Adjuvant Osimertinib Translates Meaningful OS Benefit in EGFR+ Stage IB-IIIA NSCLC

Roy S. Herbst, MD, PhD

Overall survival (OS) outcomes from the phase 3 ADAURA trial (NCT02511106) support adjuvant osimertinib (Tagrisso) as the standard of care for patients with resected EGFR-mutated, stage IB, II, or IIIA non–small cell lung cancer (NSCLC), according to Roy S. Herbst, MD, PhD. Herbst presented the updated findings during a press briefing at the 2023 ASCO Annual Meeting.¹

Compared with placebo, osimertinib produced a statistically significant and clinically meaningful improvement in OS, with findings showing 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).

“[ADAURA] is the first global phase 3 study to demonstrate statistically significant and clinically meaningful DFS [disease-free survival] and OS benefit with [adjuvant] targeted therapy [for patients with EGFR-mutated, stage IB to IIIA NSCLC], reinforcing osimertinib as the standard of care for this group,” lead study author Roy S. Herbst, MD, PhD, said.

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.² 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).³

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).⁴

In a discussion following the presentation of the OS analysis, Nathan Pennell, MD, PhD, a professor of medicine at the Cleveland Clinic Lerner College of Medicine, noted that despite the DFS improvement observed in ADAURA and the FDA approval of adjuvant osimertinib, not everyone adopted the use of osimertinib in this setting based on the DFS benefit alone.

“There have been other trials using older EGFR inhibitors that also showed improvements in DFS that did not translate into improvements in OS,” Pennell said. “Now with the unequivocal highly clinically significant improvement in OS at 5 years with 3 years of osimertinib across [patients with stage IB], II, and IIIA [NSCLC], we’ve now firmly put to rest the question about whether we should be using our most effective treatment in these [patients] based on biomarkers, and we should firmly close the door on a one-size-fits-all treatment for [patients] with NSCLC.”

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.

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).

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 Herbst said no drug-related deaths were reported during the trial. One patient died because of COVID-19–related pneumonia, but “it was hard to say that was due to [osimertinib],” Herbst noted.

“There are some [AEs] for [osimertinib]. That’s why it’s important that we can now show the patients that they have [an] OS benefit [with adjuvant osimertinib],” Herbst said. “Patients will have some fatigue, a mild rash, and some diarrhea. Occasionally there is significant interstitial lung disease, but [that is] very rare.”

References

1. Herbst RS, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR‑mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl 17):LBA3. doi:10.1200/JCO.2023.41.17_suppl.LBA3
2. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. News release. FDA. December 18, 2020. Accessed June 3, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
3. Wu Y-L, Tsuboi M, He J, et al; ADAURA Investigators. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071
4. Herbst RS, Wu Y-L, John T, et al. Adjuvant osimertinib for resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer: updated results from the phase III randomized ADAURA trial. J Clin Oncol. 2023;41(10):1830-1840. doi:10.1200/JCO.22.02186