The mitogen-activated protein kinase (MAPK) pathway consists of the series of protein kinases RAS-RAF-MEK- Extracellular signal-regulated kinase (ERK), and its function is important to cell proliferation, differentiation, motility, and survival. Certain mutations in the pathway, such as KRAS or BRAF V600 mutations are associated with cancer. Inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic, but a variety of selective ERK inhibitors are still being tested in clinical studies. To date, common adverse events associated with ERK inhibitors include diarrhea, nausea, fatigue, and rash. ERK inhibitors have demonstrated preliminary antitumor activity and may be most effective against cancers with RAS, RAF, or MAPK pathway alterations. This review discusses the MAPK pathway, the biological rationale for ERK inhibitors, and clinical trials involving ERK inhibitors.
Keywords: Cancer, clinical trials, mitogen-activated protein kinase, Extracellular signal-regulated kinase (ERK) inhibitor
|How to cite this URL:|
Chin HM, Lai DK, Falchook GS. Extracellular signal-regulated kinase (ERK) inhibitors in oncology clinical trials. J Immunother Precis Oncol [Epub ahead of print] [cited 2019 Jan 16]. Available from: http://www.jipoonline.org/preprintarticle.asp?id=249990
| Introduction|| |
The mitogen-activated protein kinase (MAPK) pathway is a cascade of protein kinases involved in many important cellular processes, including cell proliferation, differentiation, motility, and survival. The pathway is responsible for transmitting signals from extracellular growth factors to effectors in the nucleus. It is activated when the growth factors bind to cell surface receptors that activate receptor tyrosine kinases. The signal then continues down to the RAS-RAF-MEK-Extracellular signal-regulated kinase (ERK) pathway [Figure 1].,
Thefirst protein in the pathway, Ras, is a GTPase whose activation begins the signaling cascade. HRAS, KRAS, and NRAS are the three expressed RAS genes identified in humans. RAS undergoes a conformational change when it is activated, and this conformational change recruits and activates RAF, a protein kinase with three isoforms: ARAF, BRAF, and CRAF. All three isoforms can phosphorylate MEK to activate it. MEK is known as the “gatekeeper” of the MAPK cascade because only MEK 1 and 2 can phosphorylate the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). ERK1/2 is important to many cellular processes as it is responsible for phosphorylating a broad range of substrates involved in cell proliferation, differentiation, and survival. ERK and its substrates are also able to regulate the rest of the pathway through phosphorylation or feedback loops. For example, ERK can phosphorylate BRAF and CRAF to stop the activation of MEK. It also can cause the phosphorylation of SOS, preventing SOS from activating RAS. The substrates, in turn, can regulate the upstream components of the MAPK pathway positively or negatively through feedback loops.
Because normal MAPK function and has been shown to help in tumor suppression by inducing both senescence and the degradation of proteins used for cell proliferation and survival, certain mutations in the pathway can result in cancer. These mutations can overactivate or deregulate the pathway, causing the increased phosphorylation of substrates that stimulate the cell proliferation. The RAS oncogene is activated in about a third of all cancers, and RAS mutations are common in cancers of the pancreas (90%), colon (50%), thyroid (50%), lung (30%), and melanoma (25%). KRAS mutations account for the majority of RAS mutations, while NRAS and HRAS mutations are less common. BRAF mutations occur in 7% of all cancers and are observed mainly in hairy cell leukemia (100%), melanoma (50%–60%), papillary thyroid cancer (40%–60%), colorectal cancers (5%–10%), pilocytic astrocytoma (10%–15%), and nonsmall cell lung cancer (3%–5%). Finally, MEK mutations occur mostly in melanomas, ovarian cancer, and gliomas.
