Abstract CT040: A Phase I trial of talimogene laherparepvec combined with neoadjuvant chemotherapy for non-metastatic triple negative breast cancer
Authors: Soliman Hatem , Hogue Deanna , Han Hyo , Mooney Blaise , Costa Ricardo , Lee Marie C. , Niell Bethany , Khakapour Nazanin , Weinfurtner Robert J. , Hoover Susan , Rosa Marilin , Khong Hung , Czerniecki Brian 
Published: August 2019

Abstract
BACKGROUND: Talimogene laherparepvec (TVEC) is a modified oncolytic herpes simplex 1 (HSV1) virus currently FDA approved for the treatment of melanoma. TVEC preferentially lyses tumor cells over normal tissue to release tumor associated antigens, produces GM-CSF to activate dendritic cells, and stimulates T cells to infiltrate the tumor (TILs). TILs in breast cancer are associated with better response to neoadjuvant chemotherapy (NAC), so we hypothesized that intratumoral TVEC may enhance response to NAC. We report safety and outcomes of a Phase I trial combining NAC with TVEC in stage 2-3 TNBC.
METHODS: Stage 2-3 TNBC patients were enrolled into a 3+3 Phase I trial with 2 TVEC dose levels [DL1=106 PFU x 5 doses, DL2=106 PFU 1st dose then 108 PFU x 4 doses] q2week + weekly paclitaxel (80mg/m2) IV x 12, followed by dose dense AC (doxorubicin/cyclophosphamide 60/600 mg/m2) IV q2weeks x 4 alone. Patients then had surgery and were assessed for pathologic complete response (pCR). Primary endpoint is safety by CTCAE 4.03 and maximum tolerated dose (MTD), secondary is pCR rate and immune correlates. Dose limiting toxicity (DLT) rule was grade 3-5 adverse event due to TVEC during 1st 6 weeks.
RESULTS: Nine patients (DL1 [n=3], DL2 [n=6]) were enrolled. Six pts were stage II, three were stage III (6 clinically N+). No DLTs were encountered and MTD dose was DL2. Most common toxicities due to TVEC were fevers (n=8), chills (n=3), hematomas (n=3), injection site pain (n=3). One genital wild type HSV1 reactivation event occurred. Common NAC related toxicities included anemia, nausea, fatigue, neuropathy, infusion reactions, lymphopenia as expected. Thromboembolic events (n=2) and severe bradycardia (n=1) occurred during or after AC chemo. Five pts (55%) had pCR, 2 had microscopic residual disease (22%), 2 had gross residual disease (22%). Preliminary immune correlates show heavy immune infiltration in analyzed tumors, full results will be presented.
CONCLUSION: Addition of TVEC to NAC was feasible at full FDA approved dose with manageable toxicity. The combination is highly active in TNBC with an increase in pCR rate (55%) over expected rate of 30% with NAC alone. Preliminary evidence of robust immune activation was observed. This combination will continue to be evaluated in an ongoing phase II trial.
Citation Format: Hatem Soliman, Deanna Hogue, Hyo Han, Blaise Mooney, Ricardo Costa, Marie C. Lee, Bethany Niell, Nazanin Khakapour, Robert J. Weinfurtner, Susan Hoover, Marilin Rosa, Hung Khong, Brian Czerniecki. A Phase I trial of talimogene laherparepvec combined with neoadjuvant chemotherapy for non-metastatic triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT040.