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Clinical Trial
. 2020 Jun 1;26(11):2515-2523.
doi: 10.1158/1078-0432.CCR-19-2741. Epub 2020 Feb 18.

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  1 , Diane Hale  1 , Timothy J Vreeland  2 , Annelies T Hickerson  1 , Jennifer K Litton  3 , Gheath Alatrash  4 , Rashmi K Murthy  3 , Na Qiao  5 , Anne V Philips  5 , Jason J Lukas  6 , Jarrod P Holmes  7 , George E Peoples #  8 , Elizabeth A Mittendorf #  9
Affiliations
Clinical Trial

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 et al. Clin Cancer Res. .

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.

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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.

Figures

Figure 1.
Figure 1.. CONSORT Diagram.
The final analysis was performed on all patients as randomized. The safety/modified intention-to-treat population included all patients that received inoculation of nelipepimut-S or placebo and was used for comparing rates of adverse events. mITT: modified intention-to-treat; NPS: nelipepimut-S; PVS: Primary Vaccine Series
Figure 2.
Figure 2.. Left Ventricular Cardiac Ejection Fraction Over Time.
The cardiac ejection fraction was similar between patients receiving nelipepimut-S (NPS) and placebo.
Figure 3A.
Figure 3A.. In vivo Immunologic Response.
Figure 3B.
Figure 3B.. In vitro immunologic response.
Figure 3C.
Figure 3C.. TNBC In vitro immunologic response.
Figure 3D.
Figure 3D.. Hormone Receptor Positive In vitro immunologic response.
(A) Delayed type hypersensitivity (DTH) reaction was measured prior to initiating the primary vaccine series (DTH #1), and one month after completion of the primary vaccine series (DTH #2), after the second booster inoculation (DTH #3), and after the fourth (final) booster inoculation (DTH #4). (B) The E75 Specific T cell response was measured on 117 patients and within subsets of (C) TNBC and (D) hormone receptor positive patients prior to initiating the primary vaccine series (R0), one month after completion of primary vaccine series (R6), one month after first booster vaccination (RB1), and one month after third booster vaccination (RB3). *Timepoints where the treatment arms were significantly different, p<0.05.
Figures 4A-B.
Figures 4A-B.. Disease-Free Survival.
Figures 4. (A) Overall population as randomized and (B) the modified intention-to-treat (mITT) population consisting of only patients who received nelipepimut-S (NPS) or placebo. Dashed line indicated primary outcome of 24 month DFS.
Figures 4A-B.
Figures 4A-B.. Disease-Free Survival.
Figures 4. (A) Overall population as randomized and (B) the modified intention-to-treat (mITT) population consisting of only patients who received nelipepimut-S (NPS) or placebo. Dashed line indicated primary outcome of 24 month DFS.
Figures 5A-D.
Figures 5A-D.. Disease-Free Survival Subsets.
(A) Triple-negative breast cancer patients (TNBC). (B) Hormone receptor (estrogen and/or progesterone receptor) positive breast cancer patients. (C) node-positive breast cancer patients and (D) node-negative breast cancer patients. Dashed line indicated primary outcome of 24 month DFS.
Figures 5A-D.
Figures 5A-D.. Disease-Free Survival Subsets.
(A) Triple-negative breast cancer patients (TNBC). (B) Hormone receptor (estrogen and/or progesterone receptor) positive breast cancer patients. (C) node-positive breast cancer patients and (D) node-negative breast cancer patients. Dashed line indicated primary outcome of 24 month DFS.
Figures 5A-D.
Figures 5A-D.. Disease-Free Survival Subsets.
(A) Triple-negative breast cancer patients (TNBC). (B) Hormone receptor (estrogen and/or progesterone receptor) positive breast cancer patients. (C) node-positive breast cancer patients and (D) node-negative breast cancer patients. Dashed line indicated primary outcome of 24 month DFS.
Figures 5A-D.
Figures 5A-D.. Disease-Free Survival Subsets.
(A) Triple-negative breast cancer patients (TNBC). (B) Hormone receptor (estrogen and/or progesterone receptor) positive breast cancer patients. (C) node-positive breast cancer patients and (D) node-negative breast cancer patients. Dashed line indicated primary outcome of 24 month DFS.
See this image and copyright information in PMC

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