For Recurrence Breast Cancer

TECHBRIEF HORIZON SCANNING REPORT NEUVAX™ (NELIPEPIMUT-S, NP-S) FOR RECURRENCE BREAST CANCER

Report No: 006/2019

MaHTAS Medical Development Division Ministry of Health, Malaysia “DOKUMEN TERHAD”

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Prepared by:

Dr. Norrina Jamaluddin Principal Assistant Director Health Technology Assessment Section (MaHTAS) Medical Development Division Ministry of Health Malaysia

Reviewed by:

Dr. Izzuna Mudla bt Mohamed Ghazali Public Health Physician/Senior Principal Assistant Director Health Technology Assessment Section (MaHTAS) Medical Development Division Ministry of Health Malaysia

Dr. Junainah bt Sabirin Public Health Physician/Deputy Director Health Technology Assessment Section (MaHTAS) Medical Development Division Ministry of Health Malaysia

Disclosure: The author of this report has no competing interest in this subject and the preparation of this report is totally funded by the Ministry of Health, Malaysia.

Disclaimer: TechBrief report is prepared based on information available at the time of research and a limited literature. It is not a definitive statement on the safety, effectiveness or cost effectiveness of the health technology covered. Additionally, other relevant scientific findings may have been reported since completion of this report.

Horizon Scanning Unit, MaHTAS, Medical Development Division, Ministry of Health, Malaysia, Email: [email protected] Web: http://www.moh.gov.my

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TechBrief

Report No. : 006/2019 NEUVAX™ (NELIPEPIMUT-S, NP -S) FOR RECURRENCE BREAST CANCER SUMMARY it was estimated that 627,000 women died from breast cancer which was NeuVax™ (Nelipepimut-S, NP-S) is an approximately 15% of all cancer deaths investigational immunotherapy being among women.1 developed by SELLAS Life Sciences Group Incorporation to treat human In Malaysia, breast cancer is the most epidermal growth factor 2 (HER2)- common cancer in females. The associated breast cancers. International Agency for Research on Cancer (IARC) reported new cases of The vaccine is given as adjuvant breast cancer comprised of 32.7% of all therapy to prevent breast cancer new cancer cases in female.2 recurrence by binding to the specific HLA molecules on antigen presenting Research on breast cancer vaccine was cells and stimulates specific cytotoxic T intensified following the successful used lymphocyte. These activated CTLs of immunotherapy for melanoma, renal recognized, neutralized and destroyed, cancer, lung cancer, glioblastoma and through cell lysis and HER2 expressing gastric cancer. Since the approval and cancer cells. acceptance of the first peptide vaccine for prostate cancer in 2010, many Limited vaccine efficacy studies showed researches using peptide-based vaccine promising results. The vaccine is easily were carried out.3 The role of the administered, safe and potentially immune system in the emergence of provide significant efficacy for subgroup breast cancer therapy has been firmly triple negative patient. established.4,5,6

Keywords: breast cancer, vaccine, The objective of this early assessment is recurrence, immunotherapy, adjuvant to evaluate effectiveness and safety of therapy, triple negative NeuVax™ in preventing recurrence INTRODUCTION breat cancer. THE TECHNOLOGY Breast cancer is the most frequent cancer among women globally, NeuVax™ (Nelipepimut-S, NP-S) is a impacting 2.1 million women each year. HER2-targeted vaccine being It causes the greatest number of cancer- investigated for breast cancer. related deaths among women. In 2018,

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NeuVax™ is a combination of E75, a metastatic cancer cells through cell peptide from the extracellular domain of lysis.7,8 HER2 and granulocyte-macrophage colony-stimulating factor (GM-CSF); it Initially, it was developed by Galena stimulates cytotoxic T lymphocytes and BioPharma, Inc. As of December 2017, CD8+ memory cells with high affinity for Galena BioPharma merged with HLA-A2/A3.3 SELLAS Ltd. and formed SELLAS Life Sciences Group Inc. This vaccine NeuVax™ stimulates and activates aimed to prevent or delay the CD8+ CTLs and CD8+ memory cells recurrence of breast cancer in cancer against E75, MHC class I epitope. More survivors who achieve remission after precisely, the activated specific CTLs standard of care treatment (e.g., bind to HLA-A2/A3 molecules on surgery, radiation, chemotherapy). antigen-presenting cells therefore recognizing, neutralizing and destroying HER-2 expressing primary and

