Nelipepimut-S
The nine-amino-acid HER2 peptide behind the NeuVax breast cancer vaccine, and why its phase 3 trial failed
Nelipepimut-S is E75, a nine-amino-acid fragment of the HER2 protein that immune T cells can recognise on cancer cells. Mixed with the immune stimulant GM-CSF as the vaccine NeuVax, it was meant to train the immune system to keep breast cancer from coming back. Early non-randomised trials looked promising, but the 758-patient phase 3 PRESENT trial was stopped early for futility: at its interim analysis the vaccine did no better than GM-CSF alone. A later phase 2 trial with trastuzumab hinted at benefit only in triple-negative disease. It is not approved anywhere.
Used in human trials: 1,000 µg with 250 µg GM-CSF, Monthly x6, then every 6 months, Intradermal (PRESENT phase 3 (2019): adjuvant breast cancer) Details ↓
Recommended Dosing
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
HER2 is a growth-factor receptor that sits on the surface of many breast cancer cells. Drugs such as trastuzumab block it directly, but they help mainly when a tumour makes a great deal of HER2. Cancer vaccines try a different route: teach the patient's own killer T cells to recognise a piece of HER2 so they attack any cancer cells left after surgery and chemotherapy. In 1995 researchers studying T cells taken from ovarian tumours found that a nine-amino-acid HER2 fragment, KIFGSLAFL, was recognised by every T-cell line they tested. They called it E75; its later drug name is nelipepimut-S.
A peptide this small does little on its own, so in people it was always given with GM-CSF, a growth factor that draws in and activates the immune cells that show peptides to T cells. Because T cells see such peptides only on particular tissue types, the early trials vaccinated women whose cells carry HLA-A2 or HLA-A3 and followed women with other tissue types as an unvaccinated comparison group. That design was practical but not randomised, and the vaccinated women differed from the controls in ways that could bias the result.
Those phase 1 and 2 studies, run by the US military cancer trials group from the early 2000s, consistently showed that the vaccine was safe and raised E75-specific T cells and skin-test responses. They also suggested fewer recurrences: five-year disease-free survival was 89.7% with the vaccine against 80.2% in controls, a difference that did not reach statistical significance, and larger among women given the dose later judged optimal. Immunity faded with time, so booster injections were added. The benefit looked greatest in tumours with low HER2 levels, which shaped the next trial.
That trial, PRESENT, randomised 758 women with node-positive, HER2-low breast cancer to nelipepimut-S with GM-CSF or to GM-CSF alone, after standard treatment. It was stopped early for futility. At the planned interim analysis, at a median of 16.8 months, there was no significant difference in disease-free survival between the arms. The authors note that mandatory yearly scans picked up many recurrences in women without symptoms, which brought the interim analysis forward. Side effects were mostly at the injection site.
Two later trials continued. A randomised phase 2b trial in 275 women combined the vaccine with a year of trastuzumab in HER2-low cancer; the whole group showed no significant benefit, but an exploratory analysis of triple-negative patients did, a subgroup finding that needs a confirmatory trial before anyone can rely on it. A small trial in ductal carcinoma in situ found the vaccine safe before surgery and able to raise specific T cells, without a significant difference from GM-CSF alone. Nelipepimut-S has no approval from any regulator, and as a vaccine its action depends on the immune setting, the adjuvant and the patient's tissue type.
Mechanism of Action
Nelipepimut-S is a vaccine antigen, not a drug that acts on a receptor: it is shown to T cells so that they learn to recognise the same HER2 fragment on cancer cells.
A HER2 fragment on HLA molecules
Cancer cells chop HER2 up and display E75 on HLA-A2 or A3; T cells from ovarian tumours recognised it (PMID 7539040).
GM-CSF as adjuvant
Injected into the skin with GM-CSF, the peptide is taken up and presented to CD8 T cells, which expand (PMIDs 12429628, 16157940).
Killer T cells against HER2-bearing cells
Vaccine-induced T cells lysed HER2-expressing tumour cells in the laboratory; whether that prevents recurrence was not shown in the randomised trials (PMIDs 16157940, 31036542).
Published Research
These are the studies of E75 (nelipepimut-S) read from their PubMed abstracts on October 29, 2026: the phase 3 and phase 2 randomised trials, the earlier non-randomised breast and prostate cancer trials, a meta-analysis, the 1995 discovery paper and three reviews. All human studies gave the peptide with GM-CSF.