Several BRAF and/or MEK inhibitors have been approved by the FDA for clinical use. The FDA-approved BRAF kinase inhibitors are encorafenib (Braftovi, Array BioPharma), dabrafenib (Tafinlar, Novartis Pharmaceuticals), and vemurafenib (Zelboraf, Hoffmann-La Roche). The FDA-approved MEK inhibitors are binimetinib (Mektovi, Array BioPharma), trametinib (Mekinist, Novartis Pharmaceuticals), and cobimetinib (Cotellic tablets, Genentech). Encorafenib and binimetinib were approved in June 2018 for combined use against unresectable or metastatic melanoma with BRAF V600E or V600K mutations. A combination of dabrafenib and trametinib can be used for the treatment of anaplastic thyroid cancer with BRAF V600E mutations (approved May 2018), melanoma with BRAF V600E or V600K mutations (approved April 2018), and metastatic nonsmall cell lung cancer with BRAF V600E mutations (approved June 2017). Vemurafenib can be used to treat Erdheim–Chester Disease with BRAF V600 mutation (approved November 2017), or it can be used in combination with cobimetinib to treat patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations (approved November 2015).,
Although BRAF and MEK inhibitors have had some clinical success, cancers frequently develop an acquired resistance to them. Resistance to BRAF inhibitors develops in most patients after about year due to reactivation of the MAPK pathway. One way, the MAPK pathway can be reactivated is through mutations upstream of BRAF that bypass the BRAF inhibition using ARAF or CRAF. Another way to bypass the BRAF inhibition is through MEK amplification or activating mutations in MEK1/ 2. Thus, inhibition of ERK, which is downstream of these mutations, could overcome and possibly reverse the acquired drug resistance caused by the upstream kinase inhibitors. ERK inhibition seems promising in vitro as previous studies report that ERK inhibitors reversed acquired resistance to BRAF and MEK inhibition in cell lines., ERK inhibition may also be effective in deactivating the pathway, because ERK is the only substrate of MEK.
| Extracellular Signal-Regulated Kinase Inhibitors|| |
ASN007 (Asana BioSciences, Bridgewater, New Jersey) is an oral medication that inhibits ERK 1/2 [Table 1]. An open-label, dose-escalation phase I study of ASN007, began in January 2018 and is still ongoing. The study will enroll up to 110 patients with advanced solid tumors. Expansion cohorts are planned for patients with BRAF-mutated melanoma, NRAS or HRAS-mutated solid tumors, KRAS-mutated colorectal cancer, KRAS-mutated nonsmall-cell lung cancer, and pancreatic ductal adenocarcinoma. No preliminary trial results have yet been presented.
|Table 1: Published extracellular signal-regulated kinase inhibitor trials|
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Ulixertinib (BVD-523) (BioMed Valley Discoveries, Kansas City, MO) is an orally active inhibitor of ERK 1 and 2. Thefirst-in-human phase I trial of ulixertinib consisted of two parts. In the dose escalation portion, 27 patients were treated at doses of 10–900 mg twice daily. The recommended phase II dose was 600 mg twice daily. In the dose escalation portion, the partial responses were observed in 3 of 18 (17%) of patients at or above the maximum tolerated dose (MTD). Responses were observed in patients with NRAS, BRAF V600E, and non-V600 BRAF mutant cancers. In the dose expansion cohort, 11 of 81 (14%) patients had partial responses. Common adverse events included diarrhea (48%), nausea (41%), fatigue (42%), and dermatitis acneiform (31%). In the expansion cohort, 108 patients were treated (including 32% of whom required dose reduction).
Another phase I study investigated the effect ulixertinib had on the prolongation of cardiac repolarization. A two-part phase I study was conducted with adults that had advanced solid tumors. There were 105 patients in part 1 (dose escalation) and 81 patients in part 2 (dose expansion). The investigators observed a small increase in heart rate including up to 5.6 beats/minute (bpm) on day 1 and up to 7 bpm on day 15. The authors concluded that of ulixertinib had no effect on prolonging cardiac repolarization, including no effect on PR or QRS intervals.
CC-90003 (Celgene Corporation, Summit, New Jersey) is a selective ERK1/2 inhibitor., Thefirst-in-human phase Ia dose-escalation study enrolled 19 patients with locally advanced or metastatic and solid tumors. CC-90003 is an oral medication that was taken once a day, on days 1–28 in a 28-day cycle with the dose levels varying between 20 and 160 mg/day. The 19 patients had either KRAS (n = 15), NRAS (n = 1), or BRAF (n = 3) mutant tumors. The MTD was determined to be 120 mg, and the patients completed between 1–5 cycles (media, n = 2). The nontolerated dose was 160 mg because at this dose, the patients experienced grade 3 transaminase elevations (n = 2) or hypertension (n = 1). Common adverse events were asthenia, fatigue, anorexia, nausea/vomiting, diarrhea, transaminase elevations, dizziness, gait disturbance, and paresthesias. At 80–160 mg/day, neurotoxicity (grade 1–3) was also observed in patients. The study reported that PK results were variable and that there were no objective responses. Evidence of pharmacodynamic effect was observed with >80% reduction of free ERK cells by C1D8 at doses ≥80 mg. Thus, the study was terminated in May 2016 (started in January 2015).
