a concern in Asian patients, was just 3% and all low grade.

At the end of his presentation, Dr. Herbst referred to what George Sledge, MD, said when trastuzumab was first introduced in the early-stage setting at the 2005 ASCO Annual Meeting. With osimertinib, “biology has spoken again,” Dr. Herbst stated. “It’s the metastasis that kills patients. Targeted drugs like this one, based on biology with excellent [central nervous system] penetration, specifically kill tumors and prevent metastasis, allowing our patients to live longer with a better quality of life,” he added. 

DISCLOSURE: The study was funded by AstraZeneca. Dr. Herbst is a consultant for AbbVie Pharmaceuticals, Armo Biosciences, AstraZeneca, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serrano, Genentech/Roche, Genmab, Halozyme, Heat Biologics, Infinity Pharmaceuticals, Loxo Oncology, Merck, Nektar, Neon Therapeutics, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, Symphogen, Tesaro, and Tocagen; has received research support from AstraZeneca, Eli Lilly, and Merck; and is a member of the Board of Directors (nonexecutive/independent) for Junshi Biosciences.

REFERENCE

1. Herbst RS, Tsuboi M, John T, et al: Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation positive NSCLC after complete tumor resection: ADAURA. ASCO20 Virtual Scientific Program. Abstract LBA5. Presented in premeeting press briefing on May 26, 2020.