Alex A. Adjei, MD, PhD

The Journal of Targeted Therapies in Cancer

The Journal highlights advances in targeted therapies in cancer for oncology professionals in the community who wish to translate this research into practice.

also includes other cancer therapies and research in precision medicine, a topic that has garnered increased media attention since President Barack Obama announced the Precision Medicine Initiative that promises to further move this research forward.

has been on top of these clinical advances for the past 3 years, bringing readers the latest in original, peer-reviewed research articles. This issue features an article on antibody drug conjugates, and how these agents may yet fill a void in targeted treatment for breast cancer. You will also find details on PARP-1 inhibitors and their emerging role in the treatment of lung cancer. A third research article involves novel targets in relapsed and relapsed/refractory multiple myeloma.

You will also see news on: biomarker research in gastrointestinal stromal tumors, a collaboration in gene editing, recent trial data in the treatment of pancreatic NETS, and updated information on mutations in breast cancer.

This issue&rsquo;s Clinical Advances section contains information on the potential of anti-androgen therapy in patients with breast cancer. Another breast cancer feature includes a trial studying a nab-paclitaxel-based chemotherapy combination as first-line treatment for triple-negative metastatic breast cancer. This month also features key opinion leaders in 3 disease states discussing plasma-based molecular profiling.

We hope you enjoy this first issue of 2015, and as always, please send us your suggestions on topics you would like to see us highlight so that we continue to improve JTT to serve your needs.

Articles

Our physician editor-in-chief highlights the February 2015 issue of The Journal of Targeted Therapies in Cancer.

From the Editor: PARP Inhibitors, Biomarker Research, and Gene Editing

Professor and Chair, Department of Medicine

Senior Vice President of Clinical Research

The Katherine Anne Gioia Chair in Cancer Medicine

The RAS-RAF-MEK-extracellular signalregulated kinase 1 and 2 (ERK1/2) pathway is the most mutated pathway in human cancer. Thus, components of this pathway have been seen as promising targets for cancer therapy. MEK inhibitors have been in clinical evaluation for more than a decade. While low-level clinical activity has been documented with virtually all MEK inhibitors tested in clinical trials, dramatic responses have been few. Several inhibitors are at various stages of clinical evaluation. Singleagent activity has been detected in tumors harboring RAS/RAF mutations such as melanoma, and one inhibitor, trametinib, has been approved by the US Food and Drug Administration (FDA) for the treatment of melanoma. Combinations of MEK inhibitors with cytotoxic chemotherapy or other targeted agents are being investigated.

Three well-characterized subfamilies of mitogenactivated protein kinases (MAPKs) control many physiologic processes in humans. Because of its role in cell proliferation and carcinogenesis, the most characterized MAP kinase pathway is the RAS-RAF- MEK-ERK pathway. This is the most frequently dysregulated signal transduction pathway in human cancer. Common aberrations are gain-of-function mutations of

have been found in 90% of pancreatic, in 20% of non-small cell lung cancer (NSCLC), and in up to 50% of colorectal and thyroid cancers,

have been identified in more than 50% of melanoma and in 40% to 60% of papillary thyroid cancers.

Although mitogen- activated protein kinase 1/2 (MEK1/2) is rarely mutated, constitutively active MEK has been found in more than 30% of primary tumor cell lines tested.

The RAS-RAF-MEK-ERK pathway is activated by a wide array of growth factors and cytokines such as epidermal growth factor (EGF), insulin-like growth factor (IGF), and transforming growth factor (TGF), which initially bind to, and activate, transmembrane receptors located on the cell surface. Through sequential interactions with adapter proteins and nucleotide exchange proteins, these growth factors activate RAS through a conversion from the inactive guanosine diphosphate (GDP)-bound form to the active guanosine triphosphate (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.

This leads to altered gene transcription and cellular proliferation.

Most MEK inhibitors in clinical trials are allosteric inhibitors.

Single-agent activity has been seen consistently only in tumors with

Mechanism-based toxicities with these agents include ocular toxicities, skin rash, peripheral edema, left ventricular dysfunction, creatine phosphokinase elevation, and central nervous system abnormalities such as confusion and hallucinations.

Combinations of MEK inhibitors with BRAF inhibitors have demonstrated increased efficacy accompanied with reduced toxicity.

