Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade
Abstract
:1. Introduction
2. Therapies Targeting the MAPK Pathway
3. Immune Checkpoint Blockade
4. Combination of Immunotherapy and Targeted Therapy
4.1. Melanoma
4.2. Non-Small-Cell Lung Cancer (NSCLC)
4.3. Colorectal Cancer (CRC)
4.4. Pancreatic Cancer
4.5. Thyroid Cancer
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
MAPK | mitogen-activated protein kinase |
NSCLC | non-small-cell lung carcinoma |
MEK | MAPK/ERK kinase |
PD-1 | programmed death protein 1 |
PD-L1 | programmed death-ligand 1 |
PD-L2 | programmed death-ligand 2 |
CTLA-4 | cytotoxic T cell associated antigen 4 |
US FDA | United States Food and Drug Administration |
Tim-3 | T-cell immunoglobulin and mucin-domain containing-3 |
IL-2 | interleukin 2 |
PFS | progression-free survival |
OS | overall survival |
EGFR | epidermal growth factor receptor |
ALK | anaplastic lymphoma kinase |
PI3K | phosphoinositide 3-kinase |
STAT | signal transducer and activator of transcription |
CRC | colorectal cancer |
mCRC | metastatic colorectal cancer |
MSS | microsatellite stable |
mAbs | monoclonal antibodies |
PDAC | pancreatic ductal adenocarcinoma |
PARP | poly ADP ribose polymerase |
TME | tumor microenvironment |
RET/PTC | rearranged in transfusion/papillary thyroid carcinoma |
RP2D | recommended phase II dose |
ORR | overall response rate |
mPFS | median progression-free survival |
MTD | maximum tolerated dose |
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Type of Cancer | Mutations |
---|---|
Melanoma | IDH1, RB1, DDX3X, NF1, BRAF, RAS, |
Non-small-cell lung cancer | PI3K, FGFR, DDR2, PTEN, KRAS, EGFR, BRAF, ALK |
Colorectal cancer | APC, KRAS, TP53, SMAD4, FBXW7, BRAF, PI3K |
Pancreatic cancer | KRAS,BRAF,TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A, SF3B1 |
Thyroid cancer | RAS, BRAF, TP53, PI3K, RET/PTC |
Name of Drug | Company | Target | Conditions |
---|---|---|---|
Everolimus (Afinitor) | Novartis | mTOR |
|
Tamoxifen (Nolvadex) | AstraZeneca | Estrogen receptor (ER)-positive breast cancer |
|
Lapatinib (Tykerb) | GlaxoSmithKline | HER2 (ERBB2/neu), EGFR (HER1/ERBB1) |
|
Neratinib (Nerlynx) | Puma Biotech | HER2 (ERBB2/neu) |
|
Palbociclib (Ibrance) | Pfizer | CDK4, CDK6 |
|
Ribociclib (Kisqali) | Novartis | CDK4, CDK6 |
|
Ado-trastuzumab emtansine (Kadcyla) | Genentech | HER2 (ERBB2/neu) |
|
Trastuzumab (Herceptin) | Genentech | HER2 (ERBB2/neu) |
|
Erdafitinib (Balversa™) | Astex Pharmaceuticals and Janssen Pharmaceutical | FGFR |
|
Axitinib (Inlyta) | Chiron | KIT, PDGFRβ, VEGFR1/2/3 |
|
Lenvatinib (Lenvima) | Eisai | VEGFR2 |
|
Sorafenib (Nexavar) | Bayer | VEGFR, PDGFR, KIT, RAF |
|
Temsirolimus (Torisel) | Pfizer | mTOR |
|
Pazopanib (Votrient) | GlaxoSmithKline | VEGFR, PDGFR, KIT |
|
Cabozantinib (Cabometyx (tablet), Cometriq (capsule])) | Exelixis | FLT3, KIT, MET, RET, VEGFR2 |
|
Afatinib (Gilotrif) | Boehringer Ingelheim | EGFR (HER1/ERBB1), HER2 (ERBB2/neu) |
|
Alectinib (Alecensa) | Genentech | ALK |
|
Brigatinib (Alunbrig) | Takeda Pharmaceutical | ALK |
