Treatment with adjuvant osimertinib produced a statistically significant and clinically meaningful improvement in overall survival compared with placebo in patients with resected, EGFR-mutated, stage IB to IIIA non–small cell lung cancer.
Treatment with adjuvant osimertinib (Tagrisso) produced a statistically significant and clinically meaningful improvement in overall survival (OS) compared with placebo in patients with resected, EGFR-mutated, stage IB to IIIA non–small cell lung cancer (NSCLC), according to data from the phase 3 ADAURA trial (NCT02511106) presented at the 2023 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine.1,2
Findings showed that at a median follow-up of 61.7 months in the osimertinib arm and 60.4 months in the placebo arm, patients with stage II/IIIA NSCLC in the primary population who were treated with osimertinib (n = 233) experienced a 51% reduction in the risk of death vs those treated with placebo (n = 237; HR, 0.49; 95.03% CI, 0.33-0.73; P = .0004). The 36-, 48-, and 60-month OS rates in the osimertinib arm were 94%, 91%, and 85%, respectively. In the placebo arm, those rates were 86%, 80%, and 73%, respectively.
In the overall population of patients with stage IB, II, or IIIA NSCLC, osimertinib led to a 51% reduction in the risk of death vs placebo (HR, 0.49; 95.03% CI, 0.34-0.70; P < .0001).
“Osimertinib is the first targeted therapy to show significant OS benefit in the adjuvant setting. These findings reinforce adjuvant osimertinib as standard of care for patients with resected EGFR-mutated stage IB to IIIA NSCLC and highlight the importance of screening and EGFR mutation testing as early as possible to broaden treatment access for patients,” lead study author Roy S. Herbst, MD, PhD said in a presentation of the data.
Herbst is an ensign professor of medicine, professor of pharmacology, director of the Center for Thoracic Cancers, and assistant dean for Translational Research at Yale School of Medicine, deputy director of Yale Cancer Center, and chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut.
In December 2020, the FDA approved osimertinib as an adjuvant treatment following tumor resection in patients with NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.3 The regulatory decision was supported by prior data from ADAURA, which demonstrated that osimertinib elicited a statistically significant improvement in DFS vs placebo.
In the primary analysis published in the New England Journal of Medicine in October 2020, data showed that patients in the overall population treated with osimertinib experienced a median DFS that was not yet reached (95% CI, not calculable [NC]–NC) compared with 27.5 months (95% CI, 22.0-35.0) for those given placebo (HR, 0.20; 99.12% CI, 0.14-0.30; P < .0001).4
In an updated analysis for the overall population published in the Journal of Clinical Oncology in January 2023, osimertinib produced a median DFS of 65.8 months (95% CI, 61.7-NC) vs 28.1 months (95% CI, 22.1-35.0) for placebo (HR, 0.27; 95% CI, 0.21-0.34).5 Additional data from the analysis showed that patients in the osimertinib arm experienced a median central nervous system DFS that was not yet reached (NR; 95% CI, 65.8-NC) compared with NR (95% CI, NC-NC) for those in the placebo arm (HR, 0.24; 95% CI, 0.14-0.42).
“Evidence that adjuvant EGFR TKI treatment could provide benefit to patients with resected EGFR-mutated NSCLC has previously been supported by data from other studies,” Herbst said.1 “However, ADAURA was the only phase 3 study to lead to clinical practice change based on a significant improvement in DFS. Until today, no EGFR TKI has demonstrated a translation of DFS [benefit] to significant OS benefit in a phase 3 study in this setting.”
ADAURA included patients at least 18 years of age with completely resected stage IB to IIIA nonsquamous NSCLC who harbored EGFR exon 19 deletions or exon 21 L858R mutations. Adjuvant chemotherapy was allowed but not required. Key inclusion criteria included a World Health Organization performance status of 0 or 1, complete resection with negative surgical margins, and brain imaging if it was not conducted prior to surgery.1
The maximum time allowed between surgery and randomization was 10 weeks for those who did not receive adjuvant chemotherapy and 26 weeks for those who did get adjuvant chemotherapy.
Patients were randomly assigned 1:1 to receive 80 mg of osimertinib once per day or placebo for up to 3 years, or until disease recurrence or other discontinuation criteria were met. Stratification factors included stage (IB vs II vs IIIA), EGFR mutation type (exon 19 deletion vs exon 21 L858R), and race (Asian vs non-Asian).
Investigator-assessed DFS in patients with stage II/IIIA disease served as the primary end point. Secondary end points included DFS in the overall population, landmark DFS rates, OS, safety, and health-related quality of life.