PRESENT phase 3: no benefit, stopped early
758 women with node-positive, HER2-low breast cancer received 1,000 µg nelipepimut-S with 250 µg GM-CSF or GM-CSF alone, monthly for six months and then every six months. At the interim analysis after 73 events (median 16.8 months) disease-free survival did not differ. Injection-site redness (84%), hardening (56%) and itch (55%) were the commonest events.
Phase 2b with trastuzumab
275 women with HER2-low breast cancer received a year of trastuzumab plus either the vaccine or GM-CSF. Adding the vaccine caused no extra heart or other toxicity. Overall disease-free survival did not differ significantly (hazard ratio 0.62), but in the planned exploratory triple-negative group it was better with the vaccine (hazard ratio 0.26).
Who did better in the phase 2b trial
In the same trial, 36-month disease-free survival was better with the vaccine among 99 triple-negative patients and among HLA-A24 carriers. Within the triple-negative group, the gain showed in HER2 1+ tumours and after chemotherapy before surgery. Subgroup results; a phase 3 trial would be needed to confirm them.
Safety with trastuzumab
A planned safety look after 150 women had enrolled in the phase 2 trial found no difference in toxicity between vaccine plus trastuzumab and trastuzumab with GM-CSF, including heart toxicity.
Before surgery in DCIS
Thirteen HLA-A2 women with ductal carcinoma in situ were randomised to two doses of NeuVax or GM-CSF alone before surgery. More than 89% of side effects were grade 1. Specific T cells rose in both arms, numerically more with the vaccine, but the difference was not statistically significant.
Phase 1/2 final five-year report
Of 187 evaluable women, 108 vaccinated (HLA-A2 or A3) and 79 unvaccinated controls, five-year disease-free survival was 89.7% against 80.2% (p = 0.08). Optimally dosed women reached 94.6%, and one of 21 optimally boosted women recurred. Toxicity was minimal; the control group was not randomised.
Two-year landmark analysis
In 182 evaluable women, 24-month disease-free survival was 94.3% vaccinated against 86.8% in controls (p = 0.08). Benefit looked largest in HER2 1+ to 2+ tumours and in lower-grade tumours, which led to a phase 3 trial in HER2-low disease. 65% of patients had received less than the optimal dose.
Finding the dose and schedule
Ninety-nine disease-free women were vaccinated in seven dose groups over six months. The chosen dose was 1,000 µg E75 with 250 µg GM-CSF monthly for six months; it caused no more toxicity than lower doses and gave larger skin-test responses (21.5 against 11.3 mm).
Boosters for fading immunity
Among 53 women boosted after their primary series, residual E75-specific T cells were usually present at 6 months but in only about half after longer. Boosters caused only grade 1 to 2 side effects and raised immunity in 85% of those who had lost it.
HER2-low tumours responded more
Across the phase 1/2 trials, vaccinated women with low HER2 expression mounted larger immune responses than those with high expression, and showed a trend to lower mortality against controls, strongest in HER2 1+ tumours (p = 0.05). Seven women had trastuzumab first without safety problems.
Early node-positive breast cancer trial
Twenty-four HLA-A2 women were vaccinated and 29 followed as controls. All vaccinated women expanded E75-specific T cells that killed HER2-bearing cells, with one grade 3 toxicity. Recurrence was 8% against 21% at 22 months, not statistically significant.
Patients with HLA-A3
Thirteen HLA-A3 (not A2) women completed vaccination. Toxicity and skin-test responses matched those of HLA-A2 women, suggesting the peptide is presented by HLA-A3 too, which the authors estimate would widen eligibility to about three-quarters of people.
Metastatic breast and ovarian cancer
Fourteen HLA-A2 patients received 100, 500 or 1,000 µg E75 with 250 µg GM-CSF as four intradermal injections, weekly for four weeks and then monthly, ten in all. It was well tolerated; seven of eight tested developed skin-test responses and four of eight had T cells that killed HER2-bearing tumour cells.
Prostate cancer phase 1
Seventeen HLA-A2 men at high risk of PSA recurrence after prostatectomy were vaccinated and 10 followed. Toxicity was minor and every vaccinated man showed an immune response, but disease-free survival was no different at 23 months; most vaccinated men who recurred already had a rising PSA.
Prostate cancer: five-year follow-up
At a median of 58 months, PSA recurrence was 29% in 21 vaccinated men and 26% in 19 controls, not different. Excluding men who recurred during the vaccine series lengthened time to recurrence, not significantly; the authors call for a randomised trial.