IMMUNOGENETIC

ANTIGEN

NeuVax™

Figure 1: Schematic representation of NeuVax™ activity 9

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Photo by: www.thepharmaletter.com

Figure 2: NeuVax™ vaccine

PATIENT GROUP AND CURRENT PRACTICE

INDICATION According to Clinical Practice NeuVax™ is a breast cancer vaccine Guidelines, Ministry of Health (2010), indicated to prevent or delay the the current management for breast recurrence of breast cancer in cancer cancer will depends on the stage of survivors who achieve remission after diseases. For patient in early stage, standard of care treatment (e.g., surgery is the first line of treatment. Patient may be offered mastectomy; surgery, radiation, chemotherapy). However, the studies only include those with or without axillary clearance or with low expression of HER2 breast conserving surgery (BCS). (Immunohistochemistry [IHC] (1+/2+), and the only significant result was The surgery depends on the risk of improvement in DFS in the subgroup stratification; (1) BCS with axillary analysis of triple negative patients. surgery for low risk patient and (2) Other studies are still ongoing. mastectomy with axillary surgery with or without reconstruction for patients with intermediate or high risk group.

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For BCS, adjuvant radiotherapy and NeuVax™ is the only breast cancer hormonal therapy may be offered. vaccine that completed Phase 3 clinical Chemotherapy treatment with or trial [PRESENT (Prevention of without Herceptin and adjuvant Recurrence in Early Stage, Node- radiotherapy (with or without hormone Positive Breast Cancer with Low to therapy) may be considered for Intermediate HER2 Expression with intermediate or high risk patients. This NeuVax Treatment)]. The trial treatment is equivalent to patients who compared NeuVax™ plus GM-CSF underwent mastectomy with axillary with placebo plus GM-CSF in surgery (with or without preventing cancer recurrence in reconstruction).10 patients with node positive, HER2 IHC 1+/2+, and HLA-A2+ and/or A3+ For remission breast cancer survivors, patients. (NCT01479244) a psychological support and breast care nursing is provided to gear In addition to PRESENT trial, there are survivor’s needs. Psychological care is three ongoing clinical trials conducted: aim to improve the continuity of care i. Two studies evaluate NeuVax™ in and support them throughout the combination with trastuzumab 10 diagnosis, treatment and follow up. (Herceptin®; Genentech/Roche) for breast cancer. A current practice of combination trastuzumab with chemotherapy leads a) Phase 2b trial in node positive to improved disease-free survival and (or node negative if negative for overall survival compared to no both ER and PR) breast cancer treatment, in people with T1a, T1b and patients with HERS IHC 1+/2+ T1c tumours. Specifically, an additional (NCT01570036) 14% of patient would be free from disease at three years and additional b) Phase 2 trial in high-risk node nine to 15% would be alive at eight positive or negative HER2 IHC years (T1a 14%, T1b 11%, T1c 15%) 3+ patients (NCT02297698) with the combination compared to no ii. A phase 2 clinical trial of NeuVax™ 11 treatment. (Nelipepimut-S) peptide vaccine in women with ductal carcinoma in SAFETY & EFFICACY situ (DCIS). It aims to assess effectiveness of NeuVax™ plus An electronic search of databases such GM-CSF or sargamostim (Leukin®) as PubMed and Embase using in treating patients with DCIS keywords either single or combination; (NCT02636582).12 NeuVax™, peptide-based vaccine, breast cancer vaccine, recurrence A) Efficacy breast vaccine was performed. All searches were conducted between 15th The final analysis of phase 2b April 2019 to 20th September 2019. clinical trial of Nelipepimut-S plus 4 | P a g e

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GM-CSF with trastuzumab versus However, subanalysis of TNBC GM-CSF with trastuzumab to patients showed significant difference prevent recurrences in high risk, in median DFS in favour of the HER2 low-expressing breast intervention group [hazard ratio (HR) cancer was presented during 0.26 (95% Cl: 0.08,0.81)] for median ASCO-SITC Clinical Immuno- follow-up of 26.1 month Oncology Symposium in March (IQR:19.9,31.9).13 (See Figure 4) 2019. (NCT01570036).13

