In addition, toxicity was greater with the afatinib/cetuximab combination, according to study author Sarah S. Goldberg, MD, of Yale University, New Haven, Conn.
Dr. Goldberg and colleagues reported these results, from the SWOG S1403 trial, in the Journal of Clinical Oncology.
The authors noted that activating EGFR mutations are present in about 15% of patients with lung adenocarcinomas in Western populations and the mutations confer heightened sensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR-TKIs have been shown to improve clinical outcomes, quality of life, and toxicity when compared with chemotherapy.
Based on better outcomes over chemotherapy, the third-generation EGFR-TKI osimertinib is now the standard treatment for patients with T790M-mediated resistance, but osimertinib is not effective in TKI-resistant T790M-negative disease, the authors pointed out.
In a phase 1b trial of patients with EGFR-mutant NSCLC with acquired resistance to first-generation agents, afatinib/cetuximab produced a response rate of 29% and comparable activity regardless of T790M status.
The aim of the SWOG S1403 study was to test whether adding cetuximab to afatinib would improve PFS over afatinib alone in patients with treatment-naive, EGFR-mutant NSCLC by preventing or delaying resistance.
Trial details
The phase 2, multicenter trial included 168 eligible patients with EGFR-mutant NSCLC without prior treatment of advanced disease. The patients’ median age was 66 years (range, 27-93 years), and 66% were women.
The most common histology was adenocarcinoma (96%). EGFR exon 19 deletions were detected in 64% of patients and L858R point mutations in 36%.
Patients were randomly assigned 2:1 to receive afatinib at 40 mg orally daily plus cetuximab at 500 mg/m2 intravenously every 2 weeks or afatinib at 40 mg alone. Patients received diphenhydramine at 50 mg intravenously before the first dose of cetuximab to prevent hypersensitivity reaction, and it was recommended before subsequent doses.
Patients continued on treatment until disease progression, symptomatic deterioration, unacceptable toxicity, pregnancy, treatment delay greater than 28 days, or patient decision. The study’s primary endpoint was PFS.
Further accrual not supported
At the interim analysis, the SWOG data safety and monitoring committee decided there was insufficient evidence to support further accrual, and the trial was closed.
The primary endpoint analysis revealed a median PFS of 11.9 months in the afatinib/cetuximab group and 13.4 months in the afatinib-alone group (hazard ratio, 1.01; 95% confidence interval, 0.72-1.43; P = .94). A subset analysis showed no PFS differences based on clinical or tumor characteristics.
Overall survival, time to response, and overall response rate were not improved in the afatinib/cetuximab arm.
PFS and overall survival were longer in patients with tumors harboring exon 19 deletions than in patients with L858R mutations. However, there were no mutation subtype–based PFS and overall survival differences between the treatment arms.
Grade 3 or higher treatment-related adverse events were more common in the combination arm than in the monotherapy arm (72% and 40%, respectively; P < .0001).
The most common grade 3 or higher treatment-related adverse events (in the combination and monotherapy arms, respectively) were acneiform rash (27% and 2%), maculopapular rash (13% and 0%), and diarrhea (15% and 20%).
Patients receiving afatinib plus cetuximab required dose reductions more often (56.7% vs. 26.2%), and treatment discontinuation because of an adverse event was more frequent in the combination arm (14% vs. 11%).