Exploring the Pathway: Inhibiting MEK for Cancer Therapy

Exploring the Pathway: Inhibiting MEK for Cancer Therapy

Alex Adjei, MD

Yujie Zhao, MD

Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiologic processes. These enzymes are regulated by a characteristic phosphorelay system, in which a series of three protein kinases phosphorylate and activate one another. The extracellular signal-regulated kinases (ERKs) function in the control of cell division. The c-Jun amino-terminal kinases (JNKs) are critical regulators of transcription. The p38 MAPKs are activated by inflammatory cytokines and environmental stresses. Because of its role in cell proliferation and carcinogenesis, the most characterized MAPK pathway is the RAS/RAF/MEK/ERK pathway. This is one of the most frequently dysregulated signal transduction pathways in human cancers, often through gain-of-function mutations of RAS and RAF family members. Mutations in KRAS have been found in 90% of pancreatic cancers, 20% of non-small cell lung cancers (NSCLC), and up to 50% of colorectal and thyroid cancers,1 whereas mutations of BRAF have been identified in more than 60% of melanoma and 40% to 60% of papillary thyroid cancers.2-4 Although MEK1/2 is rarely mutated, constitutively active MEK has been found in more than 30% of primary tumor cell lines tested.5

MEK Signaling

The RAS/RAF/MEK/ERK pathway is activated by a wide array of growth factors and cytokines acting through receptor tyrosine kinases.  These growth factors, such as EGF, IGF, and TGF, initially bind to and then activate transmembrane receptors located on the cell surface.  The activated receptors then bind a host of adapter proteins, which in turn recruit nucleotide exchange proteins.  Exchange proteins activate RAS through a conversion from the inactive GDP-bound form to the active GTP-bound form.  Activated RAS recruits RAF kinase to the membrane, where it is activated by multiple phosphorylation events.  Activated RAF phosphorylates and activates MEK kinase.  MEK kinase in turn phosphorylates and activates ERK kinase.  Phosphorylated ERK can translocate to the nucleus where it phosphorylates and activates various transcription factors.6-8   This leads to altered gene transcription and cellular proliferation.9-12 The RAF protein kinase family consists of A-RAF, B-RAF, and C-RAF (RAF-1), all sharing RAS as a common upstream activator and MEK1/2 as principal kinase effectors.13 MEK1/2   are dual-specificity kinases, catalyzing the phosphorylation of both tyrosine and threonine on ERK1 and ERK2, their only known physiologic substrates.14 In contrast to RAF and MEK1/2, which have narrow substrate specificity, activated ERK1/2 catalyze the phosphorylation of numerous cytoplasmic and nuclear substrates, regulating diverse cellular responses such as mitosis, embryogenesis, cell differentiation, motility, metabolism, and programmed death, as well as angiogenesis (Fig. 1).15-22

Fig 1.

MEK Inhibitors

Aberrant signaling though the RAS/RAF/MEK pathway has been shown to lead to cell transformation.10  For example, conditional MAPK activation is important in gene regulation, promoting G1 cell cycle progression before DNA replication, and spindle assembly during both meiotic and mitotic cell division, among other processes.  Inappropriate activation of the MAPK pathway, through mutations in upstream proteins introduced via oncogenes (EGFR, PIK3CA, RAS, RAF), is a feature of many neoplasms. Inhibition of MEK1/2 has, therefore, been seen as an attractive approach of blocking RAS/RAF signal cascade. The structure characteristics of MEK1/2 also provide a unique advantage of targeting this molecule. It possesses a pocket structure adjacent to the MgATP-binding site that is only conserved in MEK proteins. Upon inhibitor binding, several conformational changes will occur and lock the unphosphorylated MEK1/2 into a catalytically inactive state. Because this ATP-uncompetitive mechanism does not  exert inhibitory effect through the highly conserved ATP pocket, it avoids undesired side effects associated with inadvertent inhibition of other protein kinases, and the challenge of competing with millimolar intracellular concentrations of ATP.23, 24 Several compounds with highly potent inhibitory activity that is exceptionally specific for MEK1/2 have been developed and have entered clinical study (Table 1).

