Suresh S. Ramalingam, MD, FACP, FASCO
Updates from several clinical trials of the EGFR tyrosine kinase inhibitor osimertinib across stages and settings of EGFR-mutated non–small cell lung cancer (NSCLC) were presented at the European Lung Cancer Congress (ELCC) 2025. The updated results from the phase III LAURA trial were presented by Suresh S. Ramalingam, MD, FACP, FASCO, of Winship Cancer Institute of Emory University, Atlanta.1 In other studies, the use of osimertinib was assessed in combination with other agents: The MET tyrosine kinase inhibitor savolitinib after disease progression on first-line osimertinib in the phase II SAVANNAH trial,2 the TROP2-directed antibody-drug conjugate datopotamab deruxtecan-dlnk (Dato-DXd) after disease progression on first-line osimertinib in the phase II ORCHARD trial,3 and combined with chemotherapy as first-line treatment in the phase III FLAURA2 trial.4
LAURA Trial
Suresh S. Ramalingam, MD, FACP, FASCO, of Winship Cancer Institute of Emory University, Atlanta, presented updated results from the LAURA trial. They showed a trend toward improved overall survival with osimertinib vs placebo in patients with unresectable, stage III, EGFR-mutated NSCLC (hazard ratio [HR] = 0.67; 95% confidence interval [CI] = 0.40–1.14, maturity 31%). Median overall survival was 58.8 months (95% CI = 54.1 months to not calculable) in patients treated with osimertinib vs 54.1 months with placebo (95% CI = 42.1 months to not calculable), despite 78% of patients on placebo receiving subsequent treatment with osimertinib upon disease progression. The trial will continue to assess overall survival as a key secondary endpoint at the final analysis. A statistically significant and clinically meaningful improvement in progression-free survival was previously reported from the LAURA trial in The New England Journal of Medicine.5 Safety results and treatment discontinuation rates because of adverse events were as expected, and no new safety concerns were identified.
SAVANNAH Trial
Myung-Ju Ahn, MD, PhD, of Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, presented the results from the SAVANNAH trial. In this study, osimertinib was used in combination with savolitinib (300 mg twice daily); the combination demonstrated a clinically meaningful and durable objective response rate in patients with EGFR-mutated NSCLC who had high levels of MET overexpression and/or amplification and whose disease progressed on treatment with osimertinib in the first-line setting. Among patients screened for enrollment in this trial, an estimated 62% had tumors with MET overexpression and/or amplification, and approximately 34% met the defined high MET level cutoff.
The combination therapy demonstrated a confirmed objective response rate of 56% (95% CI = 45%–67%), with a median duration of response of 7.1 months (95% CI = 5.6–9.6 months). Median progression-free survival was 7.4 months (95% CI = 5.5–7.6 months). Safety results and treatment discontinuation rates because of adverse events were consistent with the established profiles of each medicine, and no new safety concerns were reported. In all patients treated with osimertinib plus savolitinib, grade 3 or higher adverse events were reported in 57%.
ORCHARD Trial
Xiuning Le, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, reported the first results from the ORCHARD trial. In this study, the combination of osimertinib and Dato-DXd showed activity and manageable safety in patients with advanced EGFR-mutated NSCLC whose disease progressed on treatment with osimertinib.
The module enrolled an all-comer population of patients with EGFR-mutated NSCLC and evaluated two doses of Dato-DXd (4 mg/kg or 6 mg/kg). The combination of Dato-DXd and osimertinib yielded similar objective response rates of 43% (80% CI = 31%–55%) and 36% (80% CI = 25%–49%), respectively. Progression-free survival and duration of response results favored the 6-mg/kg dose, with a median progression-free survival of 11.7 months (95% CI = 8.3 months to not calculable) vs 9.5 months (95% CI = 7.2–9.8 months); a total of 64% of patients continued to respond at 9 months on the 6-mg/kg dose, and 15% of patients continued to respond at 9 months on the 4-mg/kg dose.
The safety profile this combination therapy was reported to be consistent with the known safety profiles of each medicine, and no new safety concerns were identified at either dose level. Grade 3 or higher treatment-related adverse events occurred in 34% and 56% of patients receiving the 4-mg/kg dose and the 6-mg/kg dose, respectively.
FLAURA2 Trial
David Planchard, MD, PhD, of Institut Gustave Roussy, Villejuif, France, presented the results of an exploratory post hoc analysis of the FLAURA2 trial, which assessed progression-free survival by the length of exposure to pemetrexed maintenance treatment in patients with locally advanced (stage IIIB–IIIC) or metastatic (stage IV) EGFR-mutated NSCLC. Patients were treated with osimertinib plus chemotherapy (pemetrexed plus cisplatin) followed by maintenance treatment with osimertinib and chemotherapy (pemetrexed) or osimertinib alone. Results showed a median progression-free survival of more than 2 years regardless of the length of pemetrexed maintenance exposure, with a trend associating longer progression-free survival with longer pemetrexed treatment.
The safety profile of this combination regimen was consistent with the established profiles of the individual medicines. Grade 3 or higher chemotherapy-related adverse events were reported in 16% of patients who received maintenance treatment for at least 3 to up to 9 months and in 10% of patients who received maintenance for at least 9 months. Chemotherapy discontinuation rates because of adverse events were 18% and 10%, respectively.
The combination of osimertinib and chemotherapy previously demonstrated a statistically significant and clinically meaningful improvement in progression-free survival. These results formed the basis for regulatory approvals in the United States, European Union, Japan, and China. Previously presented overall survival data from the second interim analysis showed a favorable trend with the combination (HR = 0.75; 95% CI = 0.57–0.97, maturity 41%), with consistent results across all prespecified subgroups. The trial will continue to assess overall survival as a key secondary endpoint.
DISCLOSURE: For full disclosures of the authors of these studies, visit esmo.org.
REFERENCES
1. Ramalingam SS, Özgüroglu M, Ahn MJ, et al: Osimertinib after definitive chemoradiotherapy in patients with unresectable stage III EGFR-mutated non–small cell lung cancer: Updated overall survival analysis from the LAURA study. European Lung Cancer Congress 2025. Abstract LBA4. Presented March 28, 2025.
2. Ahn MJ, Kim TM, Bonanno L, et al: SAVANNAH: Savolitinib + osimertinib (osi) in patients with EGFRm advanced NSCLC and MET overexpression and/or amplification following progressive disease on osi. European Lung Cancer Congress 2025. Abstract 2O. Presented March 26, 2025.
3. Le X, Hendriks L, Morabito A, et al: Osimertinib (osi) + datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC whose disease progressed on first-line osi: ORCHARD. European Lung Cancer Congress 2025. Abstract 1O. Presented March 26, 2025.
4. Planchard D, Cheng Y, Kobayashi K, et al: Characterization of benefit-risk by pemetrexed (pem) exposure in patients with EGFRm aNSCLC treated with 1L osimertinib + platinum-pem in FLAURA2. European Lung Cancer Congress 2025. Abstract 53P. March 28, 2025.
5. Lu S, Kato T, Dong X, et al: Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC. N Engl J Med 391:585-597, 2024.