Meta-analysis of E75 trials
Sixteen trials were pooled. Skin-test and CD8 T-cell responses were larger in vaccinated patients, and recurrence and survival differed in their favour, with minimal toxicity. The pooled trials were mostly phase 1/2 with non-randomised controls, and the phase 3 result had not yet been published.
Discovery of the peptide
Of 19 HER2 peptides chosen for their fit to HLA-A2, the nine-residue E75 (HER2 369-377, KIFGSLAFL) was recognised by all four T-cell lines grown from ovarian tumours, and a cloned T cell that recognised it also killed HER2-rich ovarian tumour cells.
Development of the E75 vaccine
A review of nelipepimut-S from preclinical work to the phase 3 trial then under way, describing early trials in women made disease-free by standard therapy as safe with a suggestion of clinical benefit.
The emerging data, 2020
A short review calls nelipepimut-S the leading HER2 peptide vaccine and summarises its immune activity and its mixed clinical results in HER2-amplified and non-amplified breast cancer.
Dosing Data
Nelipepimut-S has no approved label. The rows are the regimens of published trials, always with 250 µg of GM-CSF as adjuvant; the registry record of PRESENT (NCT01479244) gives the route as intradermal injection at four sites on the thigh. The phase 3 regimen did not prevent recurrence.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes Nelipepimut-S is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
No worked example: none of the doses on this page is a fixed amount in mg or mcg injected under the skin or into a muscle (the routes given are: intradermal). There is no home-mixing step to show. The reconstitution calculator does the arithmetic for any vial.
Source: the route and amount of each dose row in Dosing Data below.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Nelipepimut-S, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long Nelipepimut-S stays intact once mixed.
How it is taken
As it was given in human studies: Intradermal (Monthly x6, then every 6 months; PRESENT phase 3 (2019): adjuvant breast cancer).
For injection technique, sites and needle disposal, see the mixing guide.
Source: Used in human trials: the route and frequency of each row in Dosing Data below.
What to expect, and when
How long it stays in the body: not established by a measurement cited on this entry.
How long the doses were given: PRESENT phase 3 (2019): adjuvant breast cancer: To 36 months; Dose-finding (2008): optimal biologic dose: 6 doses; Phase 1 (2002): metastatic breast and ovarian cancer: 10 injections.
When effects appear: unknown; no source on this page gives a time to effect for Nelipepimut-S. Results reported in the studies are under Published Research.
Source: Used in human trials, the duration of each row in Dosing Data below.
Side effects, and when to stop or get help
From the Side Effects section: Injection-site redness (84%), hardening (56%) and itch (55%) in the phase 3 trial, at similar rates to GM-CSF alone; No added heart toxicity when given with trastuzumab (phase 2b); Mostly grade 1 side effects before surgery in DCIS; boosters caused only grade 1-2 effects; One grade 3 toxicity among 24 vaccinated women in the 2005 trial. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Nelipepimut-S. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“From the human trials read”).
Interactions
Unknown: a PubMed search for human interaction studies of Nelipepimut-S (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Nelipepimut-S products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Nelipepimut-S's expected mass, 995.2 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: In Clinical Trials (Not approved: Drugs@FDA and the EMA medicines list hold no record (searched October 28, 2026)). Sport: Prohibited (S0 catch-all).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
From the human trials read.
Contraindications & Cautions
No product label exists. These cautions follow from the trials.
Legal Status
Nelipepimut-S was never approved.
Frequently Asked Questions
?What is nelipepimut-S?
The HER2 peptide E75, nine amino acids long (KIFGSLAFL). Given with GM-CSF as the vaccine NeuVax, it was developed to prevent breast cancer from returning after standard treatment.
?Did the phase 3 trial work?
No. PRESENT randomised 758 women and was stopped early for futility after its interim analysis found no difference in disease-free survival between the vaccine and GM-CSF alone (2019).
?Why did earlier trials look better?
They were small and not randomised: vaccinated women were chosen by tissue type and compared with women of other tissue types, and their survival differences did not reach statistical significance. Randomised trials are the stronger test, and the large one was negative.
?Is there any group in which it may help?
In a phase 2b trial with trastuzumab, an exploratory analysis found better disease-free survival in triple-negative breast cancer. That is a subgroup finding and would need its own phase 3 trial.
?What were the side effects?
Mostly reactions where it was injected: redness, hardening and itch. Serious toxicity was rare in the trials.