Table 1. Allosteric MEK1/2 Inhibitors
AZD8330 (ARRY-424704) AstraZeneca, Array Biopharma
BAY 86-9766 (RDEA119) Bayer,  Ardea Bioscience
CI-1040 (PD 184352) Pfizer Inc.
GDC-0973 (XL-518, RG7421) Genentech
E6201 Eisai Inc.
MEK162 (ARRY-438162) Array Biopharma, Norvartis
PD-0325901 Pfizer Inc.
Pimasertib (AS703026, MSC1936369B EMD Serono
RO4987655 (CH4987655) Hoffmann-La Roche
RO5126766 Hoffmann-La Roche
Selumetinib (AZD6244, ARRY-142886) AstraZeneca
TAK-733 Takeda
Trametinib (GSK1120212) GlaxoSmithKline
WX-554 Wilex

MEK Inhibitors in Clinical Studies

The first MEK inhibitor, CI-1040, entered phase I clinical trials in 2000, but no MEK inhibitor has been approved for clinical use to date. This is because, although hints of single-agent activity have been demonstrated, these agents have failed to demonstrate robust clinical activity in most tumor types. Several factors may contribute to this modest clinical activity.  First, while target suppression has been demonstrated in tumor tissue, the relative level of suppression in tumors needed to produce cytotoxicity is not clear.  Second, the most commonly mutated members of the MAPK pathway (RAS and RAF) have other targets in addition to MEK, and it is likely that alternative pathways retain the ability to compensate for the effects of the MEK inhibitors.  Third, cancer most often results from dysregulation of multiple signaling pathways, and inhibition of only a single pathway may not be sufficient to promote apoptosis or growth arrest.  Finally, although MAPK is activated in many tumor cells, its function may not be necessary for tumor growth and survival in a number of tumors. Predictive biomarkers are needed to identify the subset of tumors likely to be susceptible to MEK inhibition.  Preclinical studies have identified an autoregulatory negative feedback loop between ERK and RAF that mediates sensitivity to MEK inhibitors. Activated ERK releases tonic inhibition of RAF kinases, thereby leading to activated RAF, which activates antiapoptotic downstream RAF targets, thus abrogating the cytotoxic activity of MEK inhibitors (Fig. 2). Tumors harboring BRAF V600E mutations lack this negative feedback loop and are sensitive to MEK inhibitors.25 These data predicted that a combination of MEK inhibitors and RAF inhibitors would be synergistic. This prediction has been confirmed in the clinic, as will be discussed further in this article.

Fig 2. Feedback inhibition of ERK on RAF is abrogated by MEK inhibitors, leading to activation of MEK independent downstream RAF targets and resistance to apoptosis.

Click to Expand.

Fig 2. Feedback inhibition of ERK on RAF is abrogated by MEK inhibitors, leading to activation of MEK independent downstream RAF targets and resistance to apoptosis.

Efficacy of MEK Inhibitors

As described further, single-agent activity of MEK inhibitors has been demonstrated in tumors with BRAF and NRAS mutations. However, single-agent MEK inhibitors have not consistently demonstrated efficacy in KRAS mutant tumors. A number of synergistic combinations have been described for MEK inhibitors, including combinations with RAF, PI3K, and AKT inhibitors, as well as gemcitabine and taxanes; there are ongoing studies evaluating all these combinations.

Toxicity of MEK Inhibitors

After testing multiple MEK inhibitors in many patients with cancer, a number of mechanism-based toxicities have emerged. These include toxicities common to many small-molecule kinase inhibitors, such as rash, fatigue, and diarrhea. Toxicities unique to MEK inhibitors include ocular toxicities that manifest as blurred vision and loss of visual acuity. Retinal vein occlusion has been described,26 but the most common underlying pathology is central serous retinopathy.27 This concerning toxicity is, however, reversible, after drug interruption followed by dose reduction. Peripheral edema, particularly periorbital edema occurs, as does striking elevations of creatine phosphokinase, without any associated troponin abnormalities, evidence of rhabdomyolysis, or any underlying pathology. Rare cases of left ventricular dysfunction have been reported, as have central nervous system effects including hallucinations and confusion (presumably with the subset of agents with good central nervous system penetration).

A summary of available clinical data with selected MEK inhibitors is outlined here.

CI-1040 (PD 184352)

CI-1040 (PD 184352) was the first allosteric MEK1/2 inhibitor to enter clinical trials. When evaluated in a phase I study, most common toxicities reported were diarrhea, asthenia, rash, nausea, and vomiting. An increase in drug exposure was observed when administered with a high-fat meal. Pre- and post-treatment biopsies obtained from 10 patients treated at or near the recommended phase II dose demonstrated ERK phosphorylation inhibition by a median of 73% (range 46% to 100%).28 This agent was advanced to a phase II study in patients with NSCLC, breast, colon, and pancreatic cancers; however, no objective response was observed in 67 patients enrolled on the study.29  Correlative pharmacokinetic studies demonstrated a wide interpatient variability in drug levels. Thus its development was stopped, and a backup compound (PD-0325901) with improved pharmacologic properties was developed.


