Osimertinib Shows Sustained Survival Benefit in EGFR-Mutant NSCLC

Osimertinib received FDA approval as a treatment for patients with EGFR-mutant, locally advanced, unresectable stage III NSCLC in September 2024 based on data from the LAURA trial.

Osimertinib (Tagrisso) demonstrated a sustained overall survival (OS) benefit, both as a monotherapy treatment and as a backbone for combinations with savolitinib (Orpathys) or datopotamab deruxtecan-dlnk (Datroway), in patients with EGFR-mutated non–small cell lung cancer (NSCLC), according to press release from the drug’s developer, AstraZeneca.¹

The investigational agent was assessed in 4 trials presented at the 2025 European Lung Cancer Congress (ELCC): as a monotherapy in patients with stage III EGFR-mutant NSCLC in the phase 3 LAURA trial (NCT03521154); as part of a combination therapy with savolitinib in EGFR-mutant NSCLC with high MET overexpression in the phase 2 SAVANNAH trial (NCT03778229); combined with datopotamab deruxtecan in patients with EGFR-mutant NSCLC who experienced disease progression following prior osimertinib treatment in the phase 2 ORCHARD trial (NCT03944772); and sequenced with chemotherapy in patients with locally advanced or metastatic EGFR-mutant NSCLC in the phase 3 FLAURA2 trial (NCT04035486).

“A critical goal in treating every patient with lung cancer is to not only extend a patient's life but also maintain quality of life while on treatment,” Myung-Ju Ahn, MD, PhD, professor of Hemato-Oncology in the Department of Medicine at Samsung Medical Center of Sungkyunkwan University School of Medicine in Seoul, South Korea, said in the news release.¹ “The continued [OS] trend seen here at ELCC in the unresectable stage III setting and the promising data for combinations that can address progression in the advanced setting, together reinforce osimertinib as an effective, safe, and convenient treatment for patients with EGFR-mutated lung cancer across stages and lines of treatment.”

Phase 3 LAURA Trial

Study results from the phase 3 LAURA trial presented at ELCC showed that in patients with unresectable, stage III EGFR-mutant NSCLC, osimertinib elicited an OS benefit vs placebo (hazard ratio [HR], 0.67; 95% CI, 0.40-1.14; maturity, 31%). The median OS was 58.8 months (95% CI, 54.1- not calculable [NC]) with osimertinib vs 54.1 months (95% CI, 42.1-NC) with placebo. Of note, 78% of patients who received placebo also received subsequent osimertinib treatment upon disease progression.

Additionally, previous findings presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the New England Journal of Medicine showed that the median progression-free survival (PFS) among this patient population was 39.1 months (95% CI, 31.5-NC) with osimertinib vs 5.6 months (95% CI, 3.7-7.4) with placebo.^2,3 The 12- and 24- month PFS rates were 74% (95% CI, 65%-80%) and 65% (95% CI, 56%-73%) in the investigational arm, respectively, vs 22% (95% CI, 13%-32%) and 13% (95% CI, 6%-22%) in the placebo arm.

Patients were randomly assigned 2:1 to receive oral osimertinib at a recommended dose of 80 mg once daily or placebo from August 2018 to July 2022. Treatment was continued until disease progression assessed by blinded independent central review (BICR) or fulfillment of other discontinuation criteria, and osimertinib was offered to those in the placebo cohort following disease progression.

The trial’s primary end point was PFS per BICR. Key secondary end points included OS, central nervous system (CNS) PFS per BICR, objective response rate (ORR), duration of response (DOR), and safety.

According to the news release, the impact of adverse effects (AEs) on safety results and discontinuation rates were as expected, and no new concerns were identified.

Osimertinib received FDA approval as a treatment for patients with EGFR-mutant, locally advanced, unresectable stage III NSCLC in September 2024 based on data from the LAURA trial.⁴

Phase 2 SAVANNAH Trial

Results from the phase 2 SAVANNAH trial revealed that osimertinib/savolitinib elicited a confirmed ORR of 56% (95% CI, 45%-67%), a median DOR of 7.1 months (95% CI, 5.6-9.6), and a median PFS of 7.4 months (95% CI, 5.5-7.6) in patients with EGFR-mutant NSCLC with high MET overexpression.

