Systemic versus local responses in melanoma patients treated with talimogene laherparepvec from a multi-institutional phase II study

Howard L Kaufman, Thomas Amatruda, Tony Reid, Rene Gonzalez, John Glaspy, Eric Whitman, Kevin Harrington, John Nemunaitis, Andrew Zloza, Michael Wolf, Neil N Senzer, Howard L Kaufman, Thomas Amatruda, Tony Reid, Rene Gonzalez, John Glaspy, Eric Whitman, Kevin Harrington, John Nemunaitis, Andrew Zloza, Michael Wolf, Neil N Senzer

Abstract

Background: We previously reported that talimogene laherparepvec, an oncolytic herpes virus encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), resulted in an objective response rate of 26 % in patients with advanced melanoma in a phase II clinical trial. The response of individual lesions, however, was not reported. Since talimogene laherparepvec is thought to mediate anti-tumor activity through both direct tumor cytolysis and induction of systemic tumor-specific immunity, we sought to determine the independent response rate in virus-injected and non-injected lesions.

Methods: Fifty patients with stage IIIC or IV melanoma were treated with talimogene laherparepvec in a multi-institutional single-arm open-label phase II clinical trial. In this study patients were treated until a complete response was achieved, all accessible tumors disappeared, clinically significant disease progression, or unacceptable toxicity. This report is a post hoc analysis of the systemic effects of talimogene laherparepvec in injected lesions and two types of uninjected lesions-non-visceral lesions and visceral lesions.

Results: Eleven of 23 patients (47.8 %) had a ≥ 30 % reduction in the total burden of uninjected non-visceral lesions, and 2 of 12 patients (16.7 %) had a ≥ 30 % reduction in the total burden of visceral lesions. Among 128 evaluable lesions directly injected with talimogene laherparepvec, 86 (67.2 %) decreased in size by ≥ 30 % and 59 (46.1 %) completely resolved. Of 146 uninjected non-visceral lesions, 60 (41.1 %) decreased in size by ≥ 30 %, the majority of which (44 [30.1 %]) completely resolved. Of 32 visceral lesions, 4 (12.5 %) decreased in size by ≥ 30 %, and 3 (9.4 %) completely resolved. The median time to lesion response was shortest for lesions that were directly injected (18.4 weeks), followed by uninjected non-visceral lesions (23.1 weeks) and visceral lesions (51.3 weeks), consistent with initiation of a delayed regional and systemic anti-tumor immune response to talimogene laherparepvec.

Conclusions: These results support a regional and systemic effect of talimogene laherparepvec immunotherapy in patients with advanced melanoma.

Keywords: Herpes virus; Immunotherapy; Melanoma; Oncolytic virus; T-VEC; Talimogene laherparepvec.

Figures

Fig. 1
Fig. 1
Maximum percent decrease in evaluable lesions: (a) Injected lesions, (b) Uninjected non-visceral lesions, and (c) Visceral lesions. Lesion measurements per investigator. Evaluable indicates at least 2 assessments with valid measurements. Uninjected lesion indicates baseline or new lesions never known to be injected. Safety analysis set consisted of the patients who received at least one dose of study therapy
Fig. 2
Fig. 2
Lesion level time to response (Kaplan-Meier survival curves) for talimogene laherparepvec for injected, all uninjected, uninjected non-visceral, or visceral lesions in the phase II clinical trial of talimogene laherparepvec in patients with stage IIIC or IV melanoma. Safety analysis set consisted of patients who received at least one dose of study therapy

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