References
- [other] PubChem CID 9941306, Nelipepimut-S: formula C50H78N10O11, molecular weight 995.2. Read October 28, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/9941306
- [clinical-trial] Mittendorf EA, et al. "Efficacy and Safety Analysis of Nelipepimut-S Vaccine to Prevent Breast Cancer Recurrence: A Randomized, Multicenter, Phase III Clinical Trial." Clin Cancer Res, 2019;25(14):4248-4254. PMID: 31036542.
- [clinical-trial] Clifton GT, et al. "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." Clin Cancer Res, 2020;26(11):2515-2523. PMID: 32071118.
- [clinical-trial] Chick RC, et al. "Subgroup analysis of nelipepimut-S plus GM-CSF combined with trastuzumab versus trastuzumab alone to prevent recurrences in patients with high-risk, HER2 low-expressing breast cancer." Clin Immunol, 2021;225:108679. PMID: 33485895.
- [clinical-trial] Clifton GT, et al. "Initial safety analysis of a randomized phase II trial of nelipepimut-S + GM-CSF and trastuzumab compared to trastuzumab alone to prevent recurrence in breast cancer patients with HER2 low-expressing tumors." Clin Immunol, 2019;201:48-54. PMID: 30817999.
- [clinical-trial] O'Shea AE, et al. "Phase II Trial of Nelipepimut-S Peptide Vaccine in Women with Ductal Carcinoma In Situ." Cancer Prev Res (Phila), 2023;16(6):333-341. PMID: 37259799.
- [clinical-trial] Mittendorf EA, et al. "Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients." Ann Oncol, 2014;25(9):1735-1742. PMID: 24907636.
- [clinical-trial] Mittendorf EA, et al. "Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02." Cancer, 2012;118(10):2594-602. PMID: 21989902.
- [clinical-trial] Holmes JP, et al. "Optimal dose and schedule of an HER-2/neu (E75) peptide vaccine to prevent breast cancer recurrence: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02." Cancer, 2008;113(7):1666-75. PMID: 18726994.
- [clinical-trial] Holmes JP, et al. "Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02." Cancer, 2011;117(3):463-71. PMID: 20845479.
- [clinical-trial] Benavides LC, et al. "The impact of HER2/neu expression level on response to the E75 vaccine: from U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02." Clin Cancer Res, 2009;15(8):2895-904. PMID: 19351776.
- [clinical-trial] Peoples GE, et al. "Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer patients." J Clin Oncol, 2005;23(30):7536-45. PMID: 16157940.
- [clinical-trial] Patil R, et al. "Clinical and immunologic responses of HLA-A3+ breast cancer patients vaccinated with the HER2/neu-derived peptide vaccine, E75, in a phase I/II clinical trial." J Am Coll Surg, 2010;210(2):140-7. PMID: 20113933.
- [pubmed] Murray JL, et al. "Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369-377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer." Clin Cancer Res, 2002;8(11):3407-18. PMID: 12429628.
- [clinical-trial] Hueman MT, et al. "Phase I clinical trial of a HER-2/neu peptide (E75) vaccine for the prevention of prostate-specific antigen recurrence in high-risk prostate cancer patients." Clin Cancer Res, 2005;11(20):7470-9. PMID: 16243821.
- [clinical-trial] Gates JD, et al. "Longterm followup assessment of a HER2/neu peptide (E75) vaccine for prevention of recurrence in high-risk prostate cancer patients." J Am Coll Surg, 2009;208(2):193-201. PMID: 19228530.
- [review] Chamani R, et al. "Application of E75 peptide vaccine in breast cancer patients: A systematic review and meta-analysis." Eur J Pharmacol, 2018;831:87-93. PMID: 29753042.
- [pubmed] Fisk B, et al. "Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines." J Exp Med, 1995;181(6):2109-17. PMID: 7539040.
- [review] Clifton GT, et al. "The development and use of the E75 (HER2 369-377) peptide vaccine." Future Oncol, 2016;12(11):1321-9. PMID: 27044454.
- [review] Dillon PM, et al. "Evaluating Nelipepimut-S in the Treatment of Breast Cancer: A Short Report on the Emerging Data." Breast Cancer (Dove Med Press), 2020;12:69-75. PMID: 32308474.
- [registry] ClinicalTrials.gov API v2, read October 28, 2026: NCT01479244 (phase 3, completed); NCT02297698 and NCT02636582 (phase 2, completed).
Sources & Citations
Studies were read from their PubMed records on October 29, 2026. The route comes from the ClinicalTrials.gov record NCT01479244, read the same day; formula from PubChem CID 9941306; status from Drugs@FDA and the EMA medicines list, read October 28, 2026. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.