Introduction
Structures and functions of MEK proteins
Molecular pathways and MEK inhibitors
Drug | Developer or owner | Target | In vitro IC50 for MEK (nM) | Tumor | Approval/development status |
---|---|---|---|---|---|
Trametinib (GSK1120212, JTP-74057) | NOVARTIS | MEK1/2 | 0.7 (MEK1), 0.9 (MEK2) [24] | Melanoma, NSCLC, thyroid cancer | Approved by US FDA (05/2013) |
Binimetinib (MEK162, ARRY-438162) | ARRAY BIOPHARMA INC | MEK1/2 | 12 [28] | Melanoma | Approved by US FDA (06/2018) |
Selumetinib (AZD6244, ARRY-142886) | ASTRAZENECA | MEK1/2 | 14 [23] | Neurofibroma | Approved by US FDA (4/2020) |
Cobimetinib (GDC-0973, XL518) | GENENTECH INC | MEK1/2 | 5 [29] | Melanoma | Approved by US FDA (11/2015) |
Pimasertib (AS703026, MSC1936369B) | Merck KGaA | MEK1/2 | 30 [30] | Melanoma, ovarian cancer, pancreatic adenocarcinoma, solid tumor | I/II |
Mirdametinib (PD-0325901) | Spring Works Therapeutics | MEK1/2 | 0.1–1000 [31] | Neurofibroma, solid tumor | I/II |
Refametinib (BAY 86–9766, RDEA119) | Bayer AG | MEK1/2 | 19 (MEK1), 47 (MEK2) [32] | Biliary tract cancer, hepatocellular cancer, solid tumor | I/II |
E6201 | Eisai Co Ltd./Strategia Theraputics | MEK1/FLT3 | NA | Melanoma with brain metastases, solid tumor | I |
GDC-0623 (RG 7421) | Genentech, Inc. | MEK1 | Solid tumor | I | |
CH5126766(RO5126766) | Chugai Pharmaceutical Co., Roche | MEK/BRAF/CRAF | 160/190/56 [35] | KRAS-mutant NSCLC, solid tumor | I |
HL-085 | Shanghai Kechow Pharma, Inc. | MEK1/2 | 1.9–10 [27] | Melanoma, NSCLC, solid tumor | I/II |
SHR7390 | HENGRUI MEDICINE | MEK1/2 | NA | Breast neoplasm, solid tumor | I/II |
TQ-B3234 | CHIATAI TIANQING | MEK1/2 | NA | Solid tumor | I |
CS-3006 | CSTONE PHARMACEUTICALS | MEK1/2 | NA | Solid tumor | I |
FCN-159 | FOSUN PHARMA | MEK1/2 | NA | NRAS-aberrant (Ia) and NRAS-mutant (Ib) melanoma | I |
Evidence for MEK monotherapy for NSCLC patients
Evidences for combination of BRAF and MEK inhibitors for NSCLC patients
Evidence for combination of chemotherapy and MEK inhibitors for NSCLC patients
Study | Study design | Intervention | Comparation | Patient population | Patients (n) | Median OS (months) | Median PFS (months) | ORR (%) |
---|---|---|---|---|---|---|---|---|
Jänne et al. [43] | Phase2 (NCT00890825) | Selumetinib + docetaxel | Placebo + docetaxel | KRAS-mutant advanced NSCLC | 87 (44 vs 43) | 9.4 vs 5.2 (HR:0.8, 80% CI = 0.56–1.14, P = 0.21) | 5.3 vs 2.1 (HR:0.58, 80%CI = 0.42–0.79, P = 0.014) | 37% vs 0 |
Gandara et al. [46] | Phase1 (NCT01192165) | Trametinib + docetaxel | Trametinib + pemetrexed | NSCLC | 95 (49 vs 46) | NA | KRAS wild-type:4.2 vs 5.8 KRAS-mutant type: 3.4 vs 4 | KRAS wild-type:18% vs 11% KRAS-mutant type: 24% vs 17% |
Jänne et al. [47] | Phase1 (NCT01933932) | Selumetinib + docetaxel | Placebo + docetaxel | KRAS-mutant NSCLC | 510 (251 VS 254) | 8.7 VS 7.9 (HR:1.05, 95% = 0.85–1.30, P = 0.64) | 3.9 VS 2.8 (HR:0.93, 95%CI = 0.77–1.12, P = 0.44) | 20.1% vs 13.7% (OR:1.61, 95%CI = 1–2.62, P = 0.05) |
