The phase III ADAURA trial previously found that adjuvant use of osimertinib improved disease-free survival for completely resected EGFR-mutated non–small cell lung cancer (NSCLC) in patients with stage IB, II, or IIIA disease.1 The final analysis of ADAURA, which was presented at the 2023 ASCO Annual Meeting,2 showed a statistically significant and clinically meaningful improvement in overall survival, according to lead investigator Roy S. Herbst, MD, PhD, Deputy Director of Yale Cancer Center. Survival results from ADAURA were published in The New England Journal of Medicine to coincide with the presentation at the ASCO meeting.3
Roy S. Herbst, MD, PhD
At 5 years of follow-up, patients with stage IB to IIIA NSCLC who received adjuvant osimertinib—a third-generation EGFR tyrosine kinase inhibitor—had a 51% lower risk of death compared with those treated with placebo (P < .0001). Patients with stage II to IIIA disease who were treated with osimertinib also had a 51% lower risk of death compared to placebo (P = .0004). Median overall -survival was not reached in patients with stage IB-IIIIA or in patients with stage II-IIIA.
In patients with stage IB to IIIA NSCLC, the 5-year overall survival rate was 88% with osimertinib after surgery vs 78% with placebo. In patients with stage II to IIIA NSCLC, the 5-year overall survival rate was 85% with osimertinib vs 73% with placebo. “Before this study, all we had as adjuvant treatment for NSCLC was standard chemotherapy,” said Dr. Herbst.
“About 3 years ago, ADAURA demonstrated statistically significant and clinically meaningful disease-free survival vs placebo. Currently, we see a statistically significant overall survival benefit with adjuvant osimertinib in the primary treatment of stage IB to IIIA NSCLC vs placebo,” continued Dr. Herbst. “Survival is considered the gold standard for efficacy in clinical trials. The results of ADAURA will broaden treatment access for patients with EGFR-mutated NSCLC.”
“The practice-changing disease-free survival data from our primary analysis together with the overall survival benefits reported instill confidence that adjuvant osimertinib is the standard of care for patients with resected EGFR-mutated stage IB to IIIA NSCLC. These results emphasize the importance of screening our patients and giving them the best drugs early in the course of their disease before treatment,” Dr. Herbst added. “We need to use the right drug, in the right patient, at the right time,” he emphasized.
Additional Commentary
Echoing these sentiments, ASCO expert Nathan Pennell, MD, PhD, FASCO, Director of the Lung Cancer Medical Oncology Program at the Taussig Cancer Center, Cleveland Clinic, commented: “It’s hard to convey how important this finding is and how long it has taken us to get here. We have been using one-size-fits-all adjuvant chemotherapy for every patient with NSCLC despite a decade of advances in targeted treatment for select groups of patients that result in dramatically better outcomes.”
“Adjuvant osimertinib unequivocally improves survival in people with resected EGFR-mutated NSCLC. This should be the new standard of care for these patients.”— Nathan Pennell, MD, PhD, FASCO
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Dr. Pennell continued: “In 2020, the standard of care for curable lung cancer was still chemotherapy as our preferential treatment. That changed with ADAURA showing improved disease-free survival, but not all oncologists adopted it because disease-free survival does not always translate to overall survival. Now these highly statistically significant overall survival data firmly put to rest the question of whether we should treat people with our best treatment first. Adjuvant osimertinib unequivocally improves survival in people with resected EGFR-mutated NSCLC. This should be the new standard of care for these patients.”
Background
Lung cancer is the leading cause of cancer death worldwide. NSCLC accounts for about 80% of all lung cancers, and about one-third are found when they are still resectable. EGFR mutations are present in up to 30% of all cases.
“EGFR is an on-off switch. When it is turned on, it causes cancer to grow. Osimertinib is a ‘key and a lock’ for EGFR. It differs and is more potent than other EGFR inhibitors. It can penetrate the brain and is less toxic, with less rash and diarrhea [than other drugs in its class],” Dr. Herbst explained.