Trametinib is the first MEK inhibitor to be approved by the FDA for the treatment of melanoma, alone and in combination with the BRAF inhibitor, dabrafenib.

MEK inhibitors, when used as single agents, show no activity in

-mutant melanoma that has become refractory to BRAF inhibitors and should not be used in this setting.

History of MEK Inhibitors in Clinical Studies

Notably, the RAF family consists of A-RAF, B-RAF, and RAF-1, all sharing RAS as a common upstream activator, and MEK1/2 as principal kinase effectors.

MEK1/2 are dual-specificity kinases, catalyzing the phosphorylation of both tyrosine and threonine on ERK1 and ERK2, their only known physiologic substrates.

In contrast to RAF and MEK1/2, which have narrow substrate specificity, activated ERK1/2 phosphorylates numerous cytoplasmic and nuclear substrates. This process regulates many cellular responses, such as angiogenesis, cell differentiation, embryogenesis, metastasis, metabolism, and apoptosis (

The structure of the MEK1/2 protein makes it ideal for targeting. It possesses a pocket structure adjacent to the adenoside triphosphate (ATP)-binding site that is only conserved in MEK proteins. Upon inhibitor binding, several conformational changes occur and lock the unphosphorylated MEK1/2 into a catalytically inactive state. Since this ATP-noncompetitive mechanism does not exert inhibitory effects through the highly conserved ATP pocket, it potentially avoids undesired, off-target side effects associated with inadvertent inhibition of other protein kinases, and the challenge of competing with millimolar intracellular concentrations of ATP.

Several compounds with highly potent, specific and allosteric inhibitory activity of MEK1/2 have been developed and tested in clinical studies.

Figure 1. Simplified Schematic of MEK Signaling

The first MEK inhibitor, CI-1040, entered phase I clinical trials in 2000. Since then, only one MEK inhibitor, trametinib, has been approved for clinical use. This is because these agents have failed to demonstrate significant clinical activity in most tumor types. One potential mechanism underlying this modest activity has been elucidated preclinically. An autoregulatory negative feedback loop between ERK and RAF that mediates sensitivity to MEK inhibitors has been described. Activated ERK releases tonic inhibition of RAF kinases, thereby leading to activated RAF, which activates anti-apoptotic downstream RAF targets, thus abrogating the cytotoxic activity of MEK inhibitors (

mutations lack this negative feedback loop and are sensitive to MEK inhibitors.

These data predicted that a combination of MEK inhibitors and RAF inhibitors would be synergistic. This prediction has been confirmed in the clinic, as described in the trametinib section later on in this article.

Since 2000, more than 10 MEK inhibitors have entered clinical trials, providing a large body of data on mechanism-based toxicities of these compounds. Some toxicities, such as fatigue, diarrhea, and skin rash, are common to many small-molecule kinase inhibitors. Others are relatively unique to MEK inhibitors, and include ocular toxicities manifest as blurred vision and loss of visual acuity; retinal vein occlusions

; and the most common toxicity, central serous retinopathy

). This potentially serious toxicity involves subretinal fluid accumulation, which generally subsides after drug interruption followed by dose reduction. Peripheral edema, particularly periorbital edema, occurs as dose elevation of creatine phosphokinase without any associated troponin abnormalities, evidence of rhabdomyolysis, or any underlying pathology.

Rare cases of left ventricular dysfunction have been reported. Also, central nervous system (CNS) effects have occurred, such as hallucinations and confusion (presumably with the subset of agents with good CNS penetration).

illustrates selected MEK inhibitors that are in clinical trials. Selumetinib is the MEK inhibitor with the largest amount of published data. Trametinib has received FDA approval alone and in combination with dabrafenib. These two compounds are discussed in the sections that follow. A brief description of other selected MEK inhibitors is also provided.

Selumetinib, a second-generation MEK inhibitor, was introduced in the clinic together with PD- 0325901 after the development of CI-1040 was discontinued because of limited potency and poor pharmacology.

In its initial phase I study, skin rash was the most frequent and dose-limiting toxicity (DLT). Inhibition of ERK phosphorylation was established as a pharmacodynamic biomarker. Prolonged disease stabilization was achieved in one medullary thyroid cancer patient and in one patient with uveal melanoma (out of 34 evaluable patients).