Developed as a structural analogue of CI-1040, PD0325901 possesses a much-improved oral bioavailability and markedly increased potency against MEK1/2. This agent was evaluated in a phase I/II study. Preliminary evidence of antitumor activity was seen in patients with melanoma in the phase I study; however, the enrollment had to be stopped due to retinal vein occlusion.26 A phase II study evaluating this agent in previously treated NSCLC failed to meet its primary efficacy end point.30 A recent study of PD-0325901 combined with the dual PI3K/MTOR inhibitor PF-04691502 resulted in toxicities that precluded the administration of effective doses of both agents.31

Selumetinib (AZD6244, ARRY-142886)

Selumetinib is probably the most widely studied MEK inhibitor in the clinic. In the initial phase I study, rash was the most frequently observed toxicity, as well as the dose-limiting toxicity (DLT). A mean inhibition of 79% of ERK phosphorylation was observed in 19 evaluable paired tumor biopsies. Prolonged stable disease was achieved in one patient with medullary thyroid cancer and in one patient with both uveal melanoma and renal cancer.32 A solid oral capsule formulation of this compound was subsequently developed with improved pharmacologic properties. A prolonged complete response in a patient with melanoma bearing a BRAFV600E mutation was observed with this formulation in a phase I study.33  

Single-agent selumetinib has been evaluated in multiple phase II studies in a variety of solid tumors, as well as in hematologic malignancies.34-38 Treatment with single-agent selumetinib in 28 patients with metastatic biliary cancers yielded three objective responses (12%) and 14 meaningful stable diseases, whereas no significant antitumor activity was observed in either papillary thyroid carcinoma or hepatocellular carcinoma. In a BRAFV600E/K-mutated melanoma study, no antitumor activity was observed in the 10 patients with high phosphorylated-AKT (pAKT) levels, whereas three of the five patients with low pAKT melanomas achieved tumor regression, suggesting potential role of PI3/AKT activation in MEK inhibitor-resistance.  In relapsed/refractory acute myeloid leukemia, only modest antileukemia effect was detected.      

Selumetinib has been further assessed in combination with other anticancer agents. In a phase I study combining selumetinib with an AKT inhibitor MK-2206, DLTs including rash, stomatitis, grade 2 detached retinal pigment epithelium, diarrhea, grade 4 lipase elevation, bilateral posterior, grade 1 subcapsular cataracts, and fatigue were reported. In this 51-patient trial, one patient with KRAS-mutated NSCLC and one patient with KRAS-mutated ovarian cancer achieved durable confirmed partial response and one durable unconfirmed partial response was seen in a patient with pancreatic cancer.39  In a phase I study assessing selumetinib and cetuximab in solid tumors and KRAS-mutated colorectal cancer, the most common toxicities reported were acneiform rash, fatigue, nausea/vomiting, and diarrhea.  DLT was grade 4 hypomagnesemia.40 Among 13 evaluable patients treated in the dose-escalation cohort, two partial responses were observed in patients with colorectal cancer; stable disease was achieved in one patient with tonsillar squamous cell carcinoma, one with NSCLC, and two with colorectal cancer. Results in the KRAS-mutated colorectal cancer expansion cohort have not been reported. Randomized phase II studies comparing selumetinib versus temozolomide in chemotherapy-naive melanoma, selumetinib versus pemetrexed in NSCLC beyond first- and second-line therapies, selumetinib versus capecitabine in pancreatic cancer after failing gemcitabine, and selumetinib versus capecitabine in colorectal cancer beyond first- and second-line therapies did not demonstrate superiority, although antitumor activity as single agent was observed in each study.41-44 Phase I and II trials combining selumetinib with various targeted therapies or conventional chemotherapy agents including vandetanib, cixutumumab, docetaxel, gemcitabine, and irinotecan are ongoing or have been completed.   