|
Ceritinib (Zykadia) | Novartis | ALK |
|
Crizotinib (Xalkori) | Pfizer | ALK, MET, ROS1 |
|
Erlotinib (Tarceva) | Roche | EGFR (HER1/ERBB1) |
|
Gefitinib (Iressa) | AstraZeneca | EGFR (HER1/ERBB1) |
|
Osimertinib (Tagrisso) | AstraZeneca | EGFR |
|
Cobimetinib (Cotellic) | Genentech | MEK |
|
Dabrafenib (Tafinlar) | GlaxoSmithKline | BRAF |
|
Necitumumab (Portrazza) | Eli Lilly | EGFR (HER1/ERBB1) |
|
Bortezomib (Velcade) | Takeda | Proteasome |
|
Bosutinib (Bosulif) | Pfizer | ABL |
|
Carfilzomib (Kyprolis) | Onyx | Proteasome |
|
Dasatinib (Sprycel) | Bristol-Myers Squibb | ABL |
|
Enasidenib (Idhifa) | Agios Pharmaceuticals/Celgene | IDH2 |
|
Venetoclax (Venclexta) | AbbVie and Roche | BCL2 |
|
Ibrutinib (Imbruvica) | Johnson &Johnson | BTK |
|
Idelalisib (Zydelig) | Gilead | PI3Kδ |
|
Ixazomib (Ninlaro) | Takeda Pharmaceutical | Proteasome |
|
Midostaurin (Rydapt) | Novartis | FLT3 |
|
Nilotinib (Tasigna) | Novartis | ABL |
|
Ponatinib (Iclusig) | ARIAD | ABL, FGFR1–3, FLT3, VEGFR2 |
|
Trametinib (Mekinist) | GlaxoSmithKline | MEK |
|
Vemurafenib (Zelboraf) | Genentech | BRAF |
|
Cetuximab (Erbitux) | Eli Lilly | EGFR (HER1/ERBB1) |
|
Ziv-aflibercept (Zaltrap) | Sanofi-Aventis | PIGF, VEGFA/B |
|
Panitumumab (Vectibix) | Amgen | EGFR (HER1/ERBB1) |
|
Ramucirumab (Cyramza) | Eli Lilly | VEGFR2 |
|
Regorafenib (Stivarga) | Bayer | KIT, PDGFRβ, RAF, RET, VEGFR1–3 |
|
Rucaparib (Rubraca) | Clovis Oncology | PARP |
|
Niraparib (Zejula) | Tesaro | PARP |
|
Olaparib (Lynparza) | AstraZeneca | PARP |
|
Denosumab (Xgeva) | Amgen | RANKL |
|
Dinutuximab (Unituxin) | United Therapeutics | B4GALNT1 (GD2) |
|
Imatinib (Gleevec) | Novartis | KIT, PDGFR, ABL |
|
Sonidegib (Odomzo) | Novartis | Smoothened |
|
Vismodegib (Erivedge) | Roche | PTCH, Smoothened |
|
Olaratumab (Lartruvo) | Eli Lilly | PDGFRα |
|
Ruxolitinib (Jakafi) | Incyte | JAK1/2 |
|
Tofacitinib (Xeljanz) | Pfizer | JAK3 |
|
Vandetanib (Caprelsa) | AstraZeneca | EGFR (HER1/ERBB1), RET, VEGFR2 |
|
Name of Drug | Company | Target | Conditions |
---|---|---|---|
Alemtuzumab (Campath) | Sanofi | CD52 |
|
Atezolizumab (Tecentriq) | Genentech | PD-L1 |
|
Avelumab (Bavencio) | Merck KGaA and Pfizer | PD-L1 |
|
Blinatumomab (Blincyto) | Amgen | CD19/CD3 |
|
Brentuximab vedotin (Adcetris) | Takeda Pharmaceutical | CD30 |
|
Canakinumab (Ilaris) | Novartis | IL-1β |
|
Daratumumab (Darzalex) | Janssen Pharmaceutical | CD38 |
|
Durvalumab (Imfinzi) | MedImmune/AstraZeneca | PD-L1 |
|
Elotuzumab (Empliciti) | Bristol-Myers Squibb | SLAMF7 (CS1/CD319/CRACC) |
|
Ibritumomab tiuxetan (Zevalin) | Biogen IDEC | CD20 |
|
Ipilimumab (Yervoy) | Bristol-Myers Squibb | CTLA-4 |
|
Nivolumab (Opdivo) | Bristol-Myers Squibb | PD-1 |
|
Obinutuzumab (Gazyva) | Roche | CD20 |
|
Ofatumumab (Arzerra, HuMax-CD20) | Roche | CD20 |
|
Pembrolizumab (Keytruda) | Merck &Co | PD-1 |
|
Rituximab (Rituxan, Mabthera) | Roche | CD20 |
|
Rituximab/hyaluronidase human (Rituxan Hycela) | Roche | CD20 |
|
Siltuximab (Sylvant) | Janssen Pharmaceutical | IL-6 |
|
Tocilizumab (Actemra) | Genentech | IL-6R |
