Table 2.
Efficacy outcomes reported for Phase I–II trials in advanced/metastatic, ICI-resistant melanoma.
| Trial (NCT n°) | Treatment Regimens | Trial Phase | Patients | N | Primary Endpoint | ORR, % (CI) | PFS Median, mts (HR (CI)) | OS Med., mts (HR (CI)) |
|---|---|---|---|---|---|---|---|---|
| 2nd-line combination therapy (anti-PD-1 backbone) | ||||||||
| LEAP-004 [57] (NCT03776136) | Lenvatinib 20 od + Pem 200 mg q3w | II | Adv., PD-(L)1 pre-treated (PD upon/after therapy a) [58], BRAF± | 103 | ORR | 33 (17–53) b; 23 (13–35) c |
4.2 (3.8–7.1) | 14.0 (10.8-nr) |
| IRB17-0686 [59] (NCT02743819) |
Ipi 1 mg/kg q3w × 4 + Pem 200 mg q3w | II | Adv., PD-(L)1 pre-treated (PD upon therapy d = Primary
resistance), BRAF± |
70 | ORR | 31 (nr-nr) | 4.7 (2.8–8.3) | nr |
| CA224-020 [60] (NCT01968109) |
Relatlimab 80 mg q2w + Nivo 240 mg q2w | I–II | Adv., PD-(L)1 pre-treated (PD upon ther. = Prim. resistance), BRAF± | 68 | Safety, ORR | 12 (nr-nr) | nr | nr |
| SYNERGY-001 [61] (NCT02521870) |
SD-101 2 mg/kg q1-3w + Pem 200 mg q3w | I–II | Advanced, PD-(L)1-pre-treated (PD upon/after ther.), BRAF± | 23 | ORR | 20 (nr-nr) | nr | nr |
| 2014-0922 [62] (NCT02500576) |
Cryopreserved TILe + IL-2 (Aldesleukin) (high dose/low dose) + Pem 200 mg q3w | I–II | Metastatic, un-/pre-treated (13 out of 14 pts were PD-1-pre-treated), BRAF± | 14 | ORR | 14 (nr-nr) | 3.9 (nr-nr)/2.1 (nr-nr) | 9.7 (nr-nr)/ 8.8 (nr-nr) |
| PV-10-MM-1201 [63] (NCT02557321) |
PV-10 (intralesional) + Pem 2 mg/kg q3w | I | Metastatic, ICI-pre-treated (PD upon/after therapy), BRAF± |
13 | Safety | 31 (nr-nr) | nr | nr |
| 4SC-202-2-2017 [64] (NCT03278665) |
Domatinostat + Pem 2 mg/kg q3w | I–II | Metastatic, ICI-pre-treated (PD upon/after therapy), BRAF± |
40 | Safety | 8 (nr-nr) | nr | nr |
| 16-1080.cc [65] (NCT03200847) |
all-trans-Retinoic acid + Pem 200 mg q3w | I–II | Metastatic, ICI pre-treated (PD upon/after therapy), BRAF± |
24 | Safety | 67 (nr-nr) | 20.3 | nr |
| Lipo-MERIT [66,67] (NCT02410733) | FixVak (RNA vaccine) ± anti-PD-1 | I | Metastatic, ICI-pre-treated (PD on/after therapy), BRAF± |
42 | Safety | 16 (FV mono) 35 (FV + PD1) |
nr | nr |
| 2nd-line combination therapy (anti-CTLA-4 backbone) | ||||||||
| ILLUMINATE-204 [68] (NCT02644967) | Tilsotolimod 8 mg/kg q1-6w + Ipi 3 m/kg q3w x4 | I–II | Advanced, PD-1-pre-treated (PD on/after therapy), BRAF± |
62 | Safety, ORR | 22 (12–37) | 5.1 (3.7–7.0) | 21.0 (9.8-nr) |
| ILLUMINATE-301 [69] (NCT03445533) | Tilsotolimod 8 mg/kg q1-6w + Ipi 3 m/kg q3w x4 vs. Ipi | III | Advanced, PD-1-pre-treated | 481 | OS and ORR | 9 (nr-nr) | nr | nr |
| 2nd-line monotherapy | ||||||||
| C144-01 [56] (NCT02360579) | Lifileucel (i.e., autologous, cryo-preserved TIL e) + IL-2 x6 | II | Advanced, PD-1-pre-treated, BRAF± | 66 | ORR | 36 (nr-nr) | nr | nr |
| Dutch [56] (NCT02278887) | TIL (i.e., autologous, cryo-preserved TIL e) vs. Ipi | III | Advanced, progression after the maximal one line of pre-treatment (no Ipi), BRAF±; approximately 90% of patients had PD-1 pre-treatment in both arms |
84
84 |
PFS | 48.8 21.4 |
7.2 (4.2–13.1)/3.1 (3.0–4.3), HR 0.05, p < 0.001 | 25.8 (18.2-nr) /18.9 (13.8–32.6), HR 0.83, p = 0.39 |
a Upon therapy or ≤12 weeks after last dose of an anti-PD-(L)1 agent given alone or in combination (including with anti-CTLA-4 therapy) for ≥2 doses; b PD upon prior anti-PD-1 plus CTLA-4 therapy; c primary resistance to prior anti-PD-(L)1 monotherapy; d PD (or stable disease lasting ≥24 weeks during treatment with an anti-PD-(L)1 antibody as the treatment regimen) immediately prior to recruitment to this study or PD within ≤6 months of adjuvant anti-PD1 antibody administration; e harvested TIL re-administered in patients after lymphodepleting chemotherapy comprising cyclophosphamide and fludarabine phosphate. Abbreviations: BEMPEG, Bempegaldesleukin; BICR, blinded, independent central review; BRAF±, mutated BRAF and wild-type BRAF; CI, 95% confidence interval; FV, FixVak; IA, investigator-assessed; ICI, immune checkpoint inhibitor; Ipi, Ipilimumab; MDSC, myeloid-derived suppressor cells; Nivo, Nivolumab; NR, not reported (and/or: not reached); od, once daily; ORR, overall response rate; OS, median overall survival; PD, progressive disease; Pem, Pembrolizumab; PFS, median progression-free survival; PV-10, 10% rose bengal disodium for injection; SD-101, synthetic CpG-ODN agonist of TLR 9; TIL, tumor-infiltrating lymphocytes.