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

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).

Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells

“…After a median follow-up of over 34 months, there were no recurrences (100% DFS) in any of these patients. In contrast, in the GP2 trial, the DFS rate in HER2-positive patients that received trastuzumab but were randomized to the control arm of the study was 89% (2). This observation suggests synergy between trastuzumab and these CD8 + T cell-eliciting vaccines.…”

“…A second CD8 + T cell-eliciting vaccine that we have been investigating is GP2, an MHC class I peptide derived from the HER2 protein’s intracellular domain. In a phase II trial evaluating the GP2+GM-CSF vaccine, the Kaplan-Meier estimated 5-year DFS rate was 94% in vaccinated patients versus 85% in patients receiving GM-CSF alone in the per treatment analysis ( P =0.17) (2). Although both of these trials failed to achieve statistical significance with respect to their primary endpoint of DFS, they were informative in that they confirmed the vaccines to be safe and capable of stimulating an antigen-specific immune response.…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…Peptide-based vaccination was employed as a standalone adjuvanted intervention, 140-146 or combined with chemotherapy 147-149 radiation therapy 147,150 or other forms of treatment including other immunotherapies. 148,149,151-158 These studies enrolled patients with hematological malignancies, 151,159 brain tumors, 152,153 non-small cell lung carcinoma (NSCLC), 140,147,160 breast cancer, 141,148,161 , prostate carcinoma, 142,154 melanoma, 144-146,155-158,162 . ovarian cancer.…”

“…Alongside, 15 studies are investigating the safety and efficacy of PPV, often consisting of MHC-matched peptides chosen from the immune repertoire of the patient before treatment. 226 Finally, several studies aim at testing the safety and therapeutic potential of peptide-based vaccines targeting one single TAA including not only viral antigens like HPV p16, E6 and E7, 227-229 but also shared TAAs like HER2, NY-ESO-1, survivin and telomerase reverse transcriptase (TERT), 161,230-252 as well as TAAs involved in the establishment of immunosuppression, such as PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1). 253-256 …”

Human Tumor Antigens Yesterday, Today, and Tomorrow

“…Many shared antigens in the other categories would also be appropriate in this setting. Efforts to prevent recurrence in women with DCIS by immunizing with anti-HER-2neu vaccines are ongoing (67, 68), which might set the stage for an even earlier application of this vaccine for primary prevention.…”