|
Tositumomab (Bexxar) | Corixa | CD20 |
|
Name of Drug | Company | Target | Indications |
---|---|---|---|
Ipilimumab | Bristol-Myers Squibb | CTLA-4 |
|
Tremelimumab | AstraZeneca | CTLA-4 |
|
Nivolumab | Bristol-Myers | PD-1 |
|
Pembrolizumab | Merck | PD-1 |
|
Atezolizumab | Roche | PD-L1 |
|
Avelumab | Merck Pfizer | PD-L1 |
|
Durvalumab | MedImmune/AstraZeneca | PD-L1 |
|
National Clinical Trial (NCT) Number | Title | Status | Conditions | Interventions | Phase | Start Date |
---|---|---|---|---|---|---|
NCT 01400451 | Ph I Ipilimumab Vemurafenib Combo in Patients with v-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) | Terminated (unexpected grade 2/3 hepatotoxicity) | •Melanoma | •Drug: Ipilimumab (BMS-734016) •Drug: Vemurafenib | Phase 1 | November 2011 |
NCT 01673854 | Phase II Safety Study of Vemurafenib Followed by Ipilimumab in Subjects with V600 BRAF Mutated Advanced Melanoma | Completed (no severe hepatotoxicity, but reported a grade 3/4 skin adverse event) | •Melanoma | •Drug: Ipilimumab •Biological: Vemurafenib | Phase 2 | 13 September 2012 |
NCT 03554083 | Neoadjuvant Combination Targeted and Immunotherapy for Patients with High-Risk Stage III Melanoma | Recruiting | •Clinical stage iii cutaneous melanoma ajcc v8 •Pathologic Stage III Cutaneous Melanoma AJCC v8 •Pathologic Stage IIIA Cutaneous Melanoma AJCC v8 •Pathologic Stage IIIB Cutaneous Melanoma AJCC v8 •Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 •Pathologic Stage IIID Cutaneous Melanoma AJCC v8 | •Drug: Atezolizumab •Drug: Cobimetinib •Drug: Vemurafenib | Phase 2 | 22 June 2018 |
NCT 03235245 | Immunotherapy with Ipilimumab and Nivolumab Preceded or Not by a Targeted Therapy with Encorafenib and Binimetinib | Recruiting | •Unresectable Stage III Melanoma •Stage IV Melanoma | •Drug: Nivolumab + Ipilimumab •Drug: Encorafenib+ Binimetinib | Phase 2 | 30 October 2018 |
NCT 02967692 | A Study of the Anti-PD1 Antibody PDR001, in Combination with Dabrafenib and Trametinib in Advanced Melanoma | Recruiting | •Melanoma | •Biological: Spartalizumab (PDR001) •Other: Placebo •Drug: Dabrafenib •Drug: Trametinib | Phase 3 | 17 February 2017 |
NCT 02902042 | Encorafenib + Binimetinib + Pembrolizumab in Patients with Unresectable or Metastatic BRAF V600 Mutant Melanoma | Recruiting | •Malignant Melanoma | •Drug: Encorafenib •Drug: Binimetinib •Drug: Pembrolizumab •Drug: Pembrolizumabalone | •Phase 1 •Phase 2 | 24 April 2018 |
NCT 02858921 | Neoadjuvant Dabrafenib, Trametinib and/or Pembrolizumab in BRAF Mutant Resectable Stage III Melanoma | Recruiting | •Melanoma | •Melanoma •Drug: Dabrafenib •Drug: Trametinib •Drug: Pembrolizumab | Phase 2 | 8 November 2017 |
National Clinical Trial (NCT) Number | Title | Status | Conditions | Interventions | Phase | Start Date |
---|---|---|---|---|---|---|
NCT 03991819 | Study of Binimetinib in Combination with Pembrolizumab in Advanced Non-Small-Cell Lung Cancer | Recruiting | •Non-Small-Cell Carcinoma | •Drug: Binimetinib •Drug: Pembrolizumab | •Phase 1 | 20 September 2019 |
