Molecular oncology. Causes of cancer and targets for treatment. Eds Edward P. Gelmann et al., Cambridge University Press (2014)
Aberrant HGF/Met signaling occurs in a variety of human cancers and impacts several events from tumorigenesis to metastasis. A comprehensive understanding of HGF/Met biology has facilitated the rapid development of HGF/Met pathway antagonists as anti-cancer therapy candidates. Although as a class these agents are well tolerated, widespread efficacy has not been seen in many completed Phase II studies. Promising results have been reported in lung, gastric, prostate, and PRC patients treated with Met inhibitors. An important challenge facing development of targeted agents such as these is identifying those patients most likely to achieve maximal benefit and minimal toxicity from treatment. Success will be dependent on the accurate and timely assessment of the patient’s molecular and genetic background, e.g. MET or HGF overexpression, amplification, or mutation, and indications of pathway activation, as well as genetic alterations resulting in the activation of other cancer-promoting pathways. Pre-clinical studies of several Met-targeted agents have included investigating their effectiveness against known MET mutants. Selective inhibitors such as PF-2341066/4217903 are active against some MET mutations surrounding the ATP binding site, but less active against mutations in the activation loop (70); clinical trials should be designed with this information in mind. A Phase II study showed that foretinib was more active against PRC patients with germline MET mutations compared to those without, but with otherwise histologically similar tumor phenotypes (59). These results underscore the importance of assessing MET sequence status in patient selection and/or stratification.
The use of IHC to assess Met protein abundance in tumor sections also offers promise for effective patient selection; these specimens are routinely obtained for standard pathological diagnosis. Early findings indicate that great care must be taken in qualifying antibodies for target affinity and selectivity. Phase II clinical trials of the highly selective Met antagonists onartuzumab and rilotumumab, for the treatment of NSCLC and gastroesophgeal cancer, respectively, included retrospective assessments of outcome stratified on the basis of tumor Met content by IHC, where efficacy appeared to correlate with high Met abundance. Accordingly, Met diagnostic-positive status will be included among eligibility or stratification criteria for Phase III trials of these agents.
Similar to other TKs thought to be valid anti-cancer drug targets, the use of antibodies against sites of Met tyrosyl phosphorylation implicated in kinase activation and effector binding have the potential to be powerful tools for patient selection. Unfortunately, significant obstacles to their routine use exist, including: (i) the inherent instability of protein phosphorylation during sample procurement, processing and storage; (ii) the limited antigenic features that distinguish a phosphorylated site from its unmodified counterpart; and (iii) the inherent similarity of tyrosyl phosphorylation sites among different receptor TKs that are co-expressed in many cancers. Two-site immunoassays of detergent extracts from flash frozen tissue may provide an important alternative to IHC for phosphoprotein assessments (71).
The importance of molecular diagnostic markers extends to PD markers, even more so now that combinations of highly selective targeted drugs must be investigated. In conjunction with refined patient selection, proven PD markers can dramatically improve results interpretation. Several ongoing trials of Met-targeted drugs include ancillary PD studies. Changes in plasma-soluble Met (sMet) observed independently in trials of foretinib (72–74), MGCD265 (75), and cabozantinib (76) suggest that this may be a useful marker of systemic Met TK inhibition. Changes in plasma HGF levels during cabozantinib treatment (77) were similar to those reported in a study of RCC patients treated with sorafenib (78) or pazobanib (79). Sensitive, robust, high-throughput assays for plasma and serum HGF have been available for over a decade; abnormally high HGF concentrations are already associated with advanced disease and poor outcome for several cancers, notably breast and gastric cancer (1); in a study of RCC patients, for example, serum HGF values correlated directly with clinical stage and tumor grade, and inversely with patient survival (80). The established prognostic relevance of basal HGF levels in several cancers suggests that HGF should be further investigated for PD utility.
The frequency of primary and acquired resistance to TKIs generally should be considered in the design of future clinical studies of the Met inhibitors. Strategies to overcome resistance include: (i) selecting treatments based on the presence of known susceptibility factors; (ii) combining different classes of inhibitors of a single pathway; (iii) combining targeted therapeutics with SOC treatments; and (iv) combining novel therapeutics against multiple pathways. An example of the first strategy is the use of MetMAb in NSCLC patients with a Met diagnostic-positive status, with the hope of confirming previous clinical results. A combination of HGF/Met-targeted agents with distinct activity profiles might suppress the occurrence of mutations or aberrations within the Met pathway and thereby improve clinical benefit. The third strategy is being used in independent trials combining rilotumumab, onartuzumumab, tivantinib, MK8033, amuvatinib, MGCD265, cabozantinib, or crizotinib with SOC treatments. Again, pre-clinical studies, such as those combining rilotumumab with temozolomide or docetaxel for the treatment of gastric, prostate, and colorectal cancers, provided a sound rationale and guided initial trial design (41).
Examples of the fourth strategy are also well supported by pre-clinical data (81). Met-targeted therapies are being evaluated with VEGF (50) or EGFR inhibitors, and early results are promising (Table 17.1). Rilotumumab, onartuzumumab, tivantinib, MGCD265, cabozantinib, and crizotinib are each being used in combination with erlotinib for the treatment of NSCLC (Table 17.1); MK8033, crizotinib, and tivantinib are being tested in combination with sorafenib for the treatment of advanced solid tumors (Table 17.1). Adding Met-targeted therapies to first-line therapies targeting other pathways may be particularly useful for cancers where Met participates in acquired drug resistance, as observed frequently in NSCLC treated with EGFR inhibitors. MET gene amplification was detected in 22% of lung cancer specimens that had acquired resistance to gefitinib or erlotinib, and treatment of a lung cancer cell line that had acquired gefitinib resistance through MET amplification with a Met-targeted TKI restored gefitinib sensitivity (82). Consistent with these results for NSCLC, onartuzumab and tivantinib progressed to Phase III testing in combination with erlotinib. Similar to other molecularly targeted anti-cancer drugs currently in development, the development of safe and effective Met-targeted therapies will depend on accurate and timely identification of critical oncogenic events in individual patients, the effective inhibition of which has been found to halt or reverse disease progression in pre-clinical model systems.