Results of a Randomized Phase IIb Trial of Nelipepimut-S + Trastuzumab versus Trastuzumab to Prevent Recurrences in Patients with High-Risk HER2 Low-Expressing Breast Cancer

G Travis Clifton, Diane Hale, Timothy J Vreeland, Annelies T Hickerson, Jennifer K Litton, Gheath Alatrash, Rashmi K Murthy, Na Qiao, Anne V Philips, Jason J Lukas, Jarrod P Holmes, George E Peoples, Elizabeth A Mittendorf, G Travis Clifton, Diane Hale, Timothy J Vreeland, Annelies T Hickerson, Jennifer K Litton, Gheath Alatrash, Rashmi K Murthy, Na Qiao, Anne V Philips, Jason J Lukas, Jarrod P Holmes, George E Peoples, Elizabeth A Mittendorf

Abstract

Purpose: Preclinical data provide evidence for synergism between HER2-targeted peptide vaccines and trastuzumab. The efficacy of this combination was evaluated in patients with HER2 low-expressing breast cancer in the adjuvant setting.

Patients and methods: A phase IIb, multicenter, randomized, single-blinded, controlled trial enrolled disease-free patients after standard therapy completion (NCT01570036). Eligible patients were HLA-A2, A3, A24, and/or A26+, and had HER2 IHC 1+/2+, FISH nonamplified breast cancer, that was node positive and/or hormone receptor-negative [triple-negative breast cancer (TNBC)]. Patients received trastuzumab for 1 year and were randomized to placebo (GM-CSF, control) or nelipepimut-S (NPS) with GM-CSF. Primary outcome was 24-month disease-free survival (DFS). Secondary outcomes were 36-month DFS, safety, and immunologic response.

Results: Overall, 275 patients were randomized; 136 received NPS with GM-CSF, and 139 received placebo with GM-CSF. There were no clinicopathologic differences between groups. Concurrent trastuzumab and NPS with GM-CSF was safe with no additional overall or cardiac toxicity compared with control. At median follow-up of 25.7 (interquartile range, 18.4-32.7) months, estimated DFS did not significantly differ between NPS and control [HR, 0.62; 95% confidence interval (CI), 0.31-1.25; P = 0.18]. In a planned exploratory analysis of patients with TNBC, DFS was improved for NPS versus control (HR, 0.26; 95% CI, 0.08-0.81, P = 0.01).

Conclusions: The combination of NPS with trastuzumab is safe. In HER2 low-expressing breast cancer, no significant difference in DFS was seen in the intention-to-treat analysis; however, significant clinical benefit was seen in patients with TNBC. These findings warrant further investigation in a phase III randomized trial.

Conflict of interest statement

Conflict of Interest Statement:

Dr. Litton reports grant or research support from Novartis, Medivation/Pfizer, Genentech, GSK, EMD-Serono, Astra-Zeneca, and Medimmune; Speaker’s Bureau for MedLearning, Physician’s Education Resource, Prime Oncology, Medscape, and Clinical Care Options; employment at The University of Texas MD Anderson Cancer Center; honoraria from UpToDate; advisory committee/review panel/board membership for Astra-Zeneca and Pfizer (both uncompensated); and review panels for NCCN, ASCO, and NIH PDQ. Dr. Murthy reports consulting fees for participation on advisory boards for Daiichi Sankyo, Genentech and Puma; honorarium from France Foundation for non-CME services; and research support (to institution) from EMD-Serono, Pfizer, Seattle Genetics, Daiichi Sankyo, and Genentech. Dr. Peoples reports grants from Sellas Life Sciences, during the conduct of the study. In addition, Dr. Peoples has a patent to Nelipepimut-S issued. Dr. Mittendorf reports receiving compensation for participating on Scientific Advisory Boards for Astra-Zeneca, Genentech, Genomic Health, Merck, and Sellas Life Sciences.

The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, The US Army Medical Department, the US Army Office of the Surgeon General, the Department of the Army, Department of Defense, or the US Government.