Patients in the intervention group (n=136) received vaccinations of NeuVax™ or GM-CSF intradermally every three weeks for six total vaccinations (primary vaccine series, PVS) starting with the third dose of trastuzumab maintenance therapy. Starting six months after the completion of the PVS, patients received four booster inoculations, one every six months for 30 month. The control group (n=139) received 24-month 36-month DFS (%) DFS (%) trastuzumab only. NeuVax + TZ 89.9 86.7 The intention to treat (ITT) analysis (N=136) showed significant reduction of recurrence among triple negative TZ (N=139) 83.8 80.8 breast cancer (TNBC) who received Figure 3: Disease-free survival among ITT NeuVax™ in combination with population trastuzumab (7.5%) as compared to trastuzumab alone (26.7%), p=0.01

There was no significant difference in the disease free survival (DFS) in the ITT analysis between the intervention and control group (See Figure 3). For all recurrence cases, no significant difference was reported for ITT population [treatment group: NeuVax™ and trastuzumab (n=136) compared to control group who received trastuzumab (n=139), p=0.18, HR 0.62 (95% Cl 0.31,1.25)] at median follow-up 24.7 months (IQR:18.7,32.7).13 5 | P a g e

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24-month 36-month DFS compared with trastuzumab alone. DFS (%) (%) There was no difference between NeuVax + TZ 92.6 82.3 treatment arms in cardiac ejection (N=53) fraction over time (p=0.65) and at each time point.13 TZ (N=44) 70.2 70.2 A phase 3 clinical trial PRESENT Figure 4: Disease-free survival among TNBC (NCT01479244) reported thirteen patients (3.5%) patients in the treatment group For Hormone Receptor-Positive (HR+) and 15 (3.9%) in the placebo group patient, no significant difference in discontinued study participation due to median DFS between treatment group adverse events. Adverse event were and control group reported. similar between groups, with the most common being those associated with In PRESENT study, there were 61 injections, such as erythema (84.3%), cases of suspected disease recurrence, induration (55.8%) and pruritus (54.9%). nine cases of new primary breast or Severe adverse events related to second cancers and three deaths. The treatment occurred in three or more three year Kaplan-Meier estimated DFS patients in the treatment group: rates were 77.1% in the treatment group injection site erythema (seven); versus 77.5% in the control group. The arthralgia (four); neutropaenia, difference in DFS between groups was increased alanine aminotransferase, not significant (p=0.07). From the interim increased aspartate aminotransferase, analysis, the Independent Data urticaria and increased weight (three 14 Monitoring Committee (IDMC) each). recommended the study to be stopped Cardiac events were recorded in 15 of for futility in 2016.14 372 treatment group patients and ten of

B) Safety 373 patients in placebo group. Eight (2.2%) patients in the treatment group In Phase 2b (NCT01570036) clinical and seven (1.9%) patients in placebo trial, about 94.3% (n=246/261) of group experienced changes in LVEF. patients who received an intervention One (0.3%) of the treatment group (Nelipepimut-S plus GM-CSF with patients and three (0.8%) for placebo trastuzumab) experienced at least one group experienced a new-onset or TRAE (treatment-related adverse sustained rhythm or conduction event). There was no difference abnormality, and six (1.6%) patients between groups (p=0.17). Majority of from treatment group and two (0.5%) TRAEs were grade one or two such as from placebo patients experienced a local injection site reactions, skin thromboembolic disorder. Two patients induration, pruritus and fatigue. The in the treatment group experienced new- addition of NeuVax™ to trastuzumab did onset or exacerbation of acute coronary not result in any additional cardiotoxicity syndrome.14

