Enthusiasm for the MET signaling pathway as a target for anticancer therapy has not waned despite several high-profile failures in multiple indications. This persistence appears to be paying off as promising new data emerge from more recent clinical trials.
Enthusiasm for the MET signaling pathway as a target for anticancer therapy has not waned despite several high-profile failures in multiple indications. This persistence appears to be paying off as promising new data emerge from more recent clinical trials, paving the way for active clinical development of nearly 20 new and existing agents (Table).
In addition to its role as an oncogenic driver, the MET pathway has been increasingly implicated in the development of resistance to various types of anticancer therapy. A greater understanding of the molecular mechanisms underlying this role also have prompted the development of combinations that are impacting the treatment landscape for numerous tumor types.
Finding the right patients to be treated with MET inhibitor therapy is the key to their renewed success, but the search is proving anything but straightforward due to the complex nature of responses. As researchers seek to overcome this hurdle, they are redefining the niche for MET-targeted therapies in oncology.Since its discovery more than three decades ago, the MET gene has been closely linked to the development of cancer. It was originally identified as one of the genes involved in the transformation of a sarcoma cell line and subsequently found to encode a tyrosine kinase receptor that facilitates the transmission of signals from outside the cell into the nucleus to coordinate cellular responses.
ALK indicates anaplastic lymphoma kinase; AML, acute myeloid leukemia; AXL, AXL receptor tyrosine kinase; CRC, colorectal cancer; CRPC, castration- resistant prostate cancer; EGFR, epidermal growth factor receptor; FLT, FMS-related tyrosine kinase; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; HNSCC, head and neck squamous cell carcinoma; MET, mesenchymal epithelial transition receptor; NSCLC, non—small cell lung cancer; RCC, renal cell carcinoma; RON, recepteur d’origine nantais; ROS, ROS proto-oncogene; TIE, tyrosine kinase with immunoglobulin- like and EGF-like domains; TRK, tropomyosin receptor kinase; VEGFR, vascular endothelial growth factor receptor.
The MET receptor is typically activated by the binding of its only known ligand, hepatocyte growth factor (HGF), although MET signaling can also be initiated independently of the ligand. HGF is secreted from mesenchymal cells as an inactive precursor and is activated by a group of protease enzymes, allowing it to bind to MET, which is located primarily on the surface of epithelial and endothelial cells.
In response to the binding of HGF, a single MET receptor molecule pairs up with another, which triggers its intrinsic kinase activity. Several regions of the receptor subsequently become phosphorylated, including a docking site, which recruits a whole range of intracellular proteins that activate a number of different downstream signaling cascades, including the PI3K/Akt, MAPK, STAT3 and NFκB pathways. These ultimately transmit the MET receptor’s signal to the nucleus, where it triggers the transcription of genes involved in key cellular processes.
In addition to regulating cell growth, survival and proliferation, the MET pathway orchestrates an invasive growth program in normal cells, an important process for embryogenesis and for tissue repair and wound healing in adults.
As part of this program, it coordinates the epithelial to mesenchymal transition (EMT), via which epithelial cells gain mesenchymal cell properties that allow them to break apart from one another and become more motile and invasive.
The roles of MET signaling in normal cells translate into many of the hallmark properties of cancer cells and, since its original discovery as a proto-oncogene, numerous studies have provided evidence that the MET pathway can be hijacked to drive tumorigenesis in a number of different cancer types.
Reported mechanisms of MET pathway deregulation include mutations in the MET gene, rearrangements of chromosome 7 on which the MET gene is located, MET gene amplification, and increased expression of the MET or HGF proteins. Extensive research has identified MET as an oncogenic driver in a wide range of tumor types, including lung, stomach, liver, and kidney cancers. MET activation due to mutations of the gene is thought to be relatively rare, although the frequency varies with tumor type; mutations are more common in non—small cell lung cancer (NSCLC), for example, than in other types of cancer. More often, MET is activated by amplification of the wild-type gene. Regardless, dysregulation of the pathway has been shown to result in tumors with more aggressive features and a poor prognosis for patients.Since MET is an attractive therapeutic target in oncology, a number of MET-targeting therapies have been developed, including-small molecule tyrosine kinase inhibitors that block the enzymatic activity of the receptor and monoclonal antibodies that bind to the MET receptor or its ligand HGF. There are also specific agents that target just the MET receptor and nonspecific ones for which MET is just one of several targets.
