Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies
Abstract
:Simple Summary
Abstract
1. Introduction
2. BRAF
3. MEK
4. NRAS
5. HRAS and KRAS
6. c-KIT
7. VEGFR
8. c-MET
9. PI3K/AKT
10. Combination Therapies with Immune Checkpoint Inhibitors
11. Conclusions
Funding
Conflicts of Interest
References
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Drug 1 (Target) | Drug 2 (Target) | Drug 3 (Target) | Type of Study | Reference |
---|---|---|---|---|
BRAF/MEK | ||||
Dabrafenib (BRAF) | Trametinib (MEK) | Pembrolizumab (PD-1) | Phase IIPhase I/II | [15,16] |
Dabrafenib (BRAF) | Trametinib (MEK) | Spartalizumab (PD-1) | Phase III | [17] |
Vemurafenib (BRAF) | Cobimetinib (MEK) | Atezolizumab (PD-L1) | Phase III | [18] |
NRAS | ||||
Compd A (RAF) | Trametinib (MEK) | Pre-clinical | [19] | |
Ipilimumab (CTLA-4) or anti-PD-1 (PD-1) | Binimetinib, Pimasertinib, or Trametinib (MEK) | Case control studies | [20] | |
Tivantinib (cMET) | Sorafenib (VEGFR/PDGFR/RAF/other) | Phase I | [21] | |
Binimetinib (MEK) | Ribociclib (CDK4/6) | Phase Ib/II | [22] | |
Trametinib (MEK) | XMD9-92 (ERK5) | Pre-clinical | [23] | |
Trametinib (MEK) | GSK2334470 (PDPK1) | Pre-clinical | [24] | |
Trametinib (MEK) | CCG-222740 (MRTF) | Pre-clinical | [25] | |
Trametinib or PD901 (MEK) | PHGDH siRNA | Pre-clinical | [26] | |
Cobimetinib (MEK) | CD147 inhibitor | Pre-clinical | [27] | |
HRAS | ||||
ASN007 (ERK1/2) | Copanlisib (PI3K) | Pre-clinical | [28] | |
KIT | ||||
Imatinib (KIT/other) | Pembrolizumab (PD-1) | Case Report | [29] | |
Dasatinib (KIT) | Dacarbazine | Phase 1 | [30] | |
Sorafenib (KIT/other) | Temozolomide | Case Report | [31] | |
Sorafenib (KIT) | Carboplatin | Paclitaxel | Phase I/II | [32] |
VEGFR | ||||
Apatinib (VEGFR) | Camrelizumab/SHR-1210 (PD-1) | Phase II/III | [33] | |
Apatinib (VEGFR) | Temozolomide (Antineoplastic) | Clinical trial (escalation study) | [34] | |
Axitinib (VEGFR) | Toripalimab (PD-1) | Phase Ib | [35] | |
Bevacizumab (VEGFR) | Ipilimumab (CTLA-4) | Phase I | [36] | |
Bevacizumab (VEGFR) | Paclitaxel (Antineoplastic) | Carboplatin (Antineoplastic) | Phase II | [37] |
Lenvatinib (VEGFR) | Pembrolizumab (PD-1) | Phase Ib/II | [38,39] | |
Pazopanib (VEGFR/PDGFR/c-KIT) | Paclitaxel (Antineoplastic) | Phase II | [40] | |
C-MET | ||||
Everolimus (mTOR) | XAV939 (Wnt) | SU11274 (cMET) | Pre-clinical | [41] |
LY2801653 (cMET) | Trametinib (MEK1/2) | Pre-clinical | [42] | |
Abemaciclib (CDK4/6) | Merestinib (cMET) | Pre-clinical | [43] | |
Bi-Specific antibody (cMET & PD1) | Pre-clinical | [44] | ||
PI3K/AKT | ||||
Pimasertib (MEK1/2) | Voxtalisib (pan-PI3K) | Phase Ib | [45] | |
MK-2206 (AKT) | Carboplatin/Paclitaxel, Docetaxel, or Erlotinib | Phase I | [46] |
Clinical Trials | Phase/Status | Participants | Conditions | Drug Intervention (Drug Target) | Primary Outcome Measures | Estimated Completion Date |
---|---|---|---|---|---|---|
NCT04720768 (CELEBRATE) | Ib, Recruiting | 78 | Metastatic BRAF Mutant Melanoma | Encorafenib (BRAF) + Binimetinib (MEK) + Palbociclib (CDK4/6) | Dose-Limiting Toxicity | 12/04/2023 |
NCT04835805 | Ib, Recruiting | 98 | Advanced NRAS Mutant Melanoma, Had received anti-PD-1/PD-L1 therapy | Belvarafenib (RAF) + Cobimetinib (MEK) with/without Atezolizumab (PD-L1) | Dose-Limiting Toxicity, Adverse Events | 11/11/2024 |
