Background: We have completed phase I/II clinical trials vaccinating breast cancer patients (pts) with E75, a HLA-A2/A3-restricted HER2/neu (HER2) peptide vaccine. The vaccine was administered in the adjuvant setting to prevent recurrences in high risk patients rendered disease-free with standard of care therapy. We have previously reported preliminary results indicating that the vaccine (including booster inoculations) is safe and effective in stimulating an anti-tumor immune response. Here, we report the final 5 year results from these trials. Methods: The phase I/II trials were performed as dose-escalation/schedule-optimization trials enrolling node positive and high-risk, node negative breast cancer patients with tumors expressing any level of HER2. HLA-A2/A3+ pts were enrolled into the vaccine group (VG) while HLA-A2/A3- pts were followed prospectively as the untreated control group (CG). The VG pts were given 4–6 monthly intradermal inoculations of E75 with GM-CSF during the primary vaccine series (PVS). In addition, a voluntary booster program was initiated during the trial, with booster inoculations being offered every 6 months after completion of the PVS. Patients were monitored for local and systemic toxicity (graded by NCI Common Terminology Criteria for Adverse Events). In vivo immune response was assessed in the VG by delayed type hypersensitivity (DTH) reactions to both E75 and saline, pre- and post-PVS. VG and CG pts were followed for 60 months (mo) and recurrences were documented. Demographic differences were compared with the Fisher's exact test and disease-free survival was determined using the Kaplan-Meier method and compared by log-rank test. Results: 195 pts were enrolled, 6 withdrew (2 from VG, 4 from CG), 1 was lost to follow-up prior to vaccination, and 1 was found to be ineligible, leaving 187 evaluable pts; 108 in the VG and 79 in the CG. 53 pts volunteered for the booster program and received at least one booster inoculation. The VG and CG were well-matched with the only statistically significant difference being ER−/PR- status (31.1% in VG vs 17.7% in CG, p = 0.04). Vaccination was well tolerated (maximum local toxicity: 73.1% Grade 1, 26.9% Grade 2, 0% Grade 3; maximum systemic toxicity: 72.2% Grade 1, 15.7% Grade 2, and 2.8% Grade 3). In the VG, pre- to post-PVS E75 DTH significantly increased (mean 3.8 ±1.0 vs 14.8±1.4, p < 0.001) and post-PVS E75 DTH was significantly greater than post-PVS saline DTH (1.84±0.5 vs 14.8±1.4, p < 0.001). At the end of the trial, analysis of the Kaplan Meier curves at 60 mo shows increased disease-free survival in the VG compared to the CG with a trend toward significance (89.7% vs 80.6%, p = 0.076). Conclusions: The E75 breast cancer vaccine is safe and well–tolerated. It elicits strong immune responses in vaccinated patients. At the end of the 5 year follow-up period, the E75 vaccine shows a strong trend toward preventing breast cancer recurrence in vaccinated patients. To investigate this vaccine (now known as NeuVax) further, the PRESENT trial, a prospective, randomized, double-blind, placebo-controlled, multi-center phase III registration trial has been initiated and is actively enrolling. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-16-02.
Background:HER2 low-expressing (LE) (IHC 1-2+, FISH non-amplified) breast cancer (BC) patients (pts) have not benefited from HER2-directed therapy despite HER2 antigen availability. Triple negative BC (TNBC), in particular, is immunogenic and in need of additional therapeutic options. We have previously shown the HER2-derived nelipeptimut-S (E75) + GM-CSF (NeuVax) to be synergistic with trastuzumab (Tz) in pre-clinical and pilot clinical studies. In a planned interim analysis of a multi-center, prospective, randomized, single-blinded, placebo-controlled phase 2b trial of Tz + NeuVax vs Tz to reduce recurrence in HER2 LE, node-positive (NP) and/or triple negative BC (TNBC) pts, we previously reported that the NeuVax + Tz was safe without added cardiac toxicity and demonstrated a significant reduction of recurrences in TNBC pts. This analysis examines additional subsets in this trial. Methods:HER2 LE, NP and/or TNBC pts who were clinically disease-free after standard therapy were randomized to receive Tz+NeuVax (vaccine group; VG) or Tz+GM-CSF (control group; CG). All pts received 1 yr of Tz per label. NeuVax or GM-CSF was given every 3 weeks x 6 starting with the 3rdTz dose, and then boosted every 6 months x 4. This pre-specified interim analysis was triggered 6 months after last enrollment. The primary endpoint is intention-to-treat 24 month disease-free survival (DFS) evaluated by log rank. Results: Of 275 pts randomized in the study (VG n=136, CG n=139), 98 had TNBC (VG=53, CG=45). In the interim analysis, estimated disease-free survival (DFS) was assessed with a median follow up of 18.8 months. No significant clinicopathologic differences were seen between treatment groups. In the TNBC group, estimated DFS was higher overall in VG vs CG (91.9% v 69.9%, p=0.023; hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.09-0.90). On TNBC subgroup analysis, estimated DFS was higher in VG vs CG among pts who received neoadjuvant chemotherapy (VG n=35, CG n=31; HR 0.26, CI 0.07-0.93; p=0.03), HER2 IHC 1+ BC (VG n=34, CG n=28; HR 0.20, CI 0.04-0.96; p=0.03), pts who were AJCC 7thedition stage I/II (VG n=37, CG n=27; HR incalculable, no recurrences in the VG, p=0.008), and pts 351yr of age (VG n=32 & CG n = 26; HR 0.26 CI 0.07,0.94; p=0.009). HRs did not appreciably vary based on the histologic grade or presence of lymphovascular invasion. Conclusion:Examining the subgroups from the pre-specified interim analysis demonstrates a highly significant clinical benefit in TNBC pts overall. Within the TNBC cohort, specific benefit was seen in pts who received chemotherapy neoadjuvantly, expressed lower HER2, were earlier stage, and were older in age. These factors may help enrich the TNBC population targeted in a definitive Phase 3 study in TNBC patients with residual disease after neoadjuvant chemotherapy. Citation Format: Clifton GT, Kemp Bohan PM, Hale DF, Myers JW, Brown TA, Holmes JP, Vreeland TJ, Litton JK, Murthy RK, Mittendorf EA, Peoples GE. Subgroups analysis of a multicenter, prospective, randomized, blinded phase 2b trial of trastuzumab + nelipeptimut-S (NeuVax) vs trastuzumab for prevention of recurrence in breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-01.
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