Despite a strong scientific rationale and promising results during the early stages of development, MET inhibitors have demonstrated inconsistent results in clinical testing. Although the FDA has approved two MET inhibitors, both drugs target other receptors and it is unclear how much inhibition of the MET receptor contributes to their efficacy.
Crizotinib (Xalkori) is a small-molecule inhibitor of the anaplastic lymphoma kinase (ALK), and also has activity against MET, RON, and ROS. In 2011, crizotinib received regulatory approval for the treatment of patients with ALK-positive NSCLC, followed in March 2016 by approval in ROS1-positive patients.
Cabozantinib (Cometriq/Cabometyx) inhibits vascular endothelial growth factor receptor 2 (VEGFR2) and RET in addition to MET. The FDA approved the agent for the treatment of metastatic medullary thyroid cancer in 2012 and for advanced renal cell carcinoma in 2016.
The success of more specific MET inhibitors has proved much more variable and the field has experienced a run of late-stage clinical trial failures in the two most promising indications, lung cancer and gastric cancer.
Onartuzumab is a humanized, monovalent MET-targeting monoclonal antibody. The phase III METLung trial, in which a combination of onartuzumab and erlotinib was compared with erlotinib alone, was stopped early for futility. Onartuzumab also performed poorly in the phase III METGastric trial, in which it was combined with FOLFOX (leucovorin, fluorouracil, and oxaliplatin) chemotherapy.
Similarly, the HGF-targeting monoclonal antibody rilotumumab also proved disappointing in gastric cancer. There was some success in a phase II study, which showed improved progression- free survival (PFS) and overall survival (OS) in patients with MET-positive disease treated with rilotumumab in combination with epirubicin, cisplatin, and capecitabine.
However, phase III testing in the RILOMET-1 and RILOMET-2 trials was halted amid reported deaths in the rilotumumab arm, according to an interim safety report. Currently, there are no ongoing clinical trials of rilotumumab in any indication.
The failure of onartuzumab in lung cancer was preceded by discontinuation of the phase III development of tivantinib in the same indication. Tivantinib was the first non-ATP-competitive, selective MET inhibitor developed and was evaluated in combination with erlotinib in patients with metastatic nonsquamous NSCLC in the phase III MARQUEE and ATTENTION trials.
In the MARQUEE trial, although PFS was improved in the combination arm, there was no significant difference in OS and the trial was discontinued for futility, while the ATTENTION trial was halted prematurely due to increased incidence of interstitial lung disease.Despite the string of clinical disappointments, many researchers remained convinced of the potential of MET inhibitors. Some negative trials showed hints of superior efficacy in particular patient populations and this suggested that perhaps we just haven’t figured out yet which patients are likely to respond to MET inhibition.
A number of biomarkers are being evaluated in an effort to identify patients who would best respond to MET inhibitor therapy, but none have been clinically validated and patient selection is proving far from straightforward. The most promising clinical trial results came from patient subsets in which the MET protein is overexpressed. Many randomized, phase III trials therefore used immunohistochemical techniques to identify overexpression of the MET protein.
The failure of these trials has prompted many to suggest that protein expression might not be an optimal biomarker and may be vastly underestimating the clinical response to MET inhibition.
Overexpression of the protein doesn’t necessarily mean that the MET gene is dysregulated or that it is acting as an oncogenic driver. To be certain of this, we would need to be able to detect activated MET—that is, MET protein that is phosphorylated— and this has proved technically challenging.