GDC-0973 (XL-518, RG7421)

Preliminary results from the phase I study indicated that GDC-0973 was well tolerated. A prolonged stable disease in one patient with NSCLC was reported in this study.45 This compound was further evaluated in a phase Ib study in combination with a PI3K targeting agent, GDC-0941, in advanced solid tumors. DLTs of grade 3 lipase and grade 4 creatine phosphokinase level elevations were reported. Most common adverse events of this combination were diarrhea, fatigue, nausea, and rash. Among the 46 evaluable subjects, partial responses were observed in one with BRAF-mutated melanoma, one with BRAF-mutated pancreatic cancer, and one with KRAS-mutated endometroid cancer.46,47 GDC-0973 was combined with vemurafenib in BRAFV600 mutated melanoma in another phase Ib study. Preliminary efficacy results indicated that tumor size reduction was achieved in all eight evaluable vemurafenib-naïve patients. Notably, of the 44 subjects, only one developed cutaneous squamous cell carcinoma.48 On the basis of these results, a phase III study comparing this combination with vemurafenib has been initiated.  Studies combining GDC-0973 with other targeted therapeutic agents including the PI3K inhibitor GDC-0941 and AKT inhibitor GDC-0068 are ongoing.

BAY 86-9766 (RDEA119)

BAY 86-9766 was found to be well tolerated in a phase I study, with the most common treatment-related toxicities being acneiform rash and gastrointestinal toxicity. Of the 53 evaluable patients, one patient with colorectal cancer achieved a partial response, and 11 patients had durable stable disease.49 BAY 86-9766 was combined with sorafenib as first-line systemic treatment for patients with hepatocellular carcinoma in a phase II study. Among 70 subjects, three had confirmed partial response and 25 had prolonged stable disease. However, there were four grade 5 related adverse events reported, and almost all patients required dose modifications due to adverse events.50  A phase I/II study evaluating BAY 86-9766 in combination with gemcitabine in patients with metastatic pancreatic cancer is ongoing. Preliminary results indicates a manageable safety profile.51  A phase I study combining BAY 86-9766 and the PI3K inhibitor BAY80-6946 is ongoing.

Trametinib (GSK1120212)

Trametinib was evaluated in a 206-patient phase I study.27 The most common adverse events were rash and diarrhea, and DLTs were rash, diarrhea, and central serous retinopathy.  The effective half-life of trametinib was found to be approximately 4 days. Although a dose level of 3 mg a day was determined to be maximum tolerated dose, the recommended phase II dose was 2 mg daily because of poor tolerance beyond the first cycle of treatment. Ten percent objective responses were noted at all dose levels, with the most sensitive population being those with BRAF-mutant melanoma.52 Sub-analysis of participants with BRAF-mutant melanoma revealed a 33% response rate among 30 BRAF-inhibitor–naïve patients. This result was further confirmed in a phase II study, in which a 25% objective response rate was achieved in  BRAF-inhibitor–naïve patients, but only minimal clinical activity observed in patients with BRAF-inhibitor-resistant disease.53  Trametinib was subsequently advanced to randomized phase III study. Patients with BRAFV600E/K -mutant melanoma who have not been previously treated with a BRAF or MEK inhibitors or with ipilimumab were randomly assigned to receive either trametinib or chemotherapy with either dacarbazine or paclitaxel. In this study, patients in the trametinib arm had a median duration of progression-free survival (PFS) of 4.8 months, which was statistically superior to the 1.5 months PFS achieved in the chemotherapy group.  Median overall survival had not been reached at the time of report.54 The preclinical data described by Friday et al.25 suggests that the efficacy of MEK inhibitors may be enhanced by combination with a RAF inhibitor. In addition, activation of the MAPK pathway has been postulated as a potential resistance mechanism to RAF inhibitors in melanoma. Simultaneous inhibition of RAF and MEK has, therefore, become an attractive approach to overcome resistance to BRAF-inhibitors. Trametinib was combined with dabrafenib, a BRAF inhibitor, in a phase I/ II trial to determine tolerability and to compare single-agent dabrafenib with the combination.  As predicted, cutaneous squamous cell carcinoma, a BRAF inhibition-associated adverse event that is due to paradoxical MAPK pathway activation, was found to be significantly lower in the combination arm. A significant improvement in PFS was observed in the combination arm (hazard ratio, 0.39; 95% CI: 0.25 to 0.62; p < 0.001), indicating the potential implication of MAPK inhibition in delaying resistance to BRAF inhibition.

