A Phase I Trial of Talimogene Laherparepvec in Combination with Neoadjuvant Chemotherapy for the Treatment of Nonmetastatic Triple-Negative Breast Cancer.

Abstract

Talimogene laherparepvec (TVEC) is an oncolytic herpes simplex 1 virus approved for treatment of melanoma. We hypothesized intratumoral TVEC may enhance response to neoadjuvant chemotherapy (NAC). This article reports the results of a trial combining NAC with TVEC for triple-negative breast cancer (TNBC). Patients with stage II-III TNBC enrolled in a 3+3 phase I trial (NCT02779855) of two TVEC dose levels [DL; DL 1 = 10⁶ plaque-forming units (PFU) × 5 doses; DL 2 = 10⁶ PFUs first dose, then 10⁸ PFUs × 4 doses] on weeks 1, 4, 6, 8, and 10 plus weekly paclitaxel (80 mg/m²) for 12 weeks, followed by doxorubicin/cyclophosphamide (60/600 mg/m²) every 2 weeks for 8 weeks. Postoperative response assessment using residual cancer burden (RCB) was performed. Primary endpoints were safety and MTD. Secondary endpoints were RCB0 rate and immune correlates. Dose-limiting toxicity (DLT) rule was grade 3-5 adverse events due to TVEC during first 5 weeks. Nine patients [DL 1 (<i>n</i> = 3); DL 2 (<i>n</i> = 6)] were enrolled. Six had stage II disease, and 3 had stage III (6 clinically N⁺). No DLTs occurred, and MTD was DL 2. Most common toxicities with TVEC were fever (<i>n</i> = 8), chills (<i>n</i> = 3), hematomas (<i>n</i> = 3), and injection site pain (<i>n</i> = 3). Thromboembolic events (<i>n</i> = 2) and bradycardia (<i>n</i> = 1) occurred during or after NAC. Five patients (55%) achieved RCB0, 2 had RCB1 (22%), and 2 had RCB2 (22%). The addition of TVEC to NAC was feasible at the approved dose, with manageable toxicity. The complete response rate was 55%.