GDC-0994 (Array BioPharma, Boulder, CO) is an orally active inhibitor of ERK. It inhibits the ERK phosphorylation and activation of ERK-mediated signal transduction pathways. A phase I dose escalation was conducted in patients with locally advanced or metastatic solid tumors. About 45 patients were treated on 6 dose levels ranging from 50 to 800 mg once daily for 21 days on, then 7 days off. In the expansion cohort, the patients with pancreatic adenocarcinoma and BRAF-mutant colorectal cancer were enrolled. For the expansion cohort, a 400 mg once daily dosing was chosen for safety and tolerability. MAPK pathway inhibition in paired biopsy samples ranged from 19% to 51%. There were FDG-PET metabolic responses in 11/20 patients (6/10 patients in the 400 mg cohort) that had different tumor types. A total of 15/45 (33%) patients had best overall responses of stable disease, including a patient that had pancreatic adenocarcinoma. There were confirmed partial responses in 2/13 (4%) patients with BRAF-mutant colorectal cancer. Common adverse events included nausea, diarrhea, fatigue, rash, vomiting, peripheral edema, dermatitis acneiform, asthenia, decreased appetite, dry skin, blurred vision, and periorbital edema.
Another phase I study investigated the effect of GDC-0994 in combination with cobimetinib had in patients with advanced solid tumors. A total of 23 patients were treated on two different dosing schedules. Eight patients were given schedule A, which consisted of concurrent 200 mg GDC-0994 and 40 mg cobimetinib given orally in cycles of 21 days on/7 days off. The dose of cobimetinib was decreased to 20 mg in cohort A0 as there was cumulative grade 1–2 toxicity. The other 15 patients were given schedule B which consisted of intermittent dosing of 80 mg cobimetinib on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle concurrent, with 200 mg of GDC-0994 QD for 21 straight days of a 28-day cycle. Dose escalation for cohort B2 had GDC-0994 increased to 400 mg and dose escalation for cohort B3 had cobimetinib increased to 100 mg. Intolerability was observed in both cohort B2 and B3. Common adverse events included nausea, decreased appetite, fatigue, diarrhea, vomiting, dermatitis acneiform, blurred vision, asthenia, increased blood creatinine, rash, and peripheral edema. One patient with pancreatic adenocarcinoma had an unconfirmed partial response. Six patients had the best overall responses of stable disease. The authors concluded that the combination of GDC-0994 and cobimetinib was not tolerable because of overlapping adverse events and cumulative toxicity on either dosing schedule, therefore, restricting the further development of the combination.
KO-947 (Kura Oncology, San Diego, California) is a selective small molecule inhibitor of ERK 1/2 that is administered intravenously. Afirst-in-human phase I dose-escalation study for this drug began in April 2017. It will enroll up to 72 patients with locally advanced unresectable or metastatic, relapsed, and/or refractory nonhematological malignancies that have either 1) BRAF, KRAS, NRAS, or HRAS mutations with nonsquamous histology or 2) squamous histology. Expansion cohorts are planned for patients with RAS or BRAF mutant nonsmall-cell lung cancer as well as squamous cell carcinoma of the head and neck. No preliminary trial results have yet been presented.
LTT462 (Novartis, Basel, Switzerland) is an oral medication that inhibits the ERK. To test the safety and tolerability of the drug, an ongoing phase I dose-escalation study is being conducted. This nonrandomized study began in April 2016, and currently will enroll up to 81 patients with advanced solid tumors, with MAPK pathway alterations. No preliminary trial results have yet been presented.
A separate ongoing phase Ib study is studying the effect of LTT462 in combination with either LXH254 (pan-RAF inhibitor) (Novartis, Basel, Switzerland) or trametinib (MEK inhibitor) (Novartis, Basel, Switzerland)., The study opened to accrual in February 2017 and will enroll the patients with advanced or metastatic KRAS or BRAF mutant nonsmall-cell lung cancer. No preliminary trial results have yet been presented.
LY3214996 (Eli Lilly and Company, Indianapolis, IN) is an ERK 1/2 inhibitor that is administered in a nonrandomized, open-labeled phase I study. The study began in September 2016 and will enroll up to 136 patients with advanced cancer, including expansions for colorectal cancer, pancreatic ductal adenocarcinoma, metastatic melanoma, and nonsmall-cell lung cancer. The trial consists of five arms. Thefirst arm is a LY3214996 dose-escalation study where the drug is taken orally once or twice a day for 21 days. The second arm combines the LY3214996 (dose timing to be determined) with midazolam. The third arm is a LY3214996 monotherapy study where the drug is taken orally during each 21-day cycle. The fourth arm consists of a combination of LY3214996 and abemaciclib. Abemaciclib is taken orally every 12 h twice a day during a 21-day cycle. The last arm combines LY3214996 with nab-paclitaxel and gemcitabine. Both nab-paclitaxel and gemcitabine are administered intravenously on days 1, 8, and 15 of a 28-day cycle. No preliminary trial results have yet been presented.