The median age of patients in the osimertinib and placebo arms was 64 years (range, 30-86) and 62 years (range, 31-82), respectively. The majority of patients in both arms were female (68% and 72% in the osimertinib arm and placebo arm, respectively), had no smoking history (68% and 75%), were Asian (64% and 64%), had adenocarcinoma (96% and 97%), had EGFR exon 19 deletions (55% and 55%), and received adjuvant chemotherapy (60% and 60%).
In the experimental arm, rates of stage IB, II, and IIIA disease at diagnosis were 32%, 34%, and 35%, respectively. Those rates were 32%, 34%, and 34% in the placebo arm, respectively.
Additional data showed that patients with stage IB NSCLC treated with osimertinib experienced a 5-year OS rate of 94% (95% CI, 86%-97%) compared with 88% (95% CI, 80%-93%) for those given placebo (HR, 0.44; 95% CI, 0.17-1.02). For patients with stage II disease, osimertinib elicited a 5-year OS rate of 85% (95% CI, 77%-91%) vs 78% (95% CI, 69%-85%) for placebo (HR, 0.63; 95% CI, 0.34-1.12). Patients with stage III NSCLC in the experimental arm achieved a 5-year OS rate of 85% (95% CI, 76%-91%) compared with 67% (95% CI, 57%-75%) for those in the placebo arm (HR, 0.37; 95% CI, 0.20-0.64).
An exploratory analysis showed that osimertinib provided a benefit across all subgroups in the overall population, including in patients who received adjuvant chemotherapy (HR, 0.49; 95% CI, 0.30-0.79) and those who did not (HR, 0.47; 95% CI, 0.25-0.83). Patients who received osimertinib after adjuvant chemotherapy experienced a 5-year OS rate of 87% vs 77% for those treated with placebo. The 5-year OS rates were 88% and 79% for patients who did not receive adjuvant chemotherapy in the osimertinib and placebo arms, respectively.
Twenty-two percent of patients in the osimertinib group received subsequent anticancer therapy compared with 54% of patients in the placebo group. Among patients in the experimental arm who received additional treatment (n = 76), 76% received an EGFR TKI, including osimertinib (41%) and other EGFR TKIs (37%), 26% received chemotherapy, 29% had radiotherapy, and 16% were given other anticancer treatments.
In those from the placebo arm who received subsequent treatment (n = 184), 88% were given EGFR TKIs, including osimertinib (88%) and other TKIs (62%), 25% were administered chemotherapy, 29% received radiotherapy, and 16% had other anticancer treatments.
At the April 11, 2022, data cutoff for the final DFS analysis, all patients had complete or discontinued treatment, and safety findings were consistent with results from the primary analysis and the known toxicity profile of osimertinib.4
No new adverse effects (AEs) of special interest were reported in the OS analysis, which had a data cutoff of January 27, 2023.1 No drug-related deaths were reported during the trial. One additional serious AE of COVID-19–related pneumonia was reported in the updated analysis. This AE occurred more than 28 days after treatment discontinuation, and it was deemed unrelated to treatment. This patient made a full recovery.
Any-grade AEs were reported in 98% and 90% of patients in the osimertinib arm and placebo arm, respectively. Rates of grade 3 or higher AEs were 23% and 14% in the 2 groups. Any AE leading to death occurred in 1 patient in the osimertinib arm and 2 patients in the placebo arm. Twenty percent of patients in the experimental arm experienced serious AEs vs 14% in the control arm.
Rates of AEs leading to treatment discontinuation, dose reduction, and dose interruption of osimertinib were 13%, 12%, and 27%, respectively. With placebo, those rates were 3%, 1%, and 13%, respectively.
Any-grade AEs that were deemed by investigators as possibly causally related to treatment occurred in 91% of patients treated with osimertinib and 58% of patients treated with placebo. Rates of grade 3 or higher AEs possibly related to treatment were 11% and 2% in the experimental and placebo arms, respectively.
In a discussion following the presentation at the 2023 ASCO Annual Meeting, Benjamin J. Solomon, MBBS, PhD, a medical oncologist in the Lung Service and Head & Neck service at Peter MacCullum Cancer Centre in Victoria, Australia, echoed Herbst’s sentiment on the significance of the OS data from ADAURA, explaining that these findings were practice changing or reaffirmed the decision already made by some to implement adjuvant osimertinib into clinical practice for the treatment of patients with stage IB to IIIA EGFR-mutated NSCLC.
“A key question was whether the improvement in DFS would translate to an improvement in OS. This, of course, has been a gold standard for trials of adjuvant therapy. And the answer we had [from ADAURA] was a resounding yes,” Solomon said.
Although OS data reached 21% maturity and met the prespecified threshold for the OS analysis of ADAURA, Solomon said longer-term data are needed to expand on the survival benefit experienced by patients in the osimertinib arm.
“The caveat here is that follow-up is short,” he said. “Additional follow-up is essential to understand the long-term outcomes with adjuvant osimertinib, including whether patients are cured.”