Targeting the Epidermal Growth Factor Receptor Pathway in Chemotherapy-Resistant Triple-Negative Breast Cancer: A Phase II Study.

Abstract

Epidermal growth factor receptor (EGFR) pathway activation causes chemotherapy resistance, and inhibition of the EGFR pathway sensitizes triple-negative breast cancer (TNBC) cells to chemotherapy in preclinical models. Given the high prevalence of EGFR overexpression in TNBC, we conducted a single-arm phase II study of panitumumab (anti-EGFR monoclonal antibody), carboplatin, and paclitaxel as the second phase of neoadjuvant therapy (NAT) in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02593175). Patients with early-stage, AC-resistant TNBC, defined as disease progression or ≤80% reduction in tumor volume after four cycles of AC, were eligible for this study and received panitumumab (2.5 mg/kg i.v., every week × 13), paclitaxel (80 mg/m2 i.v. every week × 12), and carboplatin (AUC = 4 i.v., every 3 weeks × 4) as the second phase of NAT. A two-stage Gehan-type design was used to detect an improvement in the pathological complete response (pCR)/residual cancer burden class I (RCB-I) rate from 5% to 20%. Whole-exome sequencing was performed on diagnostic tumor biospecimens, where available. From November 3, 2016, through August 23, 2021, 43 patients with AC-resistant TNBC were enrolled. The combined pCR/RCB-I rate was 30.2%. The most common treatment-related adverse events were neutropenia (72%) and anemia (61%), with 7 (16%), 16 (37%), and 8 (19%) patients experiencing grade 4 neutropenia, grade 3 neutropenia, and grade 3 anemia, respectively. No new safety signals were observed. This study met its primary endpoint (pCR/RCB-I = 30.2% vs. 5% in historical controls), suggesting that panitumumab should be evaluated as a component of NAT in patients with chemotherapy-resistant TNBC in a larger, randomized clinical trial. The epidermal growth factor receptor (EGFR) pathway has been implicated as a driver of chemotherapy resistance in triple-negative breast cancer (TNBC). Here, we evaluate the combination of panitumumab, carboplatin, and paclitaxel as the second phase of neoadjuvant therapy (NAT) in patients with AC-resistant TNBC. This study met its primary efficacy endpoint, and molecular alterations in EGFR pathway genes did not seem to influence response to the study regimen.