Patients in the phase 2 trial received 80 mg of oral osimertinib plus 300 mg of twice daily savolitinib. The primary study end point was ORR, and secondary end points included DOR and PFS.

According to the news release, safety results and discontinuation rates were consistent with the profiles of each agent, with no new safety signals reported. Grade 3 or higher AEs occurred in 57% of patients.

Phase 2 ORCHARD Trial

Among patients who received either 4 mg/kg or 6 mg/kg of datopotamab deruxtecan plus osimertinib, the ORRs were 43% (80% CI, 31%-55%) and 36% (80%, CI 25%-49%), respectively. Additionally, the median PFS across the dose levels were 9.5 months (95% CI, 7.2-9.8) and 11.7 months (95% CI, 8.3-NC), respectively, with 15% and 64% of patients sustaining responses at 9 months of treatment.

Patients received osimertinib at 80 mg once daily plus datopotamab deruxtecan at 4 mg/kg or 6 mg/kg on day 1 of every 3-week cycle.

The primary end point of the trial was ORR, and secondary end points included PFS, DOR, and OS.

The safety profiles of the individual agents were consistent with their known safety profiles, and no new safety concerns were identified. Grade 3 or higher treatment-related AEs (TRAEs) occurred in 34% of those receiving 4 mg/kg of datopotamab deruxtecan vs 56% of those receiving 6 mg/kg.

Phase 3 FLAURA2 Trial

An exploratory post hoc analysis of the FLAURA2 trial revealed that the median PFS with osimertinib in combination with pemetrexed plus cisplatin was greater than 2 years regardless of the length of pemetrexed maintenance exposure. Additionally, previous results presented at the 2024 ELCC showed that the median OS was not reached (NR; 95% CI, 38.0-NC) with osimertinib plus chemotherapy and 36.7 months (95% CI, 33.2-NC) with osimertinib alone (HR, 0.75; 95% CI, 0.57-0.97; maturity, 41%).⁵

Patients in the phase 3 trial received 80 mg of daily osimertinib plus 500 mg/m² of pemetrexed and either 75 mg/m² of cisplatin or carboplatin area under the curve 5 every 3 weeks for 4 cycles before osimertinib followed by maintenance with pemetrexed every 3 weeks. The trial’s primary end point was PFS.

The safety profile of osimertinib/chemotherapy was consistent with the established profiles for the individual agents. Grade 3 or higher chemotherapy-related AEs were reported in 16% of patients who received maintenance therapy for 3 to 9 months, and 10% for those who received maintenance chemotherapy for 9 or more months. AE-related discontinuation rates were 18% and 10%, respectively.

The FDA approved osimertinib plus chemotherapy as a treatment for patients with advanced or metastatic EGFR-mutant NSCLC in February 2024 based on findings from the FLAURA2 trial.⁶

References

1. New study results reinforce TAGRISSO® (osimertinib) as the backbone therapy for EGFR-mutated lung cancer across stages and settings. News release. AstraZeneca. March 25, 2025. Accessed March 27, 2025. https://tinyurl.com/mptdxvv8
2. Ramalingam SS, Kato T, Dong X, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: primary results of the phase 3 LAURA study. J Clin Oncol. 2024;42(suppl 17):LBA4. doi:10.1200/JCO.2024.42.17_suppl.LBA4
3. Lu S, Kato T, Dong X, et al. Osimertinib after chemoradiotherapy in stage III EGFR-Mutated NSCLC. N Engl J Med. 2024;391(7):585-597. doi:10.1056/NEJMoa2402614.
4. FDA approves osimertinib for locally advanced, unresectable (stage III) non-small cell lung cancer following chemoradiation therapy. FDA. News release. September 25, 2024. Accessed March 27, 2025. https://tinyurl.com/pjjj3h9v
5. Tagrisso with the addition of chemotherapy showed favourable trend in overall survival in EGFR-mutated advanced lung cancer with further follow up in FLAURA2 phase III trial. News release. AstraZeneca. March 21, 2024. Accessed March 27, 2025. https://tinyurl.com/2bnw7z3m
6. FDA approves osimertinib with chemotherapy for EGFR-mutated non-small cell lung cancer. News release. FDA. February 16, 2024. Accessed March 27, 2025. https://bit.ly/49AeXjy