Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors

Abstract

Talimogene laherparepvec is a first-in-class intralesional oncolytic immunotherapy. In a recent Phase III trial (OPTiM), talimogene laherparepvec significantly improved durable response rate compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). Overall response rate was also higher in the talimogene laherparepvec arm, and the greatest efficacy was demonstrated in patients with earlier-stage (IIIB, IIIC, or IVM1a) melanoma. Talimogene laherparepvec was well tolerated, with the majority (89%) of adverse events being grade 1 or 2. Preclinical studies have shown that talimogene laherparepvec exerts antitumor activity by selectively replicating within and destroying cancer cells, and through the release of tumor-associated antigens and expression of GM-CSF, which facilitates a wider antitumor immune response. It is hypothesized that combining talimogene laherparepvec with a systemic immunotherapy may, by bringing together complementary mechanisms of action, further enhance the efficacy of both agents. Indeed, talimogene laherparepvec is currently being assessed in combination with immune checkpoint inhibitors, including ipilimumab and pembrolizumab, in trials for melanoma and other solid tumors. Early results in melanoma indicate that the combination of talimogene laherparepvec with ipilimumab or pembrolizumab has greater efficacy than either therapy alone, without additional safety concerns above those expected for each monotherapy. In this review, we discuss the latest results from trials assessing talimogene laherparepvec in combination with other immunotherapies, provide an overview of ongoing and upcoming combination trials, and suggest future directions for talimogene laherparepvec in combination therapy for solid tumors.

Keywords: Checkpoint inhibitors; Combination treatment; Immunotherapy; Melanoma; Solid tumors; Talimogene laherparepvec.

Conflict of interest statement

Reinhard Dummer: Consultant/advisor for Roche, Bristol-Myers Squibb (BMS), Merck & Co., Novartis, GlaxoSmithKline, and Amgen Inc. Received honoraria from Roche, Novartis, BMS, GlaxoSmithKline, Merck & Co., and Amgen Inc. Research funding for institution from Roche, GlaxoSmithKline, BMS, Novartis, and Merck & Co. Christoph Hoeller: Consultant/advisor for Amgen, BMS, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Roche. Olivier Michielin: Consultant/advisor for BMS, Amgen Inc., Novartis, Roche, and Merck & Co.; travel/accommodations from BMS. Isabella Pezzani Gruter: Employee of Amgen.

Figures

Fig. 1

Key efficacy data from the Phase III talimogene laherparepvec OPTiM clinical trial [6]*. a Duration of response for all patients with response per endpoint-assessment committee (EAC) assessment. Duration of response was defined as longest period of response from entering response to first documented evidence of patient no longer meeting criteria for response. Arrows indicate patients for whom duration of response was censored at last tumor assessment, because there was no evidence (per EAC assessment) that their response had ended. b DRR in patient subgroups defined by key baseline characteristics. c Primary analysis of OS in intent-to-treat population. d OS in patient subgroups defined by key baseline characteristics. *Reprinted with permission from Andtbacka et al. [6]. © 2017 American Society of Clinical Oncology. All rights reserved. CR complete response, DRR durable response rate, ECOG Eastern Cooperative Oncology Group, GM-CSF granulocyte–macrophage colony-stimulating factor, HR hazard ratio, HSV-1 herpes simplex virus-1, OS overall survival, PS performance status, PR partial response, T-VEC talimogene laherparepvec. *p < 0.001 per Gail and Simon [28] quantitative treatment by covariate interaction test (for DRR). †One patient in the talimogene laherparepvec arm had unknown disease stage. ‡Twelve patients in the GM-CSF arm and four in the talimogene laherparepvec arm had unknown ECOG status

Fig. 2

Mechanism of action of talimogene laherparepvec combined with ipilimumab or pembrolizumab [36]*. Talimogene laherparepvec would act to enhance the cancer–immunity cycle through inducing the death of tumor cells causing the release of TDAs. Talimogene laherparepvec would also enhance the activation and recruitment of dendritic cells through the production of GM-CSF, thereby causing increased processing of TDAs by the dendritic cells. Ipilimumab could enhance the action of talimogene laherparepvec to further boost the cancer–immunity cycle by enhancing the priming and activation of T cells by dendritic cells presenting TDAs. Pembrolizumab could enhance the action of talimogene laherparepvec to further boost the cancer–immunity cycle by enhancing the recognition and killing of tumor cells by T cells. *Reprinted from Immunity, Volume 39, Chen and Mellman [36], Page 7, Copyright (2016), with permission from Elsevier. GM-CSF granulocyte–macrophage colony-stimulating factor, TDA tumor-derived antigen