Neoadjuvant nivolumab + T-VEC combination therapy for resectable early stage or metastatic (IIIB-IVM1a) melanoma with injectable disease: study protocol of the NIVEC trial

Maartje W Rohaan, Emma H A Stahlie, Viola Franke, Lisanne P Zijlker, Sofie Wilgenhof, Vincent van der Noort, Alexander C J van Akkooi, John B A G Haanen, Maartje W Rohaan, Emma H A Stahlie, Viola Franke, Lisanne P Zijlker, Sofie Wilgenhof, Vincent van der Noort, Alexander C J van Akkooi, John B A G Haanen

Abstract

Background: Trials investigating neoadjuvant treatment with immune checkpoint inhibitors (ICI) in patients with melanoma have shown high clinical and pathologic response rates. Treatment with talimogene laherparepvec (T-VEC), a modified herpes simplex virus type-1 (HSV-1), is approved for patients with unresectable stage IIIB-IVM1a melanoma and has the potential to make tumors more susceptible for ICI. Combination ICI and intralesional T-VEC has already been investigated in patients with unresectable stage IIIB-IV disease, however, no data is available yet on the potential benefit of this combination therapy in neoadjuvant setting.

Methods: This single center, single arm, phase II study aims to show an improved major pathologic complete response (pCR) rate, either pCR or near-pCR, up to 45% in 24 patients with resectable stage IIIB-IVM1a melanoma upon neoadjuvant combination treatment with intralesional T-VEC and systemic nivolumab (anti-PD-1 antibody). Patients will receive four courses of T-VEC up to 4 mL (first dose as seroconversion dose) and three doses of nivolumab (240 mg flatdose) every 2 weeks, followed by surgical resection in week nine. The primary endpoint of this trial is pathologic response rate. Secondary endpoints are safety, the rate of delay of surgery and event-free survival. Additionally, prognostic and predictive biomarker research and health-related quality of life evaluation will be performed.

Discussion: Intralesional T-VEC has the capacity to heighten the immune response and to elicit an abscopal effect in melanoma in combination with ICI. However, the potential clinical benefit of T-VEC plus ICI in the neoadjuvant setting remains unknown. This is the first trial investigating the efficacy and safety of neoadjuvant treatment of T-VEC and nivolumab followed by surgical resection in patients with stage IIIB-IVM1a melanoma, with the potential of high pathologic response rates and acceptable toxicity.

Trial registration: This trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT- number: 2019-001911-22 ) and the Central Committee on Research Involving Human Subjects (NL71866.000.19) on 4th June 2020. Secondary identifying number: NCT04330430 .

Keywords: Early metastatic; High-risk; Immune checkpoint inhibitor; Melanoma; Neoadjuvant; Nivolumab; Resectable; Talimogene laherparepvec.

Conflict of interest statement

MR declares to have no competing interests. ES declares to have no competing interests. VF declares an advisory role/consultancy agreement and travel/research grant from Amgen Inc. LZ declares to have no competing interests. SW declares to have no competing interests. VvdN declares to have no competing interests. Through AvA, NKI has received compensation for advisory roles from Amgen, BMS, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sirius Medical, Sanofi and 4SC and NKI has received grants from Amgen, Merck-Pfizer. JH received compensation (all paid to the institute except for Neogene Therapeutics) for advisory roles for Achilles Therapeutics, BioNTech, BMS, Gadeta, Immunocore, Instil Bio, Iovance Biotherapeutics, Ipsen, MSD, Merck Serono, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Third Rock Ventures, and T-knife, and has received grants (all paid to the institute) from Amgen, Asher Bio, BioNTech, BMS, MSD, Novartis, and Neogene Therapeutics.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study Schedule. Blood draw for PBMCs will be performed at screening, week 3, week 9 (prior to surgery), and first evaluation (week 12) and at moment of relapse. Tumor biopsies will be taken at screening, prior to first nivolumab administration and at moment of relapse in all patients for translational research purposes. Biopsies will be preserved and stored as fresh frozen and formalin-fixed paraffin-embedded material at all indicated time points. *The first dose of T-VEC is a seroconversion dose. CT, computed tomography; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cells; PET, Positron Emission Tomography; PFU, plaque-forming units; QoL, quality of life questionnaires; RECIST, Response evaluation criteria in solid tumors; T-VEC, Talimogene laherparepvec; ULN, upper limit of normal; WHO PS, World Health Organization performance status

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