MK-8353 (previously SCH 900353)
MK-8353 (Merck Sharp and Dohme Corp, Kenilworth, NJ) is an oral ERK1/2 inhibitor. The dose-escalation and confirmation phase I study of MK-8353 began in November 2011 and enrolled 26 patients (one patient was never treated) with advanced solid tumors., Ten patients enrolled in part 1a and received 100–800 mg of MK-8353 twice a day in a 28-day cycle. Fifteen patients with melanoma or colon cancer with RAS and/or BRAF mutations enrolled in part 1b and received 200–400 mg of MK-8353 twice daily. The preliminary MTD was 400 mg, and the mean terminal half-life was determined to be 5–14 h. At 800 mg, two of six patients experienced dose-limiting toxicity, including one patient with grade 3 diarrhea, hyperbilirubinemia, nausea, vomiting, and grade 2 vision changes, as well as a patient with grade 3 fatigue and hyperbilirubinemia. The most common adverse events for all dose levels were diarrhea (44%), fatigue (40%), nausea (32%), maculopapular rash (28%), and vomiting (28%). The most common grade 3 or 4 adverse events were diarrhea (16%), isolated asymptomatic elevated indirect serum bilirubin (16%), and maculopapular rash (8%). The study showed a 12% response rate overall, and there was antitumor response in three of eight patients with BRAF V600 mutant metastatic melanoma at doses of at least 300 mg twice daily. However, there was no antitumor response in patients with NRAS- or KRAS-mutant cancers. The study was terminated in May 2014 by the sponsor for strategic reasons and not for toxicity.
A second dose-escalation and confirmation phase Ib study of MK-8353 began in January 2017 and will enroll up to 96 patients. No preliminary trial results have yet been presented. The study consists of four arms and aims to determine the recommended phase II dose of MK-8353 in combination with a fixed dose of pembrolizumab. In thefirst arm, MK-8353 is taken orally twice a day in a 21-day cycle and 200 mg of pembrolizumab is given intravenously on day 1 of each cycle. In the second arm, MK-8353 is taken once a day in a 21-day cycle in combination with 200 mg of pembrolizumab on day 1 of each cycle. The third arm is an optional arm, where MK-8353 is administered orally once a day on days 1–7, days 15–21, and days 39–35 in combination with 200 mg of pembrolizumab on day 1 and 22 of each 42-day period. The fourth arm is also optional and consists of a run-in period where patients receive MK-8353 once a day from day 14 to day 1 before starting cycle 1. After the run-in period, MK-8353 is administered once a day in a 21-day cycle in combination with 200 mg of pembrolizumab on day 1 of each cycle.
| Discussion|| |
Selective ERK inhibitors have been used in clinical trials as a treatment for a variety of cancers, the most common being advanced solid tumors with RAS, RAF, or MAPK pathway alterations.,,, The most common solid tumor cancers treated in these clinical trials have included melanoma, pancreatic adenocarcinoma, and nonsmall cell lung cancer.,, To date, BVD-523 and GDC-0994 have demonstrated the preliminary antitumor activity. Although most antitumor activities reported has been in patients with BRAF-mutated cancers, there are also early signs of activity in RAS-mutated cancer. Out of 17 patients with NRAS-mutated melanoma, and treated with BVD-523, three had partial responses, six had stable disease, and eight had disease progression. In addition, an unconfirmed partial response was observed with GDC-0994 in one patient with pancreatic cancer and although the KRAS status of that patient was not reported, 50%–70% of patients with metastatic pancreatic cancer have KRAS mutations. The results of other ongoing trials are pending at the time of publication of this manuscript, with preliminary results anticipated in 2019 and 2020.
The more common or dose-limiting toxicities observed to date with ERK inhibitors have included diarrhea, nausea, fatigue, and rash. Although transaminase elevation, hypertension, and neurotoxicity were observed with CC-90003, and myocardial infarction was observed with GDC-0994, it remains unclear if these toxicities are a class effect., Despite reports of blurred vision and other vision changes, central serous retinopathy has not been observed with ERK inhibitors to date, in contrast to MEK inhibitors, in which this is a recognized drug class toxicity. In contrast to combinations of BRAF inhibitors with MEK inhibitors that are welltolerated, the combination of ERK inhibitor and GDC-0994 with MEK inhibitor cobimetinib was not tolerable. Future trials may explore whether GDC-0994 and other ERK inhibitors are tolerable in combination with other targeted agents.