A solid oral capsule formulation of this compound was subsequently developed with improved pharmacologic properties. A prolonged complete response (CR) in a patient with melanoma bearing a

mutation was observed with this formulation in a phase I study.

Figure 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. This may explain the lack of activity of single-agent MEK inhibitors in a number of tumors. In addition, this figure may explain the synergy between MEK inhibitors and BRAF inhibitors.

Single-agent selumetinib has been evaluated in multiple phase II studies in a variety of solid tumors as well as in hematologic malignancies.

Treatment with single-agent selumetinib in 28 patients with metastatic biliary cancers yielded 3 objective responses (ORs) (12%) and 14 stable diseases (SDs) lasting for more than 4 months, whereas no significant antitumor activity was observed in either papillary thyroid carcinoma or hepatocellular carcinoma. In a

-mutated melanoma study, no antitumor activity was observed in the 10 patients with high phosphorylated AKT (pAKT) levels, while 3 of 5 patients with low pAKT levels achieved tumor regression, suggesting a potential role of PI3/AKT activation in MEK inhibitor resistance. In a phase II study, 47 patients with relapsed/refractory acute myeloid leukemia (AML) or who were 60 years or older with untreated AML were stratified by

-internal tandem duplication (ITD) mutation status and were treated with selumetinib. In the

wildtype cohort, 6 of 36 patients (17%) had a response (1 partial response, 3 minor responses, 2 unconfirmed minor responses [uMR]). No patient with

mutations were detected in 7% and 2% of patients, respectively. The sole patient with

mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed, but this activation did not correlate with a response. A single-nucleotide polymorphism (SNP), rs3733542 in exon 18 of the

gene, was detected in a significantly higher number of patients with response/ stable disease compared with nonresponders (60% vs 23%;

Selumetinib has also been evaluated in combination with other anticancer agents. In a phase I study combining selumetinib with the AKT inhibitor MK- 2206, DLTs were rash, stomatitis, grade 2 detached retinal pigment epithelium, diarrhea, grade 4 lipase elevation, bilateral posterior, grade 1 subcapsular cataracts, and fatigue. In this 51-patient trial, 1 patient with

-mutated ovarian cancer achieved durable confirmed partial responses (PR), and 1 unconfirmed PR was seen in a patient with pancreatic cancer.

In a phase I study assessing selumetinib and cetuximab in solid tumors and

-mutated colorectal cancer (CRC), the most common toxicities reported were acneiform rash, fatigue, nausea/vomiting, and diarrhea, while the DLT was grade 4 hypomagnesemia.

Among 13 evaluable patients treated in the dose-escalation cohort, 2 PRs were observed in patients with CRC, and SD was achieved in 1 patient with tonsillar squamous cell carcinoma, 1 patient with NSCLC, and 2 patients with CRC. Results in the

-mutated CRC expansion cohort have not been reported.

Figure 3. Central serous retinopathy from a MEK inhibitor. Retinal picture and OCT stain pretreatment (A, B). Fluid collection behind retina after 2 weeks of treatment on OCT stain (C, D).

Randomized phase II studies comparing selumetinib versus temozolomide in chemotherapyna&iuml;ve melanoma, selumetinib versus pemetrexed in NSCLC beyond first/second-line therapies, selumetinib versus capecitabine in pancreatic cancer after failing gemcitabine, and selumetinib versus capecitabine in CRC beyond first/second-line therapies did not demonstrate superiority, even though antitumor activity as single agent was observed in each study.

mutation, the addition of selumetinib to docetaxel did not yield a statistically significantly improved median overall survival (OS) (9.4 months vs 5.2 months; hazard ratio [HR] 0.80; 80% confidence interval [CI]: 0.56- 1.14; 1-sided

= .21), although improvement in median progression-free survival (PFS) (5.3 months vs 2.1 months; HR = 0.58; 80% CI: 0.42-0.79; 1-sided

= .014) and OR rate (37% vs 0%; P <.0001) were seen in this study. A higher incidence of myelosuppression and fatigue was found in the selumetinib group.40 Based on the high OR rate of this combination, a phase III study has been started. Selumetinib plus dacarbazine versus placebo plus dacarbazine was compared in patients with

-mutant melanoma as first-line treatment in a phase II study. Although significantly improved PFS was observed with the addition of selumetinib, no OS benefit was demonstrated.

