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Osimertinib With or Without Chemotherapy in Advanced Non-Small Cell Lung Cancer With EGFR and Concurrent TP53
Ting Zhou1, Huaqiang Zhou1, Fangfang Gao2
1Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
Importance:
Combination therapy has emerged as a promising therapeutic approach for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, its clinical benefit-risk profile remains a focus of ongoing debate. Identifying patients most likely to derive benefit from such regimens remains an unmet clinical need.
Objective:
To prospectively compare the efficacy and safety of first-line osimertinib plus chemotherapy with osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations.
Design, Setting, And Participants:
A multicenter, randomized, open-label, phase 3 study conducted at 17 sites in China. Between March 25, 2021, and July 11, 2024, a total of 294 eligible patients with treatment-naive, stage IV or recurrent nonsquamous NSCLC harboring concurrent TP53 and EGFR-sensitizing mutations were enrolled.
Interventions:
Patients were randomized (1:1) to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n = 146) or osimertinib monotherapy (n = 148).
Main Outcomes And Measures:
The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, response, safety, and quality of life.
Results:
Among 294 enrolled patients, the median age was 57 years (range, 26-79 years), and 159 (54.1%) were female. The data cutoff date was November 11, 2025. At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median progression-free survival was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 vs 15.6 months; difference, 18.4 months [95% CI, 9.9-22.3]; hazard ratio, 0.44 [95% CI, 0.32-0.60]; P < .001). This benefit was consistent across prespecified subgroups, including those with brain metastases and L858R mutations. The overall survival data remained immature (30.6% maturity); however, a trend toward overall survival benefit with combination therapy was observed. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified.
Conclusions And Relevance:
In this randomized clinical trial, osimertinib plus chemotherapy significantly increased progression-free survival among patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. These findings provided a clinical rationale for individualized combination strategies in the management of patients with EGFR-mutated NSCLC.
Trial Registration:
ClinicalTrials.gov Identifier: NCT04695925.
Insights
First-line osimertinib plus chemotherapy significantly improved progression-free survival in patients with EGFR-mutated non-small cell lung cancer (NSCLC) and TP53 mutations. This combination offers a promising strategy for this patient population.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Combination therapy is a promising approach for EGFR-mutated non-small cell lung cancer (NSCLC).
- Identifying optimal combination regimens and patient subgroups remains crucial for improving treatment outcomes.
- The benefit-risk profile of combination therapies requires careful evaluation.
Purpose of the Study:
- To compare the efficacy and safety of first-line osimertinib plus chemotherapy versus osimertinib monotherapy.
- To evaluate outcomes in patients with EGFR-mutated advanced NSCLC and concurrent TP53 mutations.
- To determine the progression-free survival and overall survival benefits of combination therapy.
Main Methods:
- A multicenter, randomized, open-label, phase 3 study enrolled 294 treatment-naive patients with EGFR-mutated NSCLC and TP53 mutations.
- Patients received either osimertinib plus chemotherapy (pemetrexed and carboplatin) or osimertinib monotherapy.
- The primary endpoint was investigator-assessed progression-free survival; secondary endpoints included overall survival and safety.
Main Results:
- Median progression-free survival was significantly longer with osimertinib plus chemotherapy (34.0 months) compared to monotherapy (15.6 months).
- The combination therapy demonstrated a hazard ratio of 0.44 (P < .001) for progression-free survival.
- Grade 3 or higher adverse events were more frequent with combination therapy, but no new safety signals emerged.
Conclusions:
- Osimertinib plus chemotherapy significantly increases progression-free survival in patients with EGFR-mutated NSCLC and concurrent TP53 mutations.
- This combination therapy provides a clinical rationale for individualized treatment strategies in advanced NSCLC.
- Further data on overall survival will provide a more complete picture of the long-term benefits.
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