First-Line Afatinib plus Cetuximab for EGFR-Mutant Non-Small Cell Lung Cancer: Results from the Randomized Phase II
Alexis B Cortot1,2, Anne Madroszyk2,3, Etienne Giroux-Leprieur2,4
1Univ. Lille, CHU Lille, Thoracic Oncology Department, CNRS, Inserm, Institut Pasteur de Lille, UMR9020, UMR-S 1277, Canther, Lille, France. alexis.cortot@chru.lille.fr.
Purpose:
Double inhibition of epidermal growth factor receptor (EGFR) using a tyrosine kinase inhibitor plus a monoclonal antibody may be a novel treatment strategy for non-small cell lung cancer (NSCLC). We assessed the efficacy and toxicity of afatinib + cetuximab versus afatinib alone in the first-line treatment of advanced EGFR-mutant NSCLC.
Patients And Methods:
In this phase II, randomized, open-label study, patients with stage III/IV EGFR-positive NSCLC were randomly assigned (1:1) to receive afatinib (group A) or afatinib + cetuximab (group A + C). Oral afatinib 40 mg was given once daily; cetuximab 250 mg/m² was administered intravenously on day 15 of cycle 1, then every 2 weeks at 500 mg/m² for 6 months. The primary endpoint was time to treatment failure (TTF) rate at 9 months. Exploratory analysis of EGFR circulating tumor DNA in plasma was performed.
Results:
Between June 2016 and November 2018, 59 patients were included in group A and 58 in group A + C. The study was ended early after a futility analysis was performed. The percentage of patients without treatment failure at 9 months was similar for both groups (59.3% for group A vs. 64.9% for group A + C), and median TTF was 11.1 (95% CI, 8.5-14.1) and 12.9 (9.2-14.5) months, respectively. Other endpoints, including progression-free survival and overall survival, also showed no improvement with the combination versus afatinib alone. There was a slight numerical increase in grade ≥3 adverse events in group A + C. Allele frequency of the EGFR gene mutation in circulating tumor DNA at baseline was associated with shorter PFS, regardless of the treatment received.
Conclusions:
These results suggest that addition of cetuximab to afatinib does not warrant further investigation in treatment-naïve advanced EGFR-mutant NSCLC.
Insights
Adding cetuximab to afatinib did not improve treatment outcomes for advanced EGFR-mutant non-small cell lung cancer. This combination therapy showed no significant benefit in time to treatment failure or survival rates.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Epidermal Growth Factor Receptor (EGFR) plays a crucial role in non-small cell lung cancer (NSCLC) development.
- Dual inhibition strategies combining tyrosine kinase inhibitors (TKIs) and monoclonal antibodies are being explored for NSCLC.
- Afatinib (TKI) and cetuximab (monoclonal antibody) target EGFR, presenting a potential novel treatment approach.
Purpose of the Study:
- To evaluate the efficacy and toxicity of combining afatinib with cetuximab versus afatinib alone.
- To assess this combination as a first-line treatment for advanced EGFR-mutant NSCLC.
- To determine if dual EGFR inhibition offers superior outcomes compared to single TKI therapy.
Main Methods:
- A Phase II, randomized, open-label study involving patients with stage III/IV EGFR-positive NSCLC.
- Patients were assigned to receive either afatinib alone or afatinib plus cetuximab.
- Primary endpoint was time to treatment failure (TTF) at 9 months; exploratory analysis of circulating tumor DNA (ctDNA) was conducted.
Main Results:
- The 9-month TTF rate was similar between the afatinib alone group (59.3%) and the afatinib + cetuximab group (64.9%).
- Median TTF was comparable (11.1 months vs. 12.9 months), with no significant improvement in progression-free or overall survival with the combination.
- Increased grade ≥3 adverse events were observed in the combination group; baseline EGFR ctDNA allele frequency correlated with shorter PFS.
Conclusions:
- The addition of cetuximab to afatinib does not provide additional benefit in treatment-naïve advanced EGFR-mutant NSCLC.
- Further investigation of this combination therapy in this patient population is not warranted.
- EGFR ctDNA levels may serve as a prognostic biomarker for treatment response.
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