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Factors associated with a poor response to gefitinib in the NEJ002 study: smoking and the L858R mutation
Tatsuro Fukuhara1, Makoto Maemondo1, Akira Inoue2
1Department of Respiratory Medicine, Miyagi Cancer Center, 47-1 Nodayama, Medeshima-Shiode, Natori 981-1293, Japan.
Introduction:
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment is the standard therapy for non-small cell lung cancer (NSCLC) harbouring EGFR-activating mutations. The NEJ002 phase 3 clinical trial demonstrated the efficacy of EGFR-TKI; gefitinib was significantly superior in both progression-free survival (PFS) and objective response rate (ORR) than carboplatin plus paclitaxel. However, several cases showed no response. In this study, we performed further analysis of the characteristics of these non-responders.
Methods:
Available data from NEJ002 on maximum changes in tumour size were obtained from 103 cases (90.4%) and 110 cases (96.5%) in the carboplatin-paclitaxel and gefitinib groups, respectively. Waterfall plots of maximum tumour size changes were created for non-responders.
Results:
Five (4.9%) and 9 (8.2%) cases in the carboplatin-paclitaxel and gefitinib groups were non-responders, respectively. The mean pack years of the non-responders in the carboplatin-paclitaxel and gefitinib groups were 0.33 and 31.7, respectively. The ORR of total smokers (61.5%) and heavy smokers (over 40 pack years, 52.6%) in the gefitinib group were significantly lower compared to people who have never smoked (80.0%) (P=0.044 and P=0.020, respectively). Smoker cases also showed a tendency towards lower PFS and overall survival (OS). In addition, the EGFR common mutation types did not affect PFS and OS in gefitinib-treated cases in NEJ002. However, in this study, the ORR and waterfall plots showed that gefitinib-treated non-responders who had a deletion in exon 19 in the EGFR gene exhibited a tendency towards a higher response compared to those with a L858R mutation.
Conclusions:
NSCLC patients with a smoking history or the EGFR L858R mutation may demonstrate a poorer response to gefitinib treatment.
Insights
Smokers and patients with the EGFR L858R mutation may respond poorly to gefitinib treatment for non-small cell lung cancer (NSCLC). Further analysis of NEJ002 trial data revealed lower objective response rates and progression-free survival in smokers receiving gefitinib.
Area of Science:
- Oncology
- Medical Genetics
- Clinical Trials
Background:
- Gefitinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), is a standard treatment for EGFR-mutated non-small cell lung cancer (NSCLC).
- The NEJ002 trial showed gefitinib's superiority over chemotherapy, but some patients do not respond.
- This study investigates characteristics of non-responders to gefitinib in the NEJ002 trial.
Purpose of the Study:
- To analyze the characteristics of non-responders to gefitinib in the NEJ002 clinical trial.
- To identify patient factors associated with poor response to gefitinib in NSCLC.
Main Methods:
- Analysis of maximum tumor size changes from the NEJ002 trial data for non-responders.
- Waterfall plots were used to visualize tumor size changes in non-responders.
- Comparison of response rates and survival between smokers and non-smokers, and by EGFR mutation type.
Main Results:
- Non-response rates were 8.2% for gefitinib and 4.9% for carboplatin-paclitaxel.
- Smokers, particularly heavy smokers, showed significantly lower objective response rates (ORR) and a trend towards lower progression-free survival (PFS) and overall survival (OS) with gefitinib.
- Gefitinib-treated non-responders with EGFR exon 19 deletion showed a tendency towards a higher response than those with the L858R mutation.
Conclusions:
- Smoking history and the presence of the EGFR L858R mutation may predict a poorer response to gefitinib in NSCLC patients.
- These findings highlight potential subgroups of NSCLC patients who may benefit less from standard gefitinib therapy.
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