NCT 03600701 | Atezolizumab and Cobimetinib in Treating Patients with Metastatic, Recurrent, or Refractory Non-Small-Cell Lung Cancer | Recruiting | •Recurrent Lung Non-Small-Cell Carcinoma •Refractory Lung Non-Small-Cell Carcinoma •Stage IV Lung Non- Small-Cell Cancer AJCC v7 | •Drug: Atezolizumab •Drug: Cobimetinib | Phase 2 | 20 July 2018 |
NCT 03581487 | Durvalumab, Tremelimumab, and Selumetinib in Treating Participants with Recurrent or Stage IV Non-Small-Cell Lung Cancer | Recruiting | •Recurrent Lung Non-Small-Cell Carcinoma •Stage IV Lung Cancer AJCC v8 •Stage IVA Lung Cancer AJCC v8 •Stage IVB Lung Cancer AJCC v8 | •Biological: Durvalumab •Drug: Selumetinib •Biological:Tremelimumab | •Phase 1 •Phase 2 | 1 April 2019 |
NCT 03299088 | Pembrolizumab and Trametinib in Treating Patients with Stage IV Non-Small-Cell Lung Cancer and KRAS Gene Mutations | Recruiting | •KRAS Gene Mutation •Metastatic Non- Squamous Non- Small Cell Lung Carcinoma •Recurrent Non- Squamous Non- Small Cell Lung Carcinoma •Stage IV Non-Small-Cell Lung Cancer AJCC v7 | •Biological: Pembrolizumab •Drug: Trametinib | Phase 1 | 26 June 2018 |
NCT 03225664 | Trametinib and Pembrolizumab in Treating Patients with Recurrent Non-Small-Cell Lung Cancer That Is Metastatic, Unresectable, or Locally Advanced | Recruiting | •Metastatic Lung Non-Small-Cell Carcinoma •Recurrent Lung Non-Small-Cell Carcinoma •Stage III Lung Cancer AJCC v8 •Stage IIIA Lung Cancer AJCC v8 •Stage IIIB Lung Cancer AJCC v8 •Stage IIIC Lung Cancer AJCC v8 •Stage IV Lung Cancer AJCC v8 •Stage IVA Lung Cancer AJCC v8 •Stage IVB Lung Cancer AJCC v8 •Unresectable Lung Non-Small-Cell Carcinoma | •Biological: Pembrolizumab •Other: Pharmacokinetic Study •Drug: Trametinib | •Phase 1 •Phase 2 | 3 February 2018 |
National Clinical Trial (NCT) Number | Title | Status | Conditions | Interventions | Phase | Start Date |
---|---|---|---|---|---|---|
NCT 01436656 | A Phase I Study of Oral LGX818 in Adult Patients with Advanced or Metastatic BRAF Mutant Melanoma | Active, not recruiting | •Melanoma and Metastatic Colorectal Cancer | •Drug: LGX818 | •Phase 1 | September 2011 |
NCT 00959127 | A Study of ARRY-438162 (MEK162) in Patients with Advanced Cancer | Completed | •Advanced Solid Tumors •Advanced or Metastatic Biliary Cancer •Metastatic Colorectal Cancer | •Drug: ARRY-438162 (MEK162), MEK inhibitor; oral | Phase 1 | August 2009 |
National Clinical Trial (NCT) Number | Title | Status | Conditions | Interventions | Phase | Start Date |
---|---|---|---|---|---|---|
NCT 04044430 | Encorafenib, Binimetinib, and Nivolumab in Treating Patients with Microsatellite Stable BRAFV600E Metastatic Colorectal Cancer | Not yet recruiting | •Metastatic Colon Adenocarcinoma •Metastatic Colorectal Adenocarcinoma •Metastatic Microsatellite Stable Colorectal Carcinoma •Metastatic Rectal Adenocarcinoma •Stage III Colon Cancer •Stage III Colorectal Cancer •Stage III Rectal Cancer •Stage IIIA Colon Cancer •Stage IIIA Colorectal Cancer •Stage IIIA Rectal Cancer •and 18 more | •Drug: Binimetinib •Drug: Encorafenib •Biological: Nivolumab •Other: Questionnaire Administration | •Phase 1 •Phase 2 | 1 December 2019 |
