Table 2 –

Studies evaluating oncolytic virus combination therapy in the treatment of melanoma

Treatment	Study design	Target accrual	Outcomes	Trial ID (status)
T-VEC and ipilimumab	Open label, single-arm phase Ib trial of intralesional injected T-VEC and IV ipilumab in advanced melanoma	19	Tolerable safety profile with no dose-limiting toxicities (DLT.) 26.3% G3 AEs were reported with 15.8% attributable to T-VEC and 21.1% to ipiliumab. ORR = 50%; 18 month PFS = 50%; OS = 67%. 44% of patients had a durable response of ≥6 months.	NCT01740297 (active, not recruiting)
T-VEC and ipilimumab	Open label phase II randomized trial comparing T-VEC and ipilmumab vs ipilumab alone in unresectable advanced melanoma	217	Higher ORR reported with combination therapy (39% vs 18%; odds ratio, 2.9; P<0.002). AEs were tolerable and included fatigue, chills, and diarrhea. There were 45% G3 AEs in combination therapy vs 35% with ipilimumab alone.	NCT0174029 (active, not recruiting)
T-VEC and pembrolizumab	Single-arm phase Ib/III (MASTERKEY-265) of injected intralesional T-VEC and IV pembrolizumab in unresectable stage IIIB-IVM1c melanoma	21	The most common AEs were fatigue, pyrexia, and chills. Median time to response was 17 weeks, confirmed ORR was 48%, and CR rate was 14% (unconfirmed ORR = 57%; CR =24%.)	NCT02263508 (phase III is ongoing)
T-VEC and pembrolizumab	Randomized, double-blind phase III trial (KEYNOTE-034) comparing T-VEC and pembrolizumab vs T-VEC intralesional placebo and pembrolizumab in advanced melanoma	660	Recruiting.	NCT02263508 (recruiting)
Neoadjuvant T-VEC and surgical resection	Open label, parallel assignment, randomized phase II trial comparing neoadjuvant T-VEC and surgery vs surgery alone in resectable IIIB- IVM1a melanoma	150	Ongoing.	NCT02211131 (active, not recruiting)
T-VEC and US/CT	Open-label Phase I injection of T-Vec into liver tumors with US/CT guidance (primary or metastatic (including metastasis from melanoma)	14	Showed tolerability and feasibility. There were 28.6% G3 treatment related AEs. One DLT due to a G3 increase in AST and a G2 increase in bilirubin after 1 dose was reported. Treatment related serious AEs included AST increase (n=1), ALT increase (n=1), and nausea (n=1). Procedure related adverse events included: liver cholestasis due to hematoma (n=1) and hepatic hemorrhage (n=1.)	NCT025095071
T-VEC and pembrolizumab	Open label, sequential assignment, non-randomized phase Ib/II trial (MASTERKEY-318) of T-VEC injection into liver tumors (primary or metastatic; including metastasis from melanoma) under US/CT guidance in combination with IV pembrolizumab vs T-VEC alone	244	Recruiting.	NCT02509507 (recruiting)
HF-10 and ipilimumab	Open-label, single group assignment, phase II of intratumoral injections of HF-10 and IV ipilimumab in stage IIIB-IV unresectable melanoma	46	Median best ORR=41% at 24 weeks; PFS = 19 months; median OS= 21.8 months. Three patients experienced G3 adverse events as a result of HF10. 37% of patients experienced G3 adverse events as a result of ipilimumab.	NCT02272855(active, not recruiting)
Neoadjuvant trial of nivolumab in combination with HF-10	Single-arm, open label, single group assignment phase II neoadjuvant trial of IV nivolumab in combination with intratumoral injections of HF-10 in resectable stage IIIB, IIIC, IVM1a melanoma	20	Recruiting.	NCT03259425 (recruiting)
Coxsackie virus A21 (CVA21) and ipilimumab	Single group, open label phase I trial of CVA21 in combination with ipilimumab in advanced melanoma who previously progressed on a single anti-PD-1 therapy	59	Preliminary results reporting overall response rates of ~50% with no DLTs and 8% treatment related G3 AEs.	NCT02307149 (recruiting)
CVA21 and pembrolizumab	Single group, open label phase I trial of intratumoral injection of CVA21 and IV pembrolizumab in advanced melanoma	50	Ongoing. Preliminary results reporting overall response rates around 50% with no DLTs.	NCT02565992 (recruiting)
CVA21 and ipilimumab	Single group, open label, phase Ib of intratumoral CVA2 and IV ipilimumab in uveal melanoma metastatic to the liver	10	Recruiting.	NCT03408587 (recruiting)
Reolysin with carboplatin and paclitaxel	Single group, open label, phase II trial of Reolysin in combination with paclitaxel and carboplatin in metastatic melanoma	14	ORR = 21%; Combination treatment PFS =5.2 months; Combination treatment OS = 10.9 months. (Paclitaxel/carboplatin alone PFS = 3 months; = 9.) Toxicities of combination therapy were comparable to those of chemotherapy alone, although pyrexia was common and 1 case of G3 febrile neutropenia was observed.	NCT00984464 (completed)

^1.J. Randolph Hecht MP, Antonio Cubillo, Aitana Calvo, Steven Raman, Chunxu Liu, Emily Chan, Jason Alan Chesney, and Aleix Prat. Early safety from a phase 1, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected into liver tumors. Journal of Clinical Oncology. 2018;36(4):438