Trametinib combinations have also been evaluated in other tumor types. In a randomized placebo control study, the addition of trametinib to gemcitabine failed to improve efficacy parameters in 160 patients with metastatic pancreatic cancer irrespective of their KRAS mutation status.55 Other phase I/Ib studies evaluating combinations of trametinib with various targeted therapeutic and conventional chemotherapy agents, such as everolimus, pazopanib, dabrafenib, erlotinib,  and fluorouracil, as well as with radiation therapy,  the AKT inhibitor GSK2141795, and the PI3K inhibitor BKM120, are currently ongoing.56-59

Pimasertib (AS703026, MSC1936369B)

Pimasertib has been evaluated in a phase I study.60, 61 Most common adverse events observed included skin rash, diarrhea, asthenia, anorexia, nausea, vomiting, peripheral edema, anemia, and visual disorders. DLTs were grade 2 retinal vein occlusion, grade 3 liver function test elevation, skin rash, pharyngitis, acneiform rash, serous retinal detachment, and macular edema. Five patients achieved tumor shrinkage, all with either BRAF or NRAS mutations. In a phase I/II study pimasertib was added to combination 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line treatment in KRAS-mutated metastatic colorectal cancer; however, the study was unable to progress to phase II  because effective doses of pimasertib could not be reached due to toxicity.62 Ongoing studies include: a phase Ib study combining pimasertib with the PI3K/mTOR inhibitor SAR245409 in solid tumors, a phase I study combining pimasertib and temsirolimus, a phase II study comparing pimasertib and dacarbazine in NRAS-mutated melanoma, a phase I/II study comparing pimasertib combined with gemcitabine versus gemcitabine alone in pancreatic adenocarcinoma, and a phase II study of pimasertib in patients with advanced hematologic malignancies.

MEK162 (ARRY-438162)

MEK162 has been evaluated in a phase I study with expansion cohorts in advanced/metastatic biliary cancer or metastatic colorectal cancer.63, 64 Of the 26 patients with evaluable biliary cancer, one complete response and one partial response were observed. A colorectal cancer expansion cohort is ongoing. In a phase II study evaluating MEK162 in NRAS-mutated or BRAF-mutated advanced melanoma, objective responses were observed in 20% of patients with NRAS-mutated melanoma and in 20% of those with BRAF-mutated melanoma.65 No responses were reported in patients previously treated with a BRAF inhibitor. Based on the encouraging results in NRAS-mutated melanoma, an additional 70 patients with NRAS-mutated melanoma will be enrolled to further assess MEK162 in this population. A randomized trial in patients with melanoma with NRAS mutations is also planned. Studies evaluating combinations of MEK162 with various therapeutic agents, including  the PI3K inhibitors BYL719 and BKM120, the PKC inhibitor AEB071, the CDK4/6 inhibitor LEE011,  the anti–insulin-like growth factor receptor type I monoclonal antibody AMG 479, the PI3K/mTOR inhibitor BEZ235, RAF kinase inhibitors LGX818 and RAF265, and paclitaxel in melanoma and other solid tumors are ongoing.

AZD8330 (ARRY-424704)

In a phase I study evaluating AZD8330, the most frequent AZD8330-related adverse events were acneiform dermatitis, fatigue, diarrhea, and vomiting; DLTs were mental status changes and rash. One patient with malignant melanoma achieved a partial response.66

RO4987655 (CH4987655)

RO4987655 was found to be well tolerated in phase I study, with DLTs being blurred vision and elevated levels of creatine phosphokinase. Rash-related toxicity and gastrointestinal disorders were the most frequent adverse events observed. Among 38 evaluable patients, one confirmed and one unconfirmed partial response were seen in patients with melanoma.  Expansion cohorts including patients with melanoma tumors with BRAFV600 mutation, melanoma tumors without BRAFV600 mutation, NSCLC with KRAS mutations, and CRC carrying KRAS and/or BRAFV600 mutations are ongoing.67


RO5126766 is a first-in-class dual RAF/MEK inhibitor. Most common DLTs observed in phase I study were elevated creatine phosphokinase levels and blurred vision. The most frequent adverse events were rash-related toxicities, creatine phosphokinase level elevation, diarrhea, and ocular toxicities. Among 55 participants, partial response was seen in two BRAF-mutant melanoma tumors and in one NRAS-mutant melanoma.68

Other MEK inhibitors

Phase I studies evaluating WX-554, E6201, and TAK-733 are currently ongoing.69-71