Although specific ERK alterations have not been identified as actionable, tumors with alterations upstream of ERK may be sensitive to ERK inhibitors, including mutations in BRAF, NRAS, and KRAS, as observed in the early trial results presented to date. In contrast, the preclinical studies have identified the point mutations in ERK1/ 2 that may cause acquired resistance to ERK inhibition. Preclinical studies have also demonstrated that this acquired resistance may be overcome by combination with MEK inhibitors, RAF inhibitors, and PI3K/mTOR pathway inhibitors.,
The ERK combination regimes suggested by preclinical data include combinations with MEK inhibitors, BRAF inhibitors, both BRAF and MEK inhibitors, immunotherapies, and chemotherapy. For example, many preclinical studies have demonstrated that combining ERK and MEK inhibitors can overcome the acquired resistance gained by many cancers to a singular MEK, BRAF, or ERK inhibition., Although there are many mechanisms of acquired resistance to MEK inhibitors, the observed mechanisms in this preclinical study were KRAS amplification, as well as acquired mutation in the allosteric site of MEK that prevented the inhibitor from binding. Other common mechanisms of acquired resistance to MEK inhibitors are: (1) an increased amount of mutant BRAF, (2) upregulation of STAT3, and (3) feedback reactivation of the MAPK pathway., Another preclinical study showed the ERK/MEK inhibitor combination promoted the increased cell death in cell lines with acquired resistance to BRAF inhibition due to switching to a BRAF splice variant, BRAF amplification, oncogenic NRAS, and acquired mutations in MEK. Other mechanisms of acquired resistance to BRAF inhibition, include (1) receptor tyrosine kinase or NRAS upregulation and (2) feedback reactivation of the MAPK pathway., The ERK/MEK inhibitor combination has also been shown to rescue the activity of BRAF and MEK inhibitors that have become ineffective due to acquired resistance. It has been suggested that ERK inhibitor combinations may be more effective than individual inhibitors at lower doses and with less frequent dosing. In a preclinical study, the ERK/MEK inhibitor combination was most effective in KRAS and BRAF-mutant tumors, but the study expressed concerns that such combination regimens will lead to greater toxicity in a clinical setting, requiring lower doses which may lack therapeutic benefit. However, the success of BRAF/MEK inhibitor combinations in clinic suggests that ERK/MEK inhibitors may be effective as well.
Another combination with promising preclinical data is ERK inhibition with PI3K/mTOR pathway inhibition. Dual inhibition of these two pathways was effective in melanoma cell models with acquired resistance to BRAF inhibitors. In fact, the ERK/PI3K/mTOR combination was more effective at causing apoptosis in the cell models than the MEK/PI3K/mTOR inhibitor combination. Another study demonstrated that combining SCH722984 (a noncompetitive ERK1/2 inhibitor) with vemurafenib (a BRAF inhibitor) not only exhibited the synergistic activity but also delayed acquired resistance in BRAF-mutant melanoma cell lines.
Overall, selective ERK inhibitors may be promising as an effective cancer treatment. They may be most effective against cancers with RAS, RAF, or MAPK pathway alterations and serve as a possible strategy to overcome acquired resistance to BRAF and MEK inhibitors. Since data from ERK inhibitor clinical trials are still preliminary, additional ongoing research will soon further illustrate their potential efficacy and toxicity.
Financial support and sponsorship
The authors declared no funding related to this article.
Conflicts of interest
Gerald Falchook disclosed the following potential conflicts of interest: royalties from Wolters Kluwer; advisory role for EMD Serono; travel funding from Bristol-Myers Squibb, EMD Serono, Millennium; and research funding from 3-V Biosciences, Abbvie, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, Biothera, Celldex, Celgene, Ciclomed, Curegenix, Curis, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Novartis, OncoMed, Oncothyreon, Precision Oncology, Regeneron, Rgenix, Strategia, Syndax, Taiho, Takeda, Tarveda, Tesaro, Tocagen, U.T. MD Anderson Cancer Center, Vegenics. The other authors disclosed no potential conflicts of interest related to this article.
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Gerald S Falchook,
Sarah Cannon Research Institute at HealthONE, 1800 Williams Street, Suite 300, Denver, CO 80218
Source of Support: None, Conflict of Interest: None