Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB–IVM1a melanoma: a randomized, open-label, phase 2 trial


Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB–IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58–0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30–0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8+ density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB–IVM1a melanoma.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Kaplan–Meier estimates of RFS and OS at 2 years.
Fig. 2: Increased CD8 infiltration, PD-L1 expression and inflammation-related gene expression observed with neoadjuvant T-VEC treatment.

Similar content being viewed by others

Data availability

There is a plan to share data. This may include de-identified individual patient data for variables necessary to address the specific research question in an approved data-sharing request, in addition to related data dictionaries, study protocol, statistical analysis plan, informed consent form and/or clinical study report. Data-sharing requests relating to data in this manuscript will be considered after the publication date and: (1) this product and indication (or other new use) have been granted marketing authorization in both the United States and Europe; or (2) clinical development discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data-sharing request for these data. Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labeling. A committee of internal advisors reviews requests. If not approved, requests may be further arbitrated by a Data Sharing Independent Review Panel. Requests that pose a potential conflict of interest or an actual or potential competitive risk may be declined at Amgen’s sole discretion and without further arbitration. Amgen will reply by email with confirmation that your request has been received. Amgen will also confirm whether all the required request information has been received and follow up with a timeframe. Upon approval, information necessary to address the research question will be provided under the terms of a data-sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the following: The data discussed in this publication have been deposited in the National Center for Biotechnical Information’s Gene Expression Omnibus (GEO)29.) and are accessible through GEO accession no. GSE182162.


  1. Versluis, J. M., Long, G. V. & Blank, C. U. Learning from clinical trials of neoadjuvant checkpoint blockade. Nat. Med. 26, 475–484 (2020).

    Article  CAS  Google Scholar 

  2. Helmink, B. & Wargo, J. A. Neoadjuvant therapy for melanoma: is it ready for prime time? Lancet Oncol. 20, 892–894 (2019).

    Article  Google Scholar 

  3. O’Donnell, J. S., Hoefsmit, E. P., Smyth, M. J., Blank, C. U. & Teng, M. W. L. The promise of neoadjuvant immunotherapy and surgery for cancer treatment. Clin. Cancer Res. 25, 5743–5751 (2019).

    Article  Google Scholar 

  4. NCCN Clinical Practice Guidelines in Oncology: Melanoma, v.3 (National Comprehensive Cancer Network (NCCN), (accessed 10 April 2019).

  5. Michielin, O., van Akkooi, A. C. J., Ascierto, P. A., Dummer, R. & Keilholz, U., ESMO Guidelines Committee. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 30, 1884–1901 (2019).

    Article  CAS  Google Scholar 

  6. Amaria, R. N. et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol. 19, 181–193 (2018).

    Article  CAS  Google Scholar 

  7. Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018).

    Article  CAS  Google Scholar 

  8. Long, G. V. et al. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAF(V600) mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol. 20, 961–971 (2019).

    Article  CAS  Google Scholar 

  9. Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019).

    Article  CAS  Google Scholar 

  10. Huang, A. C. et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat. Med. 25, 454–461 (2019).

    Article  CAS  Google Scholar 

  11. Amaria, R. N. et al. Neoadjuvant systemic therapy in melanoma: recommendations of the international neoadjuvant melanoma consortium. Lancet Oncol. 20, e378–e389 (2019).

    Article  Google Scholar 

  12. Menzies, A. M. et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Nat. Med. 27, 301–309 (2021).

    Article  CAS  Google Scholar 

  13. Garutti, M. et al. ‘To anticipate’: neoadjuvant therapy in melanoma with a focus on predictive biomarkers. Cancers 12, 1941 (2020).

    Article  CAS  Google Scholar 

  14. Liu, B. L. et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 10, 292–303 (2003).

    Article  CAS  Google Scholar 

  15. Andtbacka, R. H. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780–2788 (2015).

    Article  CAS  Google Scholar 

  16. Andtbacka, R. H. et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III–IV melanoma. J. Immunother. Cancer 7, 145 (2019).

    Article  Google Scholar 

  17. Balch, C. M. et al. Final version of 2009 AJCC melanoma staging and classification. J. Clin. Oncol. 27, 6199–6206 (2009).