Finally, the effect of selumetinib on radioiodine sensitivity in radioiodine-resistant differentiated thyroid cancers was tested in a 24-patient pilot study. A 4-week treatment of selumetinib restored sensitivity to radioiodine that exceeded the threshold for radioiodine treatment in 8 patients, allowing administration of therapeutic radioiodine; PR and SD were achieved in 5 and 3 patients, respectively.

In this small study, selumetinib appeared to convert a higher percentage of

-mutant tumors to radioiodine sensitivity than

Phase I and II trials combining selumetinib with vandetanib, cixutumumab, gemcitabine, and irinotecan are under way or have been completed.

Trametinib, a third-generation MEK inhibitor, was evaluated in a 206-patient, phase I study.

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 about 4 days. Although a dose level of 3 mg/day was determined to be the maximum tolerated dose (MTD), because of poor tolerance beyond the first cycle of treatment, the recommended phase II dose was 2 mg/day. Twenty-one (10%) ORs were noted at all dose levels, with the most sensitive population being

-mutant melanoma revealed a 33% response rate among 30 patients who were BRAF inhibitor-na&iuml;ve. This result was further confirmed in a phase II study, in which a 25% OR rate was achieved in patients who were BRAF inhibitor- na&iuml;ve, while only minimal clinical activity was observed in patients with BRAF inhibitor-resistant disease.

Table 1. MEK Inhibitors in Clinical Development

The RAS-RAF-MEK-extracellular signalâ€“regulated kinase 1 and 2 (ERK1/2) pathway is the most mutated pathway in human cancer. Thus, components of this pathway have been seen as promising targets for cancer therapy. 

MEK Inhibitors

Alex A. Adjei, MD, PhD, Professor and Chair, Department of Medicine, Katherine Anne Gioia Chair in Cancer Medicine, Senior Vice President, Clinical Research, Roswell Park Cancer Institute, discusses the use of MEK inhibitors when treating patients with melanoma.

Adjei states that MEK inhibitors are a class of compounds that have been tested for 13 years. Researchers are interested in MEK because it is highly expressed without the presence of a mutation, since a number of proteins that drive cancer tumors signal through the MEK pathway, Adjei says. As a result, researchers believed that if they blocked MEK they would be able to affect a lot of different types of cancers.

The third generations of MEK compounds seem to have ideal properties and are more potent than earlier generations, Adjei says. The first MEK compound was approved to treat patients with melanoma. This is not surprising, since MEK is downstream from RAF, which is also effective in the treatment of melanoma, Adjei notes.

Since BRAF inhibitors are approved and work well in patients with melanoma, some doctors may argue that there is no place for a MEK inhibitor. However, Adjei believes, having two inhibitors that work well in the same space is beneficial because patients react differently to each medication. As a result, a patient that does not respond to a BRAF inhibitor may respond to a MEK inhibitor, Adjei says.

Each agent has a unique side effect profile, Adjei says. BRAF inhibitors can cause skin cancers while MEK inhibitors do not. However, MEK inhibitors can cause blurred vision, Adjei says. Stopping treatment and then continuing at a reduced dose can reverse this side effect.

The fact that two oral medications are approved for melanoma is exciting, Adjei says. More exciting, Adjei states, is that a BRAF inhibitor and a MEK inhibitor actually work better together than they do alone. Moreover, the two drugs are actually less toxic together than they are apart, which is uncommon.

Some cancer cells have high MEK expression

Since a number of proteins that drive cancer tumors signal through MEK, blocking MEK may affect a variety of different types of tumors

Since MEK is downstream of RAF, which is active in melanoma, it makes sense that MEK is also active in melanoma

Although similar, MEK and RAF inhibitors are not identical

RAF inhibitors can cause side effects such as skin cancers while MEK inhibitors do not

MEK inhibitors can cause temporary blurred vision

Having two inhibitors that work well is beneficial, since patients respond differently to each

Using BRAF and MEK inhibitors together is less toxic than using them as single agents

Videos

Alex A. Adjei, MD, PhD, discusses the use of MEK inhibitors when treating patients with melanoma.

Alex A. Adjei, MD, PhD | Authors

Articles

From the Editor: PARP Inhibitors, Biomarker Research, and Gene Editing

MEK Inhibitors

MEK Inhibitors for the Treatment of Melanoma