Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9

Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.

We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).

There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.

Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.

In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24

While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29

An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.

The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.

The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.

In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.