Future Directions

Despite the prevalence of aberrant RAS/RAF/MEK/ERK signaling in human cancers, the crucial location of MEK1/2 in this pathway, and the availability of highly potent and specific MEK inhibitors, inhibition of MEK has not demonstrated strong therapeutic activity in early-stage clinical trials. Although single-agent activity has been documented in BRAF mutant melanoma, this activity is somewhat inferior to that seen with selective BRAF inhibitors. Moreover these agents are not active in BRAF-mutant tumors that develop resistance to BRAF inhibitors. However, striking activity has been demonstrated in combination with BRAF inhibitors. This combination promises to be superior to single-agent BRAF inhibitors in terms of response rate and duration of response. The activity in NRAS-mutant tumors also appears promising. Combinations with other targeted agents may also improve efficacy and overcome resistance. However, toxicity of a number of these combinations (e.g., AKT inhibitors and PI3K inhibitors) has been problematic to date. Combinations with classical cytotoxic agents may also be efficacious, and results of ongoing trials are awaited with interest (Table 2).  



Study Drugs


Study type

Table 2. Currently Active or Recently Completed Clinical Trials Evaluating MEK Inhibitors


Vemurafenib +/- GDC-0973

Previously untreated BRAFV600 melanoma

Phase III


Pimasertib vs. dacarbazine

Previously untreated NRAS-mutant melanoma

Randomized Phase II


Gemcitabine +/- pimasertib

Pancreatic cancer

Randomized phase II with safety run-in


Selumetinib with HAART

AIDS-associated Kaposi's Sarcoma

Phase I/II


Docetaxel +/- selumetinib

Second-line NSCLC

Phase II



MCT-–related diffuse large B-cell lymphoma

Phase II


Selumetinib +/- erlotinib



Randomized phase II


Selumetinib +MK2206 vs. mFOLFOX

Pancreatic cancer

Randomized phase II


Selumetinib + MK-2206

BRAFV600 melanoma  after progression on BRAF inhibitor

Phase II


Selumetinib + erlotinib

Pancreatic cancer

Phase II


Selumetinib vs. temozolomide

Metastatic uveal melanoma

Randomized phase II



BRAF- or NRAS-mutated melanomas

Phase II


Docetaxel +/- selumetinib

Melanoma with wild-type BRAF

Randomized phase II


Docetaxel +/- selumetinib

Second-line in KRAS-mutated NSCLC

Randomized phase II


Selumetinib +MK-2206


Pilot study


Trametinib + dabrafenib

BRAF-mutant melanoma

Phase II


Dabrafenib +/- trametinib

First-line in BRAF V600E/K melanoma

Phase III


Trametinib + GSK2118436

BRAF-mutant melanoma

Phase I/II


Trametinib vs. chemotherapy

BRAF V600E/K melanoma

Phase III


Trametinib + GSK2118436 + panitumumab


Phase I/II


Dabrafenib + trametinib vs. vemurafenib

Metastatic BRAF V600E/K melanoma

Phase III


Dabrafenib alone first, then combined with trametinib, followed by surgery

Pre-surgical melanoma

Phase II biomarkers study


Trametinib vs. docetaxel

Second line in NSCLC with mutations in KRAS, NRAS, BRAF, MEK1

Randomized phase II




Phase I/II


Trametinib + GSK2118436

Melanoma refractory/resistant to BRAF inhibitor

Phase II



Solid tumors

Phase I/II


MEK162 + AEB071

Metastatic uveal melanoma

Phase Ib/II


MEK162 + LEE011

NRAS-mutant melanoma

Phase Ib/II


MEK162 vs. dacarbazine

NRAS-mutant melanoma

Phase III



BRAFV600 or NRAS-mutant melanoma

Phase II

Note: Bolding indicates MEK inhibitor. Abbreviations: HAART, highly active antiretroviral therapy; NSCLC, non-small cell lung cancer; mFOLFOX, combination 5-fluorouracil, leucovorin, and oxaliplatin; CRC, colorectal cancer.


About the Authors: Dr. Zhao is assistant professor at Roswell Park Cancer Institute. She has been an ASCO member since 2009. Dr. Adjei is professor and chair of the Department of Medicine and the  Katherine Anne Gioia Chair in Cancer Medicine at Roswell Park Cancer Institute.  He is the 2012 Conquer Cancer Foundation Drug Development Research Professorship Award recipient. Dr. Adjei has been an ASCO member since 1997, during which time he has been on several ASCO committees.