Randomized Trial of Afatinib Plus Cetuximab Versus Afatinib Alone for First-Line Treatment of EGFR-Mutant
Sarah B Goldberg1, Mary W Redman2, Rogerio Lilenbaum1
1Yale School of Medicine, New Haven, CT.
Purpose:
The irreversible ErbB family tyrosine kinase inhibitor (TKI) afatinib plus the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to EGFR TKIs. We studied whether the combination of afatinib plus cetuximab compared with afatinib alone would improve progression-free survival (PFS) in patients with treatment-naive EGFR-mutant non-small-cell lung cancer (NSCLC) by preventing or delaying resistance.
Methods:
Patients with EGFR-mutant NSCLC without prior treatment of advanced disease were enrolled in this phase II, multicenter trial and randomly assigned to receive afatinib 40 mg orally daily plus cetuximab 500 mg/m2 intravenously every 2 weeks or afatinib alone. The primary end point was PFS.
Results:
Between March 25, 2015 and April 23, 2018, 174 patients were randomly assigned, and 168 (83 on afatinib + cetuximab and 85 on afatinib) were eligible. There was no improvement in PFS in patients receiving afatinib plus cetuximab compared with afatinib alone (hazard ratio [HR], 1.01; 95% CI, 0.72 to 1.43; P = .94; median, 11.9 months v 13.4 months). Similarly, there was no difference in response rate (67% v 74%; P = .38) or overall survival (HR, 0.82; 95% CI, 0.50 to 1.36; P = .44). Toxicity was greater with the combination: grade ≥ 3 adverse events related to treatment occurred in 72% of patients receiving afatinib plus cetuximab compared with 40% of those receiving afatinib alone, most commonly rash and diarrhea. Dose reductions were more common in patients receiving the combination, and 30% of patients in this arm discontinued cetuximab due to toxicity. At interim analysis, there was insufficient evidence to support continued accrual, and the trial was closed.
Conclusions:
The addition of cetuximab to afatinib did not improve outcomes in previously untreated EGFR-mutant NSCLC, despite recognized activity in the acquired resistance setting.
Insights
Adding cetuximab to afatinib did not improve progression-free survival in patients with EGFR-mutant non-small-cell lung cancer. The combination therapy showed increased toxicity without enhancing treatment outcomes.
Area of Science:
- Oncology
- Pharmacology
Background:
- Afatinib, an irreversible ErbB family tyrosine kinase inhibitor (TKI), is used to treat non-small-cell lung cancer (NSCLC).
- Cetuximab, an EGFR monoclonal antibody, can overcome resistance to EGFR TKIs.
Purpose of the Study:
- To evaluate if combining afatinib with cetuximab improves progression-free survival (PFS) in treatment-naive EGFR-mutant NSCLC patients.
- To determine if this combination prevents or delays resistance to EGFR TKIs.
Main Methods:
- A phase II, multicenter trial randomly assigned 174 patients with EGFR-mutant NSCLC to afatinib plus cetuximab or afatinib alone.
- The primary endpoint was progression-free survival (PFS).
Main Results:
- No significant improvement in PFS was observed with afatinib plus cetuximab compared to afatinib alone (median PFS: 11.9 vs 13.4 months).
- Response rates and overall survival also showed no significant differences between the groups.
- The combination therapy resulted in higher rates of grade ≥3 adverse events, including rash and diarrhea, leading to more dose reductions and treatment discontinuations.
Conclusions:
- Adding cetuximab to afatinib did not improve outcomes in previously untreated EGFR-mutant NSCLC patients.
- The combination therapy was associated with increased toxicity and did not demonstrate superiority over afatinib alone in this setting.