Alternatively, detecting MET gene amplification through fluorescence in situ hybridization (FISH), which can identify extra copies of the gene, is emerging as a promising new biomarker. The caveat of this method is that only a small proportion of patients will be classed as MET-positive and will qualify for MET inhibitor therapy.
It may also be possible to identify other biomarkers that predict success with MET inhibitor therapy or to refine reagents and methodologies to better define MET-positive or negative status.
Furthermore, there may be other explanations for the lack of clinical efficacy, including a failure of current drugs to block ligand-independent activation of MET or the development of resistance. Different types of MET inhibitors might also require different biomarkers depending upon their mechanism of action.Ongoing clinical trials are showcasing the potential of improved patient selection in MET inhibitor therapy, and numerous recent successes have been reported with various new drugs.
AMG 337, a selective MET inhibitor, demonstrated a 62% overall response rate (ORR) among 13 patients with MET-amplified gastric cancer in a phase I clinical trial, and one patient’s primary tumor volume reduced by over 90%; there was no clinical benefit in the population as a whole. Headache was a dose-limiting toxicity experienced by half of patients, but adverse events were typically grade 1 or 2, most commonly nausea, fatigue, and vomiting.
ABT-700 is a MET-targeting monoclonal antibody currently being evaluated in a phase I trial in patients with solid tumors. ABT-700 monotherapy in six patients with advanced gastroesophageal cancer who had progressed on three or more prior lines of chemotherapy, including four patients who displayed MET amplification, indicated an ORR of 75% (3 partial responses and 1 progressive disease) and was well tolerated.
Some companies are now beginning to prospectively select patients with MET-amplified tumors for clinical trials. On the basis of the above results, a phase II trial of AMG 337 in patients with MET-amplified gastroesophageal cancer was initiated and is ongoing but not actively recruiting participants. The phase II METROS trial of crizotinib in patients with MET-amplified pretreated metastatic NSCLC is also ongoing.
Capmatinib (INC280) is being explored in patients with recurrent NSCLC in a phase II trial with four cohorts based on different levels of MET gene copy numbers. Participants also must have epidermal growth factor receptor (EGFR) wildtype, ALK-negative tumors.
Other trials that continue to use IHC protein overexpression as a measure of MET positivity also have shown some success. In a phase II trial, tivantinib was compared with placebo as second-line therapy for advanced hepatocellular carcinoma (HCC). Multiple biomarkers were evaluated and MET protein expression as determined by IHC was the strongest predictor of tivantinib benefit. A subgroup analysis of MET-positive patients demonstrated significantly improved OS, PFS, and time-to-progression in the tivantinib arm. The phase III METIV-HCC trial is ongoing in this patient population.A growing body of evidence suggests that dysregulated MET signaling not only is an oncogenic driver in several different cancers, but that it also plays a central role in the development of resistance to various forms of anticancer therapy including targeted therapies, chemotherapy, and radiation therapy.
This role is particularly well delineated for EGFR-targeted therapy. Up to one- fifth of patients who develop acquired resistance to EGFR inhibitors show evidence of aberrant MET signaling.
It is thought that crosstalk between the two pathways means that overexpression of MET can activate PI3K/Akt signaling to bypass EGFR, thus rendering the EGFR inhibitor obsolete.
In general, the development of rational combination therapy is the logical way to tackle acquired resistance. Several MET inhibitors have been tested in combination with EGFR inhibitors, although no benefit has been observed as yet.
The bispecific antibody LY3164530, which targets both EGFR and MET, is currently being evaluated in phase I clinical trials. In a preclinical study presented at the 2016 American Association for Cancer Research Annual Meeting, LY3164530 was better at overcoming MET-mediated resistance to erlotinib, gefitinib, lapatinib or vemurafenib compared with the combination of the individual monoclonal antibodies targeting these receptors in cell-based assays. MET activation has also been implicated in the development of resistance to VEGFR inhibitors in patients with renal cell carcinoma, HER2-targeted therapy in breast cancer, and chemotherapy in patients with pancreatic ductal adenocarcinoma.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in New Haven, Connecticut.