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

Abstract

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.

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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.

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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: https://wwwext.amgen.com/science/clinical-trials/clinical-data-transparency-practices. 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.

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Acknowledgements

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

Authors

Contributions

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.

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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.

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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.

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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). https://doi.org/10.1038/s41591-021-01510-7

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