    Article  Google Scholar 

  18. Larocca, C. A., LeBoeuf, N. R., Silk, A. W. & Kaufman, H. L. An update on the role of talimogene laherparepvec (T-VEC) in the treatment of melanoma: best practices and future directions. Am. J. Clin. Dermatol 21, 821–832 (2020).

    Article  Google Scholar 

  19. Ribas, A. et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170, 1109–1119 (2017).

    Article  CAS  Google Scholar 

  20. Ayers, M. et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).

    Article  Google Scholar 

  21. Miller, C. J. et al. Risk factors for positive or equivocal margins after wide local excision of 1345 cutaneous melanomas. J. Am. Acad. Dermatol. 77, 333–340 (2017).

    Article  Google Scholar 

  22. Moschos, S. J. et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J. Clin. Oncol. 24, 3164–3171 (2006).

    Article  CAS  Google Scholar 

  23. Buzaid, A. C. et al. Phase II study of neoadjuvant concurrent biochemotherapy in melanoma patients with local-regional metastases. Melanoma Res. 8, 549–556 (1998).

    Article  CAS  Google Scholar 

  24. Koyanagi, K. et al. Serial monitoring of circulating melanoma cells during neoadjuvant biochemotherapy for stage III melanoma: outcome prediction in a multicenter trial. J. Clin. Oncol. 23, 8057–8064 (2005).

    Article  Google Scholar 

  25. Lewis, K. D. et al. Phase II multicenter study of neoadjuvant biochemotherapy for patients with stage III malignant melanoma. J. Clin. Oncol. 24, 3157–3163 (2006).

    Article  CAS  Google Scholar 

  26. Gogas, H. et al. Talimogene laherparepvec (T-VEC) treatment increases intratumoral effector T-cell and natural killer (NK) cell density in noninjected tumors in patients (pts) with stage IIIB–IVM1c melanoma: evidence for systemic effects in a phase II, single-arm study. Poster presented at European Society for Medical Oncology, 19–23 October 2018, Munich, Germany.

  27. Eggermont, A. M. et al. Adjuvant therapy with pegylated interferon alpha-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372, 117–126 (2008).

    Article  CAS  Google Scholar 

  28. Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B Stat. Methodol. 57, 289–300 (1995).

    Google Scholar 

  29. Edgar, R., Domrachev, M. & Lash, A. E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002).

    Article  CAS  Google Scholar 

Download references


Medical writing support was provided by C. Nosala of Amgen Inc. The authors thank J. Gansert of Amgen Inc. for designing the study and R. Andtbacka for contributions to study design. This study was sponsored by Amgen Inc.

Author information

Authors and Affiliations



R.D. designed the protocol design, collected/acquired patient data, and analyzed and interpreted the data. D.E.G., J.H., A.C.B., R.C., L.D. and M.F. collected/acquired patient data. A.S., S.A.T., H.R., K.S.G. and E.C. analyzed and interpreted the data. A.A. conceived and designed the study, and analyzed and interpreted data. M.I.R. collected/acquired patient data, and analyzed and interpreted the data.

Corresponding author

Correspondence to R. Dummer.

Ethics declarations

Competing interests

R.D. has intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi and Catalym outside the submitted work. D.E.G. received travel expenses and an honorarium from Amgen Inc. J.H. is a contracted reviewer for Ebix publishing (but does not deem this to be relevant to the content of the current publication). He also received travel funding from BMS and served on advisory boards for BMS and Nektar. A.C.B. served on the speaker’s bureau for Cardinal Health. R.C. served on the speaker’s bureau for Merck, BMS, Amgen Inc., Novartis, Array and Regeneron-Sanofi. L.D. received research grants from Novartis, consulting fees for MSD, BMS, Novartis and Roche, served on the advisory board for Novartis, and received honoraria from MSD, BMS, Novartis and Roche. E.C., A.S., S.A.T., H.R., A.A. and K.S.G. are employees of and stockholders in Amgen Inc. M.F. received consulting fees from Delcath Systems Inc. and served on the advisory board for Pulse Biosciences and Novartis. M.I.R. received honoraria from Merck and Amgen Inc., served on the advisory board for Merck and Amgen Inc., received research funding from Amgen and Provectus, and travel expenses from Merck, Amgen Inc., Provectus, Novartis and Castle Biosciences.