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None of the serious adverse events dose monthly for six months, followed were determined to be related to the by booster inoculations every six vaccine. Three deaths were considered months for a total of 11 doses over 36 not related to treatment.14 months. ESTIMATED COST For breast cancer recurrence, essential assessment is protocol-specified A projection study using decision imaging at the 12, 24 and 36 month analytic model study conducted by follow-up visits and compared with Patel et al. in 2010 on breast cancer mandatory baseline images. Imaging vaccine in comparison to current assessment includes mammogram standard treatments reported the costs (except when bilateral mastectomy had included for standard treatments of been performed), computed breast cancer ranged from $20,000 to tomography (chest, abdomen, pelvis) $45,000 (RM 84,000 to RM 198,000) and bone scan. If computed and the price of the vaccine was tomography scan (CT scan) is not assumed at $450 (RM 1900) for three feasible, MRI is indicated and positron doses; therefore, the cost for vaccine emission tomography (PET scan) is ranged from $300 to $2000 (RM 1300 performed if bone scan is not to RM 8400) depending on the number feasible.14 of doses.15 Generally, there is an issues on Vaccination was found to be a chemical and immunologic nature of potentially cost-effective option with an the vaccine composition that can result ICER of USD2384.14 per QALY gained in local tissue damage or altered (RM 9990.74 per QALY gained) relative immunologic cascade. It should be to standard treatment. The incremental considered to determine the optimal effectiveness was 8.2 life-years saved route and depth of injection to for disease-free status of the patient. maximise safety and immunogenicity. The highest cost-effectiveness of the vaccine was at 90% success and a cost In terms of vaccine delivery, some of not more than USD1000 (RM 4200) cancer vaccines are facility dependent per individual.15 in manufacturing or delivery. It is difficult to expand the usage to Currently, no peptide-based vaccines community setting outside cutting-edge 16 available in the market. research facilities. The vaccine platform should be designed with the widening ORGANIZATIONAL ISSUES of accessibility.17

The vaccine is easy to use and no The optimum interval spacing or doses particular training is required. of cancer vaccines are largely unknown NeuVax™ is supplied in 1mL water for because of a lack of information from injection (WFI) at a concentration of clinically successful cancer vaccines in 1.5mg/ml. The dose is one intradermal

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contrast to vaccines against infectious 2. Breast Cancer in Malaysia, The organisms.17 Global Cancer Observatory Fact Sheets, WHO March 2019. Generally, peptide-based vaccines are usually water-soluble, freeze-dried and 3. Makhoul I, Atiq M, Alwbari A, et al. stable under simple storage Breast Cancer Immunotherapy: An conditions.18 Update. Breast Cancer (Auckl). 2018 POTENTIAL IMPACT 4. Loi S, Michiels S, Salgado R, et al. NeuVax™ is a novel investigational Tumor infiltrating lymphocytes are breast cancer vaccine. It is indicated to prognostic in triple negative breast prevent or delay breast cancer cancer and predictive for recurrence among breast cancer trastuzumab benefit in early breast survivors who achieve remission after cancer: results from the FinHER standard of care treatment. trial. Ann Oncol. 2014;25:1544– 1550. doi:10.1093/annonc/mdu112. The peptide-based cancer vaccines demonstrated positive outcomes in 5. Adams S, Gray RJ, Demaria S, et early phases, which resulted in further al. Prognostic value of tumor- clinical trials being conducted. It has infiltrating lymphocytesin triple- synergistic effects with checkpoint negative breast cancers from two inhibitors and conventional cancer phase III randomized adjuvant therapies.19,20,21 breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. One clinical trial showed promising 2014;32:2959–2966. result. It reduced the recurrence rate in subgroup of patient with TNBC when 6. Denkert C, von Minckwitz G, Brase given in combination with trastuzumab. JC, et al. Tumor-infiltrating However, more evidence is required to lymphocytes and response to prove its efficacy. The vaccine is easily neoadjuvant chemotherapy with or administered and only mild adverse without carboplatin in human events were reported after vaccine epidermal growth factor receptor 2- administration. positive and triple-negative primary breast cancers. J Clin Oncol. REFERENCES 2015;33:983–991.

1. World Health Organization: Breast 7. Peoples GE, Gurney JM, Hueman Cancer. Available at: MT, et al. Clinical Trial Results Of A https://wwwt.who.int/cancer/preventi HER2/Neu (E75). Vaccine to on/diagnosis-screening/breast- Prevent Recurrence in High-Risk cancer/en/ Breast Cancer Patients. J Clin Oncol. 2005