NCT 03428126 | Study of Durvalumab (MEDI4736) (Anti-PD-L1) and Trametinib (MEKi) in MSS Metastatic Colon Cancer | Enrolling by invitation | •Malignant Neoplasms of Digestive Organs •Colorectal Cancer •Colon Cancer | •Drug: Durvalumab •Drug: Trametinib | Phase 2 | 21 March 2018 |
NCT 03374254 | Safety and Efficacy of Pembrolizumab (MK-3475) Plus Binimetinib Alone or Pembrolizumab Plus Chemotherapy with or without Binimetinib in Metastatic Colorectal Cancer (mCRC) Participants (MK-3475-651) | Recruiting | •Metastatic Colorectal Cancer | •Biological: Pembrolizumab •Drug: Binimetinib •Drug: Oxaliplatin •Drug: Leucovorin •Drug: 5-Fluorouracil [5-FU] •Drug: Irinotecan | Phase 1 | 16 February 2018 |
National Clinical Trial (NCT) Number | Title | Status | Conditions | Interventions | Phase | Start Date |
---|---|---|---|---|---|---|
NCT 03193190 | A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants with Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus Pancreatic Cancer) | Recruiting | •Pancreatic Adenocarcinoma | •Drug: NabPaclitaxel •Drug: Gemcitabine •Drug: Oxaliplatin •Drug: Leucovorin •Drug: Fluorouracil •Drug: Atezolizumab •Drug: Cobimetinib •Drug: PEGPH20 •Drug: BL-8040 •Drug: Selicrelumab •and 3 more | •Phase 1 •Phase 2 | 5 July 2017 |
NCT 03637491 | A Study of Avelumab, Binimetinib and Talazoparib in Patients with Locally Advanced or Metastatic RAS-mutant Solid Tumors | Recruiting | •Pancreatic Cancer | •Drug: Avelumab •Drug: Binimetinib •Drug: Talazoparib | Phase 2 | 15 August 2018 |
National Clinical Trial (NCT) Number | Title | Status | Conditions | Interventions | Phase | Start Date |
---|---|---|---|---|---|---|
NCT 04061980 | Encorafenib and Binimetinib with or without Nivolumab in Treating Patients with Metastatic Radioiodine Refractory BRAF V600 Mutant Thyroid Cancer | Not yet recruiting | •BRAF NP_004324.2:p.V600M •BRAF V600E Mutation Present •Metastatic Thyroid Gland Carcinoma •Refractory Thyroid Gland Carcinoma •Stage IV Differentiated Thyroid Gland Carcinoma AJCC v8 •Stage IVA Differentiated Thyroid Gland Carcinoma AJCC v8 •Stage IVB Differentiated Thyroid Gland Carcinoma AJCC v8 | •Drug: Binimetinib •Drug: Encorafenib •Biological: Nivolumab | Phase 2 | 30 August 2019 |
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Shin, M.H.; Kim, J.; Lim, S.A.; Kim, J.; Lee, K.-M. Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade. Int. J. Mol. Sci. 2020, 21, 2531. https://doi.org/10.3390/ijms21072531
Shin MH, Kim J, Lim SA, Kim J, Lee K-M. Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade. International Journal of Molecular Sciences. 2020; 21(7):2531. https://doi.org/10.3390/ijms21072531
Chicago/Turabian StyleShin, Min Hwa, Jiyoung Kim, Siyoung A. Lim, Jeongsoo Kim, and Kyung-Mi Lee. 2020. "Current Insights into Combination Therapies with MAPK Inhibitors and Immune Checkpoint Blockade" International Journal of Molecular Sciences 21, no. 7: 2531. https://doi.org/10.3390/ijms21072531