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Clinical Trial
. 2016 Oct 4;7(40):66192-66201.
doi: 10.18632/oncotarget.11751.

Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide GP2 vaccine in breast cancer patients to prevent recurrence

Elizabeth A Mittendorf  1 , Alexandros Ardavanis  2 , Jennifer K Litton  3 , Nathan M Shumway  4 , Diane F Hale  5 , James L Murray  3 , Sonia A Perez  2 , Sathibalan Ponniah  6 , Constantin N Baxevanis  2 , Michael Papamichail  2 , George E Peoples  7
Affiliations
Clinical Trial

Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide GP2 vaccine in breast cancer patients to prevent recurrence

Elizabeth A Mittendorf et al. Oncotarget. .

Abstract

GP2 is a HER2-derived, HLA-A2+ restricted peptide. Phase I studies showed GP2 administered with GM-CSF to be safe and immunogenic. Here we report the primary analysis of a prospective, randomized, multicenter phase II adjuvant trial conducted to determine the vaccine's efficacy. The trial enrolled HLA-A2+, clinically disease-free, node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2 (immunohistochemistry[IHC] 1+-3+). Patients were randomized to GP2+GM-CSF versus GM-CSF alone. Disease-free survival (DFS) was analyzed in intention-to-treat (ITT) and per-treatment cohorts; pre-specified subgroup analyses were performed for patients with IHC 3+ or FISH+ disease. The trial enrolled 180 patients; 89 received GP2+GM-CSF and 91 received GM-CSF alone. The groups were well-matched for clinicopathologic characteristics. Toxicities have been minimal. The Kaplan-Meier estimated 5-year DFS rate in the ITT analyses was 88% (95% CI:78-94%) in vaccinated vs. 81% (95% CI:69-89%) (P = 0.43) in control patients after a 34 month median follow-up. In the per-treatment analysis, the estimated 5-year DFS rates were 94% (95% CI:83-98%) and 85% (73-92%) (P = 0.17). In IHC 3+/FISH+ patients, the estimated 5-year DFS rate was 94% (82-98%) in vaccinated patients (n = 51) vs. 89% (71-96%) in control patients (n = 50), (P = 0.86) in the ITT analyses and 100% vs. 89% (71-96%) in vaccinated vs. control patients in the per-treatment analyses (P = 0.08). While the overall ITT analysis did not demonstrate benefit to vaccination, this trial confirmed that the GP2 vaccine is safe and suggests that vaccination may have clinical activity, particularly in patients with HER2 overexpression who received the full vaccine series (ie per-treatment group).

Keywords: HER2; breast cancer; cytotoxic T lymphocytes; trastuzumab; vaccine.

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Conflict of interest statement

CONFLICTS OF INTEREST

Drs. Peoples and Ponniah have partial inventor rights to GP2. If licensed, they are entitled to financial proceeds associated with this license per Federal policy. All other authors have no relevant financial disclosures.

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 U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, Department of Defense or the U.S. Government.

Figures

Figure 1
Figure 1. Consort diagram
Flow of patients through the study. ^The number of patients that did not complete the primary vaccination series (PVS) includes patients that withdrew, met the primary endpoint (recurrence, second malignancy, or death from any cause), or chose not to continue on study before completing the PVS.
Figure 2
Figure 2. Maximum toxicity
The maximum local and systemic toxicity experienced by patients administered the GP2+GM-CSF vaccine were comparable to those experienced by patients receiving GM-CSF alone.
Figure 3
Figure 3. In vivo immunologic response to vaccination
In vivo immune responses were determined using a delayed type hypersensitivity (DTH) reaction. Patients who were vaccinated with GP2+GM-CSF had a significant increase in their DTH reaction to both the immunizing peptide post-vaccination compared to pre-vaccination. (* = P < 0.001).
Figure 4
Figure 4. Ex vivo immunologic response to vaccination
Ex vivo immune responses were determined for GP2-specific CTL clonal expansion by Ig:A2 dimer assays and CTL function by granzyme B ELISPOT. The GP2+GM-CSF vaccine induced significant increases in both clonal expansion as well as improved CTL function compared to pre-vaccine levels while GM-CSF alone had no such affect. (RC6 = response 6 months after primary vaccination series [PVS] completion, BRC6 = response 1 month after booster #1 was administered [occurred 6 months after PVS completion], RC12 = response 12 months after PVS completion, BRC12 = response 1 month after booster #2 was administered [occurred 12 months after PVS completion], RC18 = response 18 months after PVS, RC24 = response 24 months after PVS; * = P < 0.05, ** = P < 0.01, *** = P < 0.001).
Figure 5
Figure 5. Disease-free survival
Disease-free survival is shown for A. all patients, intention to treat, B. all patients, per treatment, C. patients with HER2-positive breast cancer, intention to treat, and D. patients with HER2-positive breast cancer, per treatment.
See this image and copyright information in PMC

References

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