Potential clinical and immunotherapeutic utility of talimogene laherparepvec for patients with melanoma after disease progression on immune checkpoint inhibitors and BRAF inhibitors

Abstract

Talimogene laherparepvec is a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy for the local treatment of unresectable subcutaneous and nodal tumors in patients with melanoma recurrent after initial surgery. We report on two patients with melanoma who, after progression on numerous systemic therapies, derived clinical benefit from talimogene laherparepvec in an expanded-access protocol (ClinicalTrials.gov, NCT02147951). Intralesional talimogene laherparepvec (day 1, ≤4 ml 106 PFU/ml; after 3 weeks, ≤4 ml 108 PFU/ml every 2 weeks) was administered until complete response, no injectable tumors, progressive disease, or intolerance occurred. Patient 1 was 71 years old, had stage IIIB disease, and had previously received granulocyte–macrophage colony-stimulating factor, vemurafenib, metformin, ipilimumab, dabrafenib, trametinib, and pembrolizumab. Patient 2 was 45 years old, had stage IIIC disease, and had previously received nivolumab/ipilimumab combination therapy. There were marked reductions in the number and size of melanoma lesions during treatment with talimogene laherparepvec. Both patients experienced mild-to-moderate nausea and vomiting, which were managed using ondansetron, metoclopramide, and pantoprazole. Both patients completed treatment with talimogene laherparepvec in the expanded-access protocol on 24 November 2015, but received talimogene laherparepvec in clinical practice. Patient 1 continues to receive therapy (>60 weeks); patient 2 experienced a complete response at 23 weeks. Immunohistochemistry of a biopsied dermal metastasis from patient 1 showed a marked infiltration of CD4+ and CD8+ T cells after 1 year of treatment. Talimogene laherparepvec was active in patients with advanced melanoma with disease progression following multiple previous systemic therapies; no new safety signals were identified.

Talimogene laherparepvec treatment to overcome loco-regional acquired resistance to immune checkpoint blockade in tumor stage IIIB–IV M1c melanoma patients

“…Two case series highlight the clinical efficacy of T-VEC after progression on multiple previous therapies [26,27]. In accordance with these publications, in our center, four out of eight patients profited from T-VEC after ICB or/and targeted therapy.…”

“…Patients with high tumor burden and a rapid tumor progression did not respond to second-line T-VEC treatment. Even though LDH level is not reported or not correlated to clinical response in other case series with pre-treated melanoma patients who received T-VEC as second-line treatment [12,15,26,27], we suggest that elevated LDH level can serve as a useful indicator. A sensible selection of suitable patients seems to be crucial and high medical need patients seem to require more aggressive therapeutic intervention.…”

“…This indicates that options for prior therapy were limited compared to contemporary state of the art therapy. The impact of previous systemic therapy on response to T-VEC thus remains an open question [26]. A retrospective analysis of 27 melanoma patients treated with T-VEV found a decreased ORR for pre-treated patients without describing details of these patients [13].…”

“…A recently published case report describes the clinical course of a heavily pre-treated 71-year-old patient with stage IIIB disease who profited from T-VEC. Prior therapies included GM-CSF, vemurafenib, dabrafenib, trametinib, ipilimumab, and pembrolizumab [26].…”

High response rates for T‐VEC in early metastatic melanoma (stage IIIB/C‐IVM1a)

“…This corresponds with the findings of Chesney et al . in their recent publication on the clinical benefit of T‐VEC treatment after disease progression on systemic therapies . Moreover, T‐VEC was well tolerated, no new sAEs were observed compared to what is known from the OPTiM study.…”