Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy
Clinical development of T-VEC
In 2006, a Phase I clinical trial of T-VEC was conducted to determine the safety profile, optimal dose and schedule, and biologic effects of therapy [7]. This study included 30 patients with refractory breast cancer (n?=?14), head and neck cancer (n?=?5), colorectal cancer (n?=?2), and melanoma (n?=?9) who had tumors in cutaneous, subcutaneous, or nodal sites that were amenable to direct injection. The trial employed a single dosing cohort and a multi-dosing arm in which an initial low dose of virus was administered to allow seroconversion of herpes virus naïve subjects. In the single-dose group, patients were exposed to a single dose of 106, 107, or 108 plaque-forming units (PFU)/mL. In this group, the most common adverse event was pyrexia, which was mostly mild (grade 1). Local inflammation at the injected tumor site was also observed, which tended to be more severe in herpes seronegative patients, especially at higher viral doses. Injection site erythema was also commonly reported and tended to subside more quickly in seropositive patients.
In the multi-dose group, seronegative patients were given an initial dose of 106 PFU /mL 3 weeks before escalation to higher viral concentrations up to 108 PFU/mL, which was then repeated every two weeks [7]. Approximately one third of patients were seronegative for HSV with all seroconverting 3 to 4 weeks after the first dose. The seropositive patients also had slight increases noted in antibody titer levels [7]. To date, there has been no correlation between antibody titters and therapeutic responses or emergence of adverse events. Using a lower starting concentration of virus, the pronounced injection site reactions seen in seronegative patients were avoided even when they were subsequently administered higher viral concentrations. No dose-limiting toxicities were observed when the initial dose was 106 PFU/ml. This was, thus, selected as the starting dose, and followed 3 weeks later by a higher dose of 108 PFU/ml in continued two week intervals until maximum clinical response, toxicity or confirmed disease progression. This regimen, designed to reduce injection site reactions and flu-like side effects particularly in seronegative patients, became the standard dosing schedule for subsequent clinical development.
Biological activity was assessed clinically and through mechanistic correlatives including viral replication and necrosis at the injection site, GM-CSF expression, cytokine and antinuclear antibody levels [7]. No complete or partial responses occurred according to standard clinical response criteria. However, injected lesions and nearby lesions demonstrated flattening by clinical examination [7]. Histological examination of biopsies taken following injection showed inflammation and necrosis in 14 out of 19 biopsies where tumor was detected. In contrast, non-tumor cells within the tumor microenvironment showed no evidence of necrosis, thus supporting the tumor specificity of viral infection. Furthermore, areas of necrosis strongly stained for HSV proteins, while non-tumor tissue rarely stained positively for virus [7]. Baseline serostatus did not negatively impact cell necrosis following T-VEC administration.
Based on the biologic activity that was seen in the Phase I study, a Phase II trial was conducted in 50 patients with stage III and IV melanoma that was not amenable to surgery [8]. Patients received a median of six T-VEC injection cycles. In this study, 85 % patients experienced adverse effects, which were most commonly mild to moderate flu-like symptoms [8]. The overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 26 %, with 8 patients achieving a complete response and 5 patients achieving a partial response. Notably, responses were seen in injected, uninjected skin and soft tissue sites and in visceral lesions. The responses observed were durable, as 92 % of the responses were maintained for 7 to 31 months [8]. The 1-year survival rate was 58 % in all intention-to-treat patients and 93 % in patients who demonstrated an initial objective response to T-VEC. Evidence of anti-tumor immunity was seen in a patient who achieved a complete response and was found to have increased local and systemic MART-1-specific CD8+ effector T cells following treatment [9]. The frequency of CD4?+?Foxp3+ regulatory T cells and myeloid-derived suppressor cells (MDSC) was lower in tumor samples from T-VEC- treated patients compared with tumor from non-treated melanoma patients. Within the same patient, injected tumors had fewer regulatory T cells than uninjected tumors [9].
A randomized phase III study known as the OPTiM trial became the first study of an oncolytic virus to demonstrate a statistically significant clinical benefit for the treatment of melanoma [10]. In this open-label study, T-VEC was compared with recombinant GM-CSF in patients with unresectable stages IIIB, IIIC, and IV melanoma. Patients were assigned in a 2:1 randomization to receive intratumoral T-VEC (106 PFU/mL followed 3 weeks later by 108 PFU/mL every two weeks) or subcutaneous recombinant GM-CSF (125 ?g daily for 14 days in a 28 day cycle). The primary endpoint was durable response rate (DRR), defined as a an objective response as measured by modified World Health Organization (WHO) criteria occurring within the first 12 months of therapy and lasting at least 6 months. Secondary endpoints included progression-free and overall survival, objective response rate (ORR) by independent committee assessment, and duration of response.
Of the 436 patients enrolled, 43 % had stage IV M1b/c disease and 53 % had received prior systemic therapy. Analysis of efficacy demonstrated that DRR was significantly higher in the T-VEC arm compared with the GM-CSF arm (16.3 % versus 2.1 %, p??.001). ORR was also higher in the T-VEC arm (26 %) compared with the GM-CSF arm (5.7 %). A response in 15 % of visceral metastases (all uninjected) was observed,. Median time to treatment failure (TTF) was prolonged in the T-VEC versus GM-CSF arm (8.2 versus 2.9 months). Overall median survival was 23.3 months in the T-VEC arm compared with 18.9 months in the control arm, which approached but did not cross the significance threshold (hazard ratio 0.79, p?=?.051).
T-VEC therapy in OPTiM was associated with an excellent safety profile. Similar to the experience in the earlier studies, the most common adverse events were pyrexia, chills, flu-like symptoms, injection site reactions, and fatigue. Serious treatment-related side effects were rare. The only grade 3 or 4 adverse event that occurred in more than 2 % of patients was cellulitis, which occurred in 2.1 % of T-VEC treated patients. There were no treatment-related deaths.
Based on the results of these studies, T-VEC garnered approval by the U.S. Food and Drug Administration (FDA) in October 2015 for the local treatment of unresectable lesions in patients who have recurrent melanoma after initial surgery with cutaneous, subcutaneous, or nodal lesions [11, 12]. This was followed by approval by the European Medicine Agency (EMA) with T-VEC approved for the treatment of patients with stage III unresectable or IVM1a melanoma citing the significant overall survival benefit seen in this subset of patients on analysis of the data. Regulatory approval in Australia quickly followed.