NCT04109456 | Ib, Recruiting | 52 | Metastatic Uveal Melanoma, Metastatic NRAS Mutant Melanoma | IN10018 (FAK) + Cobimetinib (MEK) | Safety, Tolerability | 06/30/2023 |
NCT02974725 | Ib, Active, not recruiting | 241 | Metastatic/Advanced KRAS or BRAF Mutant Non-Small Cell Lung Cancer or NRAS Mutant Melanoma | Naporafenib (RAF) + LTT462 (ERK1/2)/Trametinib (MEK)/Ribociclib (CDK4/6) | Adverse Events, Dose-Limiting Toxicities, Tolerability | 11/25/2022 |
NCT04417621 | II, Recruiting | 320 | Previously Treated Unresectable or Metastatic BRAFV600 or NRAS Mutant Melanoma | Naporafenib (RAF) + LTT462 (ERK1/2)/Trametinib (MEK)/Ribociclib (CDK4/6) | Overall Response Rate | 09/08/2023 |
NCT03979651 (CHLOROTRAMMEL) | I, Recruiting | 29 | Metastatic/Advanced NRAS Melanoma | Trametinib (MEK) + Hydroxychloroquine (autophagy) | Dose-Limiting Toxicities, Partial or Complete response | 03/31/2022 |
NCT04903119 | I, Recruiting | 15 | Metastatic or Unresectable melanoma with BRAF V600 | Nilotinib (cKIT) + Dabrafenib (BRAF) + Trametinib (MEK) | Dose-Limiting Toxicities | 03/31/2027 |
NCT02298959 | I, Recruiting | 78 | Advanced Solid Tumors | Aflibercept (VEGFR) + Pembrolizumab (PD-1) | Safety, Recommended Phase II Dosing | 11/31/2022 |
NCT02159066 (LOGIC-2) | II, Active, not recruiting | 160 | Locally Advanced or Metastatic BRAF V600 Melanoma | Encorafenib (BRAF) + Binimetinib (MEK) + Ribociclib (CDK4/6)/Infigratinib (FGFR kinase)/Buparlisib (PI3K)/ Capmatinib (MET) | Overall Response Rate | 01/17/2023 |
NCT03957551 | Ib/II, Recruiting | 39 | Advanced Melanoma | Cabozantinib (VEGFR/cMET/AXL) + Pembrolizumab (PD-1) | Dose-Limiting Toxicities, Overall Response Rate | 07/01/2024 |
NCT03131908 | I/II, Active, not recruiting | 36 | Refractory Metastatic Melanoma with loss of PTEN | GSK2636771 (PI3Kβ) + Pembrolizumab (PD-1) | Maximum Tolerated Dose, Objective Response Rate | 12/31/2022 |
NCT02637531 | I, Active, not recruiting | 219 | Advanced Melanoma | IPI-549 (PI3K-gamma) + Nivolumab (PD-1) | Dose-limiting Toxicity, Adverse Events | 12/2022 |
NCT03673787 (IceCAP) | I/II, Recruiting | 87 | Solid Tumors with Hyperactive PI3K | Ipatasertib (AKT) + Atezolizumab (PD-L1) | Maximum Tolerated Dose, Adverse Events | 11/2023 |
NCT01480154 | I, Active, not recruiting | 62 | Advanced Solid Tumors | MK-2206 (AKT) + Hydroxychloroquine | Maximum Tolerated Dose, Dose-Limiting Rate | 02/14/2020, not published |
NCT03470922 (RELATIVITY-047) | II/III, Active, not recruiting | 714 | Previously Untreated Metastatic or Unresectable Melanoma | Relatlimab (LAG-3) + Nivolumab (PD-1) | Progression Free Survival | 11/30/2023 |
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Share and Cite
Rager, T.; Eckburg, A.; Patel, M.; Qiu, R.; Gantiwala, S.; Dovalovsky, K.; Fan, K.; Lam, K.; Roesler, C.; Rastogi, A.; et al. Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies. Cancers 2022, 14, 3779. https://doi.org/10.3390/cancers14153779
Rager T, Eckburg A, Patel M, Qiu R, Gantiwala S, Dovalovsky K, Fan K, Lam K, Roesler C, Rastogi A, et al. Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies. Cancers. 2022; 14(15):3779. https://doi.org/10.3390/cancers14153779
Chicago/Turabian StyleRager, Taylor, Adam Eckburg, Meet Patel, Rong Qiu, Shahina Gantiwala, Katrina Dovalovsky, Kelly Fan, Katie Lam, Claire Roesler, Aayush Rastogi, and et al. 2022. "Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies" Cancers 14, no. 15: 3779. https://doi.org/10.3390/cancers14153779