Soria et al. [49] | Phase2 (NCT01750281.) | Selumetinib + docetaxel | Placebo + docetaxel | NSCLC | 212 | 5.7 vs 7.7 vs 11.5 | 3 vs 4.2 vs 4.3 (HR = 1.12,0.92) | 33% vs 14% (OR:3.26, 95%CI = 1.47–7.95) |
Greystoke et al. [50] | Phase1 (NCT01809210) | Selumetinib + gemcitabine/cisplatin or carboplatin | Selumetinib + pemetrexed/cisplatin or carboplatin | NSCLC | 55 | NA | NA | 36% vs 33% vs 19% vs 13% |
Seto et al. [51] | Phase1 (NCT01605916) | Selumetinib + docetaxel | Selumetinib | Solid tumor of NSCLC | 25 | NA | NA | NA |
Melosky et al. [44] | phase2 | Selumetinib + pemetrexed + cisplatin | No selumetinib | Non-squamous NSCLC | 62 | 10 vs 10.1 vs 15.3 (HR = 1.56,1.72)(P = 0.31,0.2) | 7.2 vs 6.9 vs 4 (HR = 0.82,0.77)(P = 0.56,0.44) | 35% vs 62% vs 24% |
Study | Main grade 3 or higher adverse events (over 10%) |
---|---|
Jänne et al. [43] | Neutropenia (67%), febrile neutropenia (18%), dyspnea (2%), and asthenia (9%) |
Gandara et al. [46] | Trametinib + docetaxel: anemia (16%), asthenia (4%), diarrhea (10%), dyspnea (4%), fatigue (10%), hypoalbuminemia (4%), mucosal (4%), neutropenia (22%), and stomatitis (4%). Trametinib + pemetrexed: anemia (13%), AST increased (4%), asthenia (9%), decreased appetite (4%), diarrhea (4%), dyspnea (7%), hyponatremia (15%), nausea (7%), and neutropenia (20%) |
Jänne et al. [47] | Diarrhea (6%), rash (3%), nausea (1%), fatigue (2%), stomatitis (3%), edema peripheral (1%), vomiting (2%), asthenia (5%), decreased appetite (1%), dermatitis acneiform (2%), neutropenia (6%), anemia (1%) and dyspnea (2%) |
Greystoke et al. [50] | Neutropenia (26%), anemia (22%), and thrombocytopenia (20%) |
Seto et al. [51] | Selumetinib monotherapy: blood and lymphatic system disorders (6%), neutropenia (6%), investigations (18%), AST increase (6%), GGT increase (6%), WBC count decrease (6%), infections and infestations (6%), pneumonia (6%), gastrointestinal disorders (12%), diarrhea (6%), vomiting (6%), respiratory, thoracic and mediastinal disorders (12%), interstitial lung disease (6%), metabolism and nutrition disorders (6%) and hypoalbuminemia (6%) |
Evidence for combination of immune checkpoint inhibitors and MEK inhibitors for NSCLC patients
Evidence for combination of EGFR tyrosine kinase inhibitors (TKIs) and MEK inhibitors for NSCLC patients
Mechanisms of resistance to MEK inhibitors
Other combined therapies and ongoing studies
Trial NCT number | Intervention | Cancer type | Phase | Status |
---|---|---|---|---|
03170206 | Binimetinib + Palbociclib | KRAS-mutant NSCLC | I/II | Recruiting |
01859026 | Erlotinib + Binimetinib | KRAS- or EGFR-mutant NSCLC | I/IB | Active, not recruiting |
02185690 | Carboplatin + Pemetrexed + Binimetinib | NSCLC | I | Active, not recruiting |
