Osimertinib-Gefitinib Combo Shows Modest Benefits in EGFR NSCLC
Publication Title: Osimertinib Plus Gefitinib in Patients with EGFR-Mutated Advanced Non-Small Cell Lung Cancer and EGFR (C797X) Mutation Following First-Line Osimertinib: ORCHARD.
Summary
- Question
- This study evaluated whether combining osimertinib, a third-generation drug that targets mutations in the epidermal growth factor receptor (EGFR), with gefitinib, an earlier-generation drug, could improve outcomes for patients with advanced non-small cell lung cancer (NSCLC) who developed resistance to osimertinib due to a specific mutation in the EGFR gene called C797X.
- Why it Matters
- Osimertinib is a common first-line treatment for patients with advanced NSCLC that harbors EGFR mutations. However, resistance often develops, frequently involving a genetic change known as the C797X mutation. Current treatment options for patients with this resistance are limited, and there is a critical need for new strategies. Understanding whether a combination therapy with gefitinib can effectively target this resistance could help guide future treatments and improve patient outcomes.
- Methods
- The researchers conducted a phase II clinical trial with 31 patients who had advanced NSCLC, an EGFR mutation, and evidence of resistance due to the C797X mutation after being treated with osimertinib. Patients were treated with a daily combination of osimertinib and gefitinib until disease progression or intolerable side effects occurred. The primary goal was to assess the objective response rate (ORR), or the percentage of patients whose tumors shrank significantly.
- Key Findings
- The combination therapy resulted in a partial response in 26% of patients, meaning their tumors shrank significantly. However, the responses were short-lived, lasting a median of 4.2 months. Most patients (71%) experienced some tumor shrinkage, but nearly all eventually saw their disease progress. The median progression-free survival (time until the disease worsened) was 5.1 months, and the median overall survival was 19 months. Safety findings showed that side effects were consistent with known profiles of the two drugs, including diarrhea and skin-related issues.
- Implications
- While the combination of osimertinib and gefitinib showed modest tumor-shrinking effects, the results suggest that this regimen may not provide sufficient long-term benefits to justify further study in this patient group. The limited efficacy may be due to tumor heterogeneity (genetic diversity within tumors) and additional resistance mechanisms that emerged during treatment.
- Next Steps
- The authors recommend focusing on developing new treatments, such as fourth-generation EGFR inhibitors, which are designed to specifically target the C797X mutation. Future research should also investigate other combination strategies or therapies that can address tumor heterogeneity and resistance pathways.
- Funding Information
- This research was supported by AstraZeneca, which funded the ORCHARD study (ClinicalTrials.gov identifier NCT03944772). Yale University also provided funding and support for this research.
Full Citation
Goldberg SB, Ahn MJ, Baik C, De Castro Carpeño J, Cho BC, de Langen AJ, Fidler MJ, Goldman JW, Grønberg BH, Akamatsu H, Kim SW, Kim YJ, Le X, Marrone KA, Piotrowska Z, Riess JW, Shiraishi Y, Fraenkel PG, Merchan Ruiz B, Smith PE, Tang KH, Yu HA. Osimertinib Plus Gefitinib in Patients with EGFR-Mutated Advanced Non-Small Cell Lung Cancer and EGFR (C797X) Mutation Following First-Line Osimertinib: ORCHARD. Clin Cancer Res 2026 PMID: 42440354, DOI: 10.1158/1078-0432.CCR-26-0704.
This AI-assisted summary has been reviewed and approved by at least one of the study's authors to ensure it accurately reflects the research.
Authors
Sarah Goldberg, MD, MPH
First AuthorProfessor of Internal Medicine (Medical Oncology & Hematology)