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8. Schneble EJ, Berry JS, Trappey FA, at-the-European-Society-for- et al. The HER2 Peptide Medical-Oncology-ESMO-20/ Nelipepimut-S (E75) Vaccine (Neuvax) In Breast Cancer Patients 13. Combination Immunotherapy With at Risk for Recurrence: Correlation Herceptin and the HER2 Vaccine Of Immunologic Data with Clinical NeuVax, Phase 2b Clinical Trial, Response. Immunotherapy. 2014 NCT01570036, Available at: https://clinicaltrials.gov/ct2/show/NC 9. Benedetti R, Dell' Aversana C, T01570036?term=NCT01570036&r Giorgio C, et al. Breast Cancer ank=1 Vaccines: New Insights. Frontiers in Endocrinology. 2017;8:270 14. Efficacy and safety analysis of Nelipepimut-S Vaccine to Prevent 10. Clinical Practice Guidelines, Breast Cancer Recurrence: A Management of Breast Cancer, Randomized, Multicenter, Phase III Ministry of Health, 2nd edition, 2010 Clinical Trial (PRESENT, NCT01479244), Available at : 11. National Institute for Health and https://clinicaltrials.gov/ct2/show/NC Care, Excellence Early and locally T0147924 advanced breast cancer: diagnosis and treatment. Evidence reviews for 15. Patel T, Zaveri V, Gohil N, et al. adjuvant biological Therapy. Projecting The Potential Cost- January 2018. Effectiveness of A Breast Cancer Vaccine in Comparison to Other 12. SELLAS Life Sciences Announces Standard Treatments: A Decision Positive Final Data in Triple Analytic Model. Value in Health. Negative Breast Cancer Patients 2010;13(7) (abstract) from Phase 2b Clinical Trial of Nelipepimut-S (NeuVax™) in 16. Skwarczynski M, Toth I. Peptide- Combination with Trastuzumab Based Synthetic Vaccines. (Herceptin®) Presented at the Chemical Science. 2016;7(2):842- European Society for Medical 854. Oncology (ESMO) 2018 Annual Meeting, Available at: 17. Maeng HM, Berzofsky JA. https://www.sellaslifesciences.com/i Strategies for Developing and nvestors/news/News- Optimizing Cancer Vaccines. Details/2018/SELLAS-Life- F1000Research. 2019;8. Sciences-Announces-Positive-Final- 18. Nevagi R.J, Toth, I, Skwarczynski, Data-in-Triple-Negative-Breast- M. Peptide-based vaccines. In Cancer-Patients-from-Phase-2b- Peptide Applications in Biomedicine, Clinical-Trial-of-Nelipepimut-S- Biotechnology and Bioengineering; NeuVax-in-Combination-with- Koutsopoulos, S., Ed.; Woodhead Trastuzumab-Herceptin-Presented- Publishing: Sawston, UK, 2018; pp. 327–358. 9 | P a g e

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19. Kumai T, Kobayashi H, Harabuchi 21. Hu Z, Ott PA, Wu CJ. Towards Y, et al. Peptide Vaccines in personalized, tumour-specific, Cancer—Old Concept Revisited. therapeutic vaccines for cancer. Nat Current Opinion in Immunology. Rev Immunol. (2018) 18:168–182. 2017;45:1-7

20. Guo Y, Lei K, Tang L. Neoantigen vaccine delivery for personalized anticancer immunotherapy. Front Immunol. (2018) 9:1499.

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Prepared by: Dr. Norrina binti Jamaluddin Medical Officer/Principal Assistant Director Health Technology Assessment Section (MaHTAS) Medical Development Division Ministry of Health Malaysia

Reviewed by: Dr. Izzuna Mudla Binti Mohamed Ghazali Public Health Physician Senior Principal Assistant Director Health Technology Assessment Section (MaHTAS) Medical Development Division Ministry of Health Malaysia

Dr. Junainah Binti Sabirin Public Health Physician Deputy Director Health Technology Assessment Section (MaHTAS) Medical Development Division Ministry of Health Malaysia

External reviewer: Dr. Ros Suzanna binti Ahmad Bustamam Head of Service Radiotherapy & Oncology Consultant Oncologist (Radiotherapy & Oncology) Hospital Kuala Lumpur

Dr.Eznal Izwadi Mahidin Clinical Oncologist, Radiotherapy & Oncology Department Hospital Kuala Lumpur

Disclosure: The author of this report has no competing interest in this subject and the preparation of this report is totally funded by the Ministry of Health, Malaysia.

Disclaimer: TechBrief report is prepared based on information available at the time of research and a limited literature. It is not a definitive statement on the safety, effectiveness or cost-effectiveness of the health technology covered. Additionally, other relevant scientific findings may have been reported since completion of this report.

Horizon Scanning Unit, MaHTAS, Medical Development Division, Ministry of Health, Malaysia, Email: [email protected] Web: http://www.moh.gov.my

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