02964689 | Cisplatin + Pemetrexed + Binimetinib | KRAS-mutant NSCLC | I | Active, not recruiting |
03581487 | Durvalumab + Selumetinib + Tremelimumab | NSCLC | I/II | Recruiting |
03991819 | Binimetinib + Pembrolizumab | NSCLC | I | Active, not recruiting |
01586624 | Selumetinib + Vandetanib | NSCLC | I | Active, not recruiting |
04526782 | Encorafenib + Binimetinib + Docetaxel | BRAF V600E-mutant NSCLC | II | Not yet recruiting |
01336634 | Dabrafenib + Trametinib | BRAF V600E-mutant NSCLC | II | Active, not recruiting |
04005144 | Brigatinib + Binimetinib | ALK or ROS1 rearranged NSCLC | I | Recruiting |
03087448 | Ceritinib + Trametinib | ALK-positive NSCLC | I/II | Recruiting |
01933932 | Selumetinib + Docetaxel | KRAS-mutant NSCLC | III | Active, not recruiting |
03600701 | Atezolizumab + Cobimetinib | NSCLC | II | Recruiting |
03202940 | Alectinib + Cobimetinib | ALK rearranged NSCLC | IB/II | Recruiting |
02642042 | Trametinib + Docetaxel | KRAS-mutant stage IV NSCLC | II | Active, not recruiting |
03299088 | Pembrolizumab + Trametinib | KRAS-mutant NSCLC | I | Recruiting |
03516214 | EGF816 + Trametinib | EGFR-mutant NSCLC | I | Recruiting |
03225664 | Trametinib + Pembrolizumab | NSCLC | I/II | Recruiting |
01750281 | Selumetinib + Docetaxel | NSCLC | II | Active, not recruiting |
02664935 | National Lung Matrix Trial: AZD4547/Vistusertib/Palbociclib/ Crizotinib/ Selumetinib/Docetaxel/AZD5363/ Osimertinib/ Durvalumab/ Sitravatinib/AZD6738 | NSCLC | II | Recruiting |
03990077 | HL-085 + Docetaxel | KRAS-mutant NSCLC | I | Not yet recruiting |
01912625 | Trametinib + Carboplatin + Paclitaxel + Radiation Therapy | NSCLC | I | Active, not recruiting |
Conclusions/expectations
Study | Phase | MEK inhibitors | Drug therapy |
---|---|---|---|
Hainsworth et al. [36] | Phase II | Selumetinib | MEKi |
Haura et al. [37] | Phase II | Mirdametinib | MEKi |
Blumenschein et al. [38] | Phase II | Trametinib | MEKi |
Lopez-Chavez et al. [39] | Phase II | Selumetinib | MEKi |
Planchard et al. [40] | Phase II | Trametinib | MEKi + BRAFi |
Planchard et al. [41] | Phase II | Trametinib | MEKi + BRAFi |
Salama et al. [42] | Phase II | Trametinib | MEKi + BRAFi |
Jänne et al. [43] | Phase II | Selumetinib | MEKi + CT |
Gandara et al. [46] | Phase I/ Ib | Trametinib | MEKi + CT |
Jänne et al. [47] | Phase III | Selumetinib | MEKi + CT |
Soria et al. [49] | Phase II | Selumetinib | MEKi + CT |
Greystoke et al. [50] | Phase I | Selumetinib | MEKi + CT |
Seto et al. [51] | Phase I | Selumetinib | MEKi + CT |
Melosky et al. [44] | Phase II | Selumetinib | MEKi + CT |
Hellmann et al. [56] | Phase Ib | Cobimetinib | MEKi + ICI |
Gaudreau et al. [57] | Phase I/II | Trametinib | MEKi + ICI |
Carter et al. [59] | Phase Ib | Selumetinib | MEKi + EGFR-TKI |
Oxnard et al. [60] | Phase Ib | Selumetinib | MEKi + EGFR-TKI |