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. 2020 Jul 27;123(6):885–897. doi: 10.1038/s41416-020-0994-4

Table 2.

Efficacy of combination therapy with HIT-IT and systemic immunotherapies.

Type of intratumoural agent Agent and study phase Enrolled patients Disease stage Comparator Primary endpoint Anti–PD-1 refractory/previous treatment ORR CR
Combination trials with systemic ipilimumab
Oncolytic viruses T-VEC Phase 239,99 198 IIIB–IVM1c Systemic ipilimumab ORR (in accordance with irRC) 2% versus 3% had previously received anti–PD-1 therapy

39% versus 18%; OR, 2.9; p = 0.002

Stage IIIB–IVM1a: 44% versus 19%; OR, 3.3; p = 0.007

Stage IVM1b/c: 33% versus 16%; OR, 2.6; p = 0.09

 13% versus 7%

Coxsackievirus A21

MITCI

Phase 1b34,120

 26 IIIC–IVM1c None Safety – 57% (23% in 15 patients with previous anti–PD-1 treatment) –

Canerpaturev

Phase 258,112

 46 IIIB–IV None BORR at 24 wk –

41%

Stage IIIB–IVM1a: 47%

Stage IVM1b/c: 20%

 18%

Canerpaturev

Phase 2101,121

 28 IIIB–IVM1c None BORR at 24 wk 89% of patients had previously received anti–PD-1 therapy 7% 0%
PRR agonists

IMO-2125

ILLUMINATE-204

Phase 1/231

 21 III–IV None To determine RP2D All patients had previously received anti–PD-1 therapy 38% 10%
Cytokines

IL-2

Phase 22

 15 Pretreated melanoma with distant metastasis None DCR at wk 12 – 0% –
Combination trials with systemic pembrolizumab
Oncolytic viruses

T-VEC

MASTERKEY-265

Phase 1b/3 (data from Phase 1b)37,93,94

 21 IIIB–IVM1c Systemic pembrolizumab (for Phase 3 part only) Incidence of DLTs – 62% 33%

Coxsackievirus A21

CAPRA

Phase 1b36

 50 (19 included in safety analysis) IIIB/C–IV None Safety – 60% –
PRR agonists

SD-101

SYNERGY-001/KEYNOTE-184

Phase 1b/266,67

 87 IIIB–IVM1c None (SD-101 given at 2 or 8 mg per lesion)

Safety, evaluate the expression of IFN-inducible genes in whole blood 24 h after

SD-101 administration as a pharmacodynamic marker of SD-101 activity, determine the RP2D

 All patients were naïve to anti–PD-1/L1 therapy

70% (SD-101 2 mg/lesion)

48% (SD-101 8 mg/lesion)

11% (SD-101 2 mg/lesion)

5% (SD-101 8 mg/lesion)

SD-101

SYNERGY-001/KEYNOTE-184

Phase 1b/233

 30 IIIC–IV None ORR All patients were resistant or refractory to anti–PD-1 therapy 21% 3%

CMP-001

Phase 1b32

 69 III–IVM1d None To determine RP2D All patients had previously received anti–PD-1 therapy. In total, 91% of patients had progressive disease and 9% had stable disease on previous anti–PD-1 therapy 22% –
Cytokines Tavokinogene telseplasmid (pIL‐12) Phase 279,96 23 IIIB–IVM1c Plasmid IL-12 monotherapy – – 50 versus 25–35% 41 versus 0–19%

Full details of lesions eligible for injection not provided for all studies; however, Phase 2 study of talimogene laherparepvec with systemic ipilimumab confirmed inclusion of nodal lesions.39

BORR best overall response rate, CAPRA CAvatak and PembRolizumab in Advanced melanoma, CR complete response, DCR disease control rate, DLT dose-limiting toxicity, HIT-IT human intratumoural immunotherapy, IFN interferon, IL-12 interleukin-12, IL-2 interleukin-2, irRC immune-related response criteria, MITCI Melanoma Intra-Tumoral Cavatak and Ipilimumab, OR odds ratio, ORR overall response rate, PD-1/L1 programmed death receptor 1/programmed death receptor ligand 1, PRR pattern recognition receptor, RP2D recommended phase 2 dose, T-VEC talimogene laherparepvec.