Additional information

Peer review information Nature Medicine thanks Kim Margolin, Alain Algazi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Saheli Sadanand was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Trial profile.

T-VEC = talimogene laherparepvec.

Extended Data Fig. 2 Patient demographics and clinical characteristics.

*An additional stage IVM1c patient was determined to be ineligible after going on study. Arm 1 immunotherapies include pembrolizumab for one patient, ipilimumab for one patient, and interferon for one patient. Arm 2 immunotherapies include pembrolizumab for one patient and ipilimumab for two patients. Arm 1 n = 76, Arm 2 n = 73. §Arm 1 n = 62, Arm 2 n = 59. CRF = case report form; ECOG = Eastern Cooperative Oncology Group; IVRS = interactive voice response system; SPD = sum of products of two largest perpendicular diameters of baseline measurable lesions; T-VEC = talimogene laherparepvec.

Extended Data Fig. 3 Baseline demographics of patients who progressed prior to surgery in Arm 1 and patients who recurred within 14 weeks in Arm 2.

ECOG = Eastern Cooperative Oncology Group; HSV-1=herpes simplex virus 1; LDH = lactate dehydrogenase; T-VEC = talimogene laherparepvec; ULN = upper limit of normal.

Extended Data Fig. 4 Margin of resection.

n = number of patients with protocol-defined surgery in the analysis set. Histopathology tumor-free margin (R0) surgical resection is defined by pathologist as absence of ink on the tumor in the resected specimen. 80% exact CI for binary rate of each arm is calculated using the Clopper-Pearson method. An 80% exact CI for between-arm differences in binary rate is calculated using Wilson’s score method with continuity correction. R1 surgical resection is defined as complete resection with no grossly visible tumor left behind as defined by the surgeon. R2 surgical resection is defined as partial resection with grossly visible tumor left behind as defined by the surgeon. CI = confidence interval; T-VEC = talimogene laherparepvec.

Extended Data Fig. 5 Subsequent anticancer treatment.

CTLA-4=cytotoxic T-lymphocyte-associated protein 4; PD-1=programmed cell death protein 1; PD-L1 = programmed death-ligand 1; T-VEC = talimogene laherparepvec.

Extended Data Fig. 6 IFN-γ signature and T-cell–inflamed gene expression before and after T-VEC administration.

Black circles: Arm 1 at baseline before T-VEC administration. Yellow squares: Arm 1 after T-VEC administration before surgery. Graphs depict model estimated least squares means along with 95% confidence intervals. IFN-γ = interferon-gamma; T-VEC = talimogene laherparepvec; W = week.

Extended Data Fig. 7 CD8+ density, CD3 expression, and CD274 (PD-L1) expression correlation with recurrence-free survival in the 2-year primary analysis.

Vertical bar (|) indicates patients that were censored. For subfigure a, patients were divided into three equally sized groups based on fold change: ≥-23.03x to <1.08x (decrease), ≥1.08x to <3.51x (intermediate increase), and ≥3.51x to ≤582.81x (intense increase). Patients were divided into three groups of equal size (a). For subfigures b and c, increase vs no-change or decrease were defined based on fold change. Increased was defined as a fold change greater than 1x, no change or decreased included everything else (b,c). Time 0 at time of randomization. CI = confidence interval; HR = hazard ratio; PD-L1 = programmed death-ligand 1.

Extended Data Fig. 8 Summary of 3-year analysis.

CI = confidence interval; DMFS = distant metastasis-free survival; HR = hazard ratio; KM = Kaplan-Meier; LRFS = local recurrence-free survival; OS = overall survival; RFS = recurrence-free survival; RRFS = regional recurrence-free survival; T-VEC = talimogene laherparepvec.

Supplementary information

Supplementary Information

Supplementary Table 1 and Fig. 1.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dummer, R., Gyorki, D.E., Hyngstrom, J. et al. Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB–IVM1a melanoma: a randomized, open-label, phase 2 trial. Nat Med 27, 1789–1796 (2021).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing