1 Introduction
2 Biological rationale
2.1 Immunomodulatory effects of MAPK-inhibitors to augment CPI therapy
2.2 Preclinical evidence on synergistic effects of MAPKi and CPI therapy
3 Safety and efficacy of triple combination regimens with CPI and MAPKi in clinical trials
National Clinical Trial (NCT) Number | Title | Regimen | No. of patients | Median follow-up (months) | Main outcomes | AE | Start Date |
---|---|---|---|---|---|---|---|
A Concomitant administration of MAPKi-directed and CPI therapy for BRAFV600-mutant melanoma | |||||||
[71] | Phase I trial of vemurafenib (VEM) and IPI in subjects with metastatic melanoma | IPI 3 mg/kg + VEM 960 mg vs. IPI 3 mg/kg + VEM 720 mg vs. VEM 720 mg | 12 | Not given | Trial was terminated due to unexpected grade 2/3 hepatotoxicity | 7/10 (70%) grade 2–3 hepatotoxicity | 11/2011 |
Phase I study of dabrafenib (DAB) and trametinib (TRA) in combination with IPI for unresectable or metastatic melanoma | IPI 3 mg/kg + DAB 150 mg vs. DAB 100 mg + TRA 1 mg followed by IPI 3 mg/kg | 16 | Not given | Trial was closed following 2 cases of dose-limiting toxicity (DLT) in the triple therapy arm (colitis with subsequent perforation); no efficacy data reported | No DLT in the double therapy arm; 28.5% DLT observed in the triple therapy arm | 02/2013 | |
Phase Ib study of Atezolizumab (ATE) in combination with VEM or VEM plus cobimetinib (COB) in participants with metastatic melanoma | VEM 960 mg + COB 60 mg (28d), followed by VEM 720 mg + COB 60 mg + ATE 840 mg vs. VEM 960 mg + COB 60 mg + Placebo; cohorts 1–3 tested for different run-in periods of VEM/COB | 56 | 29.9 | ORR: 71.8% with CR in 20.5%; median DOR: 17.4 mo; median PFS: 12.9 mo; median OS: not reached | Grade 3/4 treatment-related AE: 66.7%; AE leading to discontinuation in 28.2%; three fatal events were reported | 08/2012 | |
NCT 02908672 (IMspire150) [75] | Phase III, double-blinded, randomized, placebo-controlled study of ATE + COB + VEM vs. placebo + COB + VEM in previously untreated patients with unresectable locally advanced or metastatic melanoma (IMspire150) | VEM 960 mg + COB 60 mg (21d), followed by VEM 720 mg + COB 60 mg + ATE 840 mg vs. VEM 960 mg + COB 60 mg (21d) + Placebo | 514 | 18.9 | ORR: 66.3% vs. 65.0% Median DOR: 21.6 vs. 12.6 mo Median PFS: 15.1 vs. 10.6 months (HR: 0.78, p = 0.025) Median OS: not reached in interim analysis | Grade 3/4 treatment-related AE: 79% vs. 73%; AE leading to discontinuation of all treatments: 13% vs. 16% | 01/2017 |
(MK-3475–022/KEYNOTE-022) [81] | Phase I Study to assess the safety and efficacy of MK-3475 in combination with TRA and DAB in subjects with advanced melanoma | Pembrolizumab (PEM) 2 mg/kg + DAB 150 mg + TRA 2 mg | 15 | 27.0 | ORR: 73%; ongoing response: 40%; median PFS: 15.4 months | Grade 3/4 treatment-related AE: 73%; AE resulting in discontinuation: 33%; DLT were reported in 20% (neutropenia and impaired liver functions); no treatment related deaths | 05/2014 |
NCT 02130466 (KEYNOTE-022) | A Phase II study to assess the safety and efficacy of MK-3475 in combination with TRA and DAB in subjects with advanced melanoma | PEM 2 mg/kg + DAB 150 mg + TRA 2 mg vs. placebo + DAB 150 mg + TRA 2 mg | 120 | 9.6 | ORR: 63.3% vs. 71.7%; ongoing response: 44.7%; median DOR: 18.7 vs. 12.5 mo; median PFS: 16.0 vs. 10.3 mo (HR: 0.66, p = 0.043, ns); median OS: not reached | Treatment-related AE of grade 3 or higher: 58.3% vs. 26.7%; discontinuation of treatment: 25 vs. 15%; one treatment-related death due to pneumonitis | 05/2014 |
NCT 02130466 (Extended follow-up) [76] | A phase II study to assess the safety and efficacy of MK-3475 in combination with TRA and DAB in subjects with advanced melanoma | PEM 2 mg/kg + DAB 150 mg + TRA 2 mg vs. placebo + DAB 150 mg + TRA 2 mg | 120 | 36.6 | ORR: 63% vs. 72%; ongoing response: 29% vs. 9%; median DOR: 25.1 vs. 12.1 mo; median PFS: 16.9 vs. 10.7 mo (HR: 0.53); median OS: NR vs. 26.3 mo | Treatment-related AE of grade 3 or higher: 58% vs. 25% | 05/2014 |
(COMBI-i) [83] | Part 1 and 2 of the randomized, double-blind, placebo-controlled phase III study comparing the combination of PDR001, DAB and TRA vs. placebo, DAB and TRA in previously untreated patients with unresectable or metastatic melanoma | Spartalizumab (SPA) 400 mg + DAB 150 mg + TRA 2 mg vs. placebo + DAB 150 mg + TRA 2 mg | 36 | 24.3 | ORR: 78%, with 44% showing CR; median PFS: 23 mo; median OS: not reached | Grade 3/4 treatment-related AE: 72%; AE leading to permanent discontinuation: 17%; no treatment-related deaths; DLT were reported in 11% during initial safety run-in | 02/2017 |
(COMBI-i) | Part 3 of the randomized, double-blind, placebo-controlled phase III study comparing the combination of PDR001, DAB and TRA vs. placebo, DAB and TRA in previously untreated patients with unresectable or metastatic melanoma | SPA 400 mg + DAB 150 mg + TRA 2 mg vs. placebo + DAB 150 mg + TRA 2 mg | 532 | 27.2 | ORR: 69% vs. 64%; median DOR: NR vs. 20.7 mo; median PFS: 16.2 vs. 12.0 mo (HR: 0.82, p = 0.042) | Treatment-related AE of grade 3 or higher: 55% vs. 33%; permanent discontinuation of treatment: 12 vs. 8% | 02/2017 |
NCT 03625141 (TRICOTEL) [95] | A study evaluating the safety and efficacy of COB plus ATE in BRAF wild-type melanoma With Central Nervous System Metastases and COB plus ATE and VEM in BRAFV600-Mutated melanoma with central nervous system (CNS) metastases | COB 60 mg + ATE 840 mg (BRAF wild-type) vs. VEM 960 mg + COB 60 mg (28d run-in) + ATE 840 mg (BRAFV600 mutant) | 15 + 65 | 6.2 vs. 9.7 | Intracranial ORR: 27% vs. 42% | Treatment-related AE of grade 3 or higher: 53% vs. 68%; one treatment-related death in triple combination group | 08/2018 |
(IMMU-TARGET) [129] | Randomized phase I/II open label, multicenter study of encorafenib (ENC) plus binimetinib (BIN) and PEM in patients with unresectable or metastatic Melanoma (IMMU-TARGET) | ENC 450 mg + BIN 45 mg + PEM 200 mg vs. PEM 200 mg only | 15 | 25 | ORR: 64%; 12-month PFS: 41% | Treatment-related AE of grade 3 or higher: 53%; DLT were not observed | 04/2018 |
NCT 02910700 (TRIDENT) [130] | A Phase II study of the TRIplet combination of DAB, nivolumab (NIVO), and TRA (TRIDeNT) or BIN, ENC and NIVO (TRIBECA) in patients with metastatic melanoma | NIVO 3 mg/kg + DAB 150 mg + TRA 2 mg (A) vs. NIVO 3 mg/kg + TRA 2 mg (B) vs. NIVO 3 mg/kg + ENC + BIN (C) | 27 | 18.4 | Preliminary results: ORR: 92%; ORR in NIVO-refractory patients: 88%; median PFS: 8.5 mo vs. 8.2 mo for NIVO-refractory patients | Preliminary results: 78% of patients showed treatment-related AE of grade 3 or higher; discontinuation due to toxicity in 22% | 12/2016 |
B Concomitant administration of MAPK-directed and CPI therapy for BRAF wild-type melanoma | |||||||
[79] | Phase I open-label study of safety and tolerability of durvulumab (DUR) in combination with DAB and TRA or with TRA alone in subjects with metastatic or unresectable melanoma | DUR 10 mg/kg + DAB 150 mg + TRA 2 mg vs. DUR 10 mg/kg + TRA 2 mg (concurrent) vs. TRA 2 mg followed by DUR 10 mg/kg (sequential) | 68 | 20.8 | ORR: 69.2% vs. 20.0% vs. 31.8% Ongoing response: 50% vs. 75% vs. 42.9%; median DOR: 15.5 vs. NA vs. 8.7 mo; median PFS: 11.2 vs. 4.9 vs. 5.9 mo; median OS: 31.4 vs. NA vs. 21.7 mo | Grade 3/4 treatment-related AEs: 69% vs. 80% vs. 73%; AE leading to discontinuation: 46.2% vs. 35% vs. 50%; no deaths related to toxicity | 12/2013 |
[86] | Phase III, open-label, multicenter, two arm, randomized study to investigate the efficacy and safety of COB plus ATE versus PEM in patients with previously untreated advanced BRAF wild-type melanoma | COB 60 mg + ATE 840 mg vs. PEM 200 mg | 446 | NA | ORR: 26 vs. 32%; median PFS: 5.5 vs. 5.7 mo; median OS: NA vs. 29.3 mo | Grade 3/4 treatment-realted AE: 67% vs. 33%; AE leading to discontinuation of all treatments: 12% vs. 6% | 12/2017 |
C Optimal treatment sequencing upon disease progression for BRAF/MEK-directed targeted therapy and CPI therapy | |||||||
(DREAMSeq) | Phase III trial (DREAMseq) (Doublet, randomized evaluation in advanced melanoma sequencing) | IPI 3 mg/kg + NIVO 1 mg/kg followed by DAB 150 mg + TRA 2 mg (Arm A) vs. DAB 150 mg + TRA 2 mg followed by IPI 3 mg/kg + NIVO 1 mg/kg (Arm B) | 265 | 27.7 | ORR: 46% vs. 43% (Step 1) and 47.8% vs. 29.6% (Step 2); median duration of response: NR vs. 12.7 mo; median PFS: 11.8 vs. 8.5 mo; 2-year PFS rate: 41.9% vs. 19.2%; 2-year OS rate: 71.8% vs. 51.5%; | Treatment-related AE grade 3 or higher: 59.5% vs. 53.8%. Three treatment related deaths (two in Arm A, one in Arm B) | 08/2014 |
(SECOMBIT) [126] | Three arms prospective, randomized phase II study to evaluate the best sequential approach With Combo Immunotherapy (IPI/NIVO) and Combo Target Therapy (ENC + BIN) in patients With Metastatic Melanoma and BRAF Mutation (SECOMBIT) | ENC 450 mg + BIN 45 mg until PD, then NIVO 1 mg/kg + IPI 3 mg/kg (Arm A) vs. NIVO + IPI for 4 doses, followed by NIVO 3 mg/kg, until progressive disease (PD) then ENC + BIN (Arm B) vs. ENC + BIN for 8 weeks followed by NIVO + IPI for 4 doses, then NIVO until PD; then ENC + BIN (Arm C) | 209 | 32.2 | ORR: 87% vs. 44.9% vs. 82.4% (Step 1); 25.7% vs. 57.9% vs. 62.2% (Step 2); 2-year OS: 65% vs. 73% vs. 69%; 2-year PFS rate: 46% vs. 65% vs. 57% | trAE grade 3 or higher: 39% vs. 59% vs. 38%. AE leading to discontinuation occurred in 10% vs. 10% vs. 9%; no fatal events were being reported | 11/2016 |
D Sequential administration of BRAF/MEK-directed targeted therapy and CPI therapy | |||||||
[72] | Single arm open-label phase II study of VEM followed by IPI in subjects with previously untreated advanced melanoma | VEM 960 mg administered for 6 weeks followed by IPI 10 mg/kg | 46 | 15.3 | no severe hepatotoxicity, but other grade 3/4 AE; median OS: 18.5 mo; median PFS: 4.5 mo | Grade 3/4 AE of the skin (32.6%), GI-tract (21.7%) and hepato-biliary system (4.3%) | 09/2012 |
(ImmunoCobiVem) [128] | Phase II, open-label, randomized-controlled trial evaluating the efficacy and safety of sequential of VEM plus COB followed by immunotherapy with ATE for the treatment of patients with unresectable or metastatic BRAFV600-mutant melanoma (ImmunoCobiVem) | 3 month run-in period with VEM 960 mg + COB 60 mg, followed by VEM 960 mg + COB 60 mg until PD, then ATE 1200 mg vs. 3 months run-in period with VEM 960 mg + COB 60 mg, followed by ATE 1200 mg until PD, then cross-back to VEM 960 mg + COB 60 mg | 185 | 19.0 | Arm A: 52% discontinued treatment due to PD and switched to ATE; Arm B: 71% discontinued ATE due to PD and switched to VEM/COB; median PFS was longer in Arm A vs. Arm B (HR: 0.55, p = 0.001); median OS: similar between both arms (HR: 1.22, p = .37) | trAE grade 3 or higher were reported in 55% vs. 64% | 11/2016 |
3.1 Combined application
3.1.1 Triple therapy regimen in patients with melanoma brain metastases
3.1.2 Intermittent administration of MAPKi in triplet combination regimens
3.1.3 Combined application of MAPKi and CPI for patients with BRAF wild-type melanoma
3.1.4 Triple combination regimens in the neoadjuvant setting for resectable BRAF-mutant melanoma
National Clinical Trial (NCT) Number | Title | Status | Conditions | Interventions | Clinical Phase | Start Date |
---|---|---|---|---|---|---|
A BRAF-mutant melanoma: concomitant administration of MAPKdirected and CPI therapy | ||||||
Randomized, double-blind study of ENC and BIN plus PEM versus placebo plus PEM | Recruiting | Unresectable or metastatic BRAFV600-mutant melanoma | ENC 450 mg + BIN 45 mg + PEM 200 mg vs. PEM 200 mg only | 3 | 12/2020 | |
(SWOG S2000) | Randomized trial of ENC plus BIN plus NIVO vs. IPI plus NIVO in BRAFV600-mutant melanoma with MBM | Recruiting | Metastatic cutaneous melanoma with MBM | ENC 450 mg + BIN 45 mg + NIVO 3 mg/kg vs. IPI 3 mg/kg + NIVO 1 mg/kg | 2 | 12/2020 |
Randomized, double-blind study of ENC and BIN plus PEM versus placebo plus PEM | Recruiting | Metastatic or unresectable locally advanced BRAFV600E/K-mutant- melanoma | ENC 450 mg + BIN 45 mg + PEM 200 mg vs. PEM 200 mg only | 3 | 01/2021 | |
B BRAF-mutant melanoma: sequential administration of MAPK-directed and CPI therapy | ||||||
MAPK-targeted therapy followed by CPI (IPI and NIVO) vs. IPI plus NIVO (EORTC randomized study (EBIN) | Recruiting | Unresectable, BRAFV600-mutant stage III melanoma and BRAFV600-mutant stage IV melanoma | ENC 450 mg + BIN 45 mg for 12 weeks, followed by IPI 1 mg/kg + NIVO 3 mg/kg vs. IPI 1 mg/kg + NIVO 3 mg/kg only | 2 | 10/2018 | |
(IMPemBra) | Comparison of PEM with intermittent/short-term dual MAPK inhibition plus PEM | Recruiting | BRAFV600-mutant stage IV melanoma | PEM 200 mg vs. short-term DAB 150 mg + TRA 2 mg + PEM 200 mg vs. intermediate DAB + TRA + PEM vs. long-scheme DAB + TRA + PEM | 2 | 12/2015 |
A Multi-center phase I/II open label study to evaluate safety and efficacy in participants with ENC alone and with BIN in combination with NIVO and low-dose IPI. (QUAD 01: quadruple melanoma therapy) | Recruiting | Unresectable or metastatic BRAFV600-mutant melanoma high-risk patients | ENC 300 mg + IPI 1 mg/kg + NIVO 3 mg/kg vs. ENC 450 mg + BIN 45 mg + IPI 1 mg/kg + NIVO 3 mg/kg | 1/2 | 02/2021 | |
C BRAF-wild-type: sequential or concomitant administration of MAPK-directed and CPI therapy | ||||||
Abbreviated MAPK-targeted therapy plus PEM | Active | Unresectable or metastatic melanoma | PEM + DAB + TRA (BRAFV600-mutant) vs. PEM + TRA (BRAF wild-type) | 2 | 11/2017 | |
D Administration of MAPK-directed and CPI therapy in a neoadjuvant setting | ||||||
Neoadjuvant therapy: A pilot clinical trial | Recruiting | High-risk stage III BRAFV600-mutant melanoma | VEM + COB + ATE for up to 3 months followed by surgery and ATE for up to 8 cycles vs. COB + ATE for up to 3 months followed by surgery and ATE for up to 8 cycles | 2 | 06/2018 | |
Phase II, randomised, open label study of neoadjuvant DAB, TRA w/o and with PEM (NeoTrio) | Recruiting | BRAFV600-mutant resectable stage IIIB/C melanoma | DAB 150 mg + TRA 2 mg (1 we) plus consecutive PEM 2mg/kg for 6 we followed by surgery and PEM 2 mg/kg for 46 we vs. concurrent DAB 150 mg + TRA 2 mg + PEM 200 mg for 6 we followed by surgery and PEM 200mg for 46 we vs. PEM 200 mg only with surgery at week 6 | 2 | 11/2017 | |
NEOadjuvant Plus Adjuvant Therapy with VEM, COB, and ATE applied in combination or sequentually | Recruiting | High-risk resectable melanoma (stage III B-D and oligometastatic stage IV), both BRAF wild-type and BRAFV600-mutant | VEM 960 mg + COB 60 mg followed by surgery and ATE 1200 mg vs. VEM 720 mg + COB 60 mg for 6 we and 2 cycles of ATE 840 mg followed by surgery and ATE 1200 mg vs. COB 60 mg + ATE 840 mg for 6 we followed by surgery and ATE 1200 mg | 2 | 12/2020 |