Study Details and Results
The global randomized, placebo-controlled ADAURA study was conducted in 26 countries across Europe, Asia-Pacific, North America, and South America. Patients had stage IB, II or IIIA EGFR-mutated NSCLC harboring either the exon 19 deletion or the L858R mutation in EGFR. Approximately two-thirds of patients in the study were women. The age of participants ranged from 30 to 86, with a median age of about 63. About two-thirds of patients had no smoking history, and two-thirds were Asian.
A total of 682 patients were randomly assigned 1:1 to receive osimertinib at 80 mg/d or placebo and were treated until disease progression, for 3 years, or a criterion for treatment discontinuation was met. The primary endpoint was disease-free survival in stage II to IIIA, and key secondary endpoints were disease-free survival in stage IB to IIIA as well as safety.
In the primary analysis of ADAURA, osimertinib significantly improved disease-free survival vs placebo, improving it by 83% This benefit was over an additional 2 years of follow-up, improving the likelihood of disease-free survival by 73%.
The overall survival benefit of osimertinib vs placebo was observed consistently across all predefined subgroups, including stage IB, II, and IIIA, and regardless of receipt of prior chemotherapy.
There were no new safety signals in the overall survival analysis. Adverse events were reported to be mild or moderate. Planned treatment was delivered to 66% of those in the osimertinib group and 41% of those in the placebo group. Grade 3 or higher adverse events of any cause were reported in 23% of the osimertinib-treated group vs 14% of the placebo group. Treatment discontinuations because of adverse events were reported in 13% of the osimertinib group vs 3% of the placebo group.
Future steps will include analysis of tumor tissue and circulating tumor DNA profiling for measurable residual disease. Osimertinib is also being studied in stage IA disease, in the neoadjuvant setting, and for 5-year duration of adjuvant treatment in stage II to IIIB disease.
DISCLOSURE: The study was funded by AstraZeneca. Dr. Herbst has served on the advisory board of Immunocore and Junshi Biosciences; has received consulting fees from Junshi Biosciences, AstraZeneca, Bolt Biotherapeutics, Bristol Myers Squibb, Cancel Therapeutics, Checkpoint Therapeutics, Cybrexa Therapeutics, Dynamicure Biotechnology, eFFECTOR Therapeutics, Eli Lilly, EMD Serono, Genentech, Gilead Sciences, HiberCell, I-Mab Biopharma, Immune-Onc Therapeutics, Immunocore, Janssen, Johnson and Johnson, Loxo Oncology, Merck and Company, Mirati Therapeutics, Nexcure, Novartis, Ocean Biomedical, Oncocyte Corp, Oncternal Therapeutics, Pfizer, Regeneron Pharmaceuticals, Revelar Biotherapeutics, Ribbon Therapeutics, Roche, Sanofi, and Xencor; and has received research funding from AstraZeneca, Eli Lilly, Genentech/Roche, and Merck and Company. Dr. Pennell has served as a consultant or advisor for Anheart Therapeutics, Bayer, Genentech, Janssen Oncology, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, ResistanceBio, Sanofi/Regeneron, Summit Therapeutics, Takeda, and Vial CRO; and has received research funding from Anheart Therapeutics, AstraZeneca, Bristol Myers Squibb, Loxo, Merck, Mirati Therapeutics, Navire, Sanofi, and Spectrum Pharmaceuticals.
REFERENCES
1. Wu YL, Tsuboi M, He J, et al: Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med 383:1711-1723, 2020.
2. Herbst RS, Tsuboi M, John T, et al: Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with EGFR-mutated stage IB–IIIA non-small cell lung cancer. 2023 ASCO Annual Meeting. Abstract LBA3. Presented June 4, 2023.
3. Tsuboi M, Herbst RS, John T, et al: Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med. June 4, 2023 (early release online).
