Phase 2 study of afatinib among patients with recurrent and/or metastatic esophageal squamous cell carcinoma

Abstract

Background: The objective of the current study was to investigate the clinical activity of, safety of, and predictive biomarkers for afatinib, an irreversible pan‐ErbB kinase inhibitor, in patients with recurrent and/or metastatic esophageal squamous cell carcinoma (R/M‐ESCC).

Methods: Patients with R/M‐ESCC that was refractory to platinum‐based chemotherapy were enrolled in the current multicenter, single‐arm, phase 2 study and received afatinib at a dose of 40 mg/day. The primary endpoint was the objective response rate. Secondary endpoints included progression‐free survival, overall survival, the disease control rate, and the safety profile. To identify predictive biomarkers, single‐nucleotide variations, short insertions/deletions, and somatic copy number alterations were assessed using whole‐exome sequencing and their associations with clinical outcomes were analyzed.

Results: Among 49 enrolled patients, the objective response rate and disease control rate were 14.3% and 73.3%, respectively. With a median follow‐up of 6.6 months, the median progression‐free survival and overall survival were 3.4 months and 6.3 months, respectively. Treatment‐related adverse events were noted to have occurred in 33 patients (67.3%), with the majority being of grade 1 to 2 (adverse events were graded and recorded based on the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). Whole‐exome sequencing demonstrated that the ESCC genomes of patients who demonstrated a response to afatinib were enriched with genomic alterations of TP53 and epidermal growth factor receptor (EGFR). As a predictive marker, a score derived from TP53 disruptive mutations and EGFR amplifications and/or missense mutations demonstrated a significant association with the response to afatinib. The score based on the mutational status of EGFR and TP53 achieved a performance of an area under the curve of 0.86 in predicting the sensitivity of afatinib.

Conclusions: The results of the current study demonstrated that afatinib can confer modest clinical benefits with manageable toxicity in patients with platinum‐resistant R/M‐ESCC. Identification of TP53 alterations and EGFR amplifications may serve as predictive markers with which to identify patients with R/M‐ESCC who may benefit from afatinib.