Non-small cell lung cancer (NSCLC) remains the leading cause of cancer related death worldwide, with a median survival that rarely exceeds 12 months in unselected patients with metastatic disease treated with conventional chemotherapy. In the last decade, the identification of key genetic events driving tumor growth and metastatic spread led to postulate the concept of oncogene-addiction. According to this model, the inhibition of certain molecular drivers by targeted agents could be effective in reducing tumor burden and improving patients outcome. In this context, due to its central role in cancer proliferation and metastasis, mesenchymal-epidermal transition (MET) has recently emerged as a potential tumor-driver and also as a promising therapeutic target in several malignancies, particularly in NSCLC where MET is often deregulated by overexpression, gene amplification or mutations (1). Furthermore, preclinical data showed a potential cross-talk between MET and epidermal growth factor receptor (EGFR) pathways. Indeed, these receptors are often co-expressed and their functional transactivation potentiates downstream signaling (1). In addition, MET gene amplification has been recognized as one of the mechanisms responsible for EGFR-Tyrosine Kinase Inhibitor (TKI) secondary resistance in EGFR mutant NSCLC (2,3). As a consequence, there is a strong rationale to combine dual MET/EGFR inhibition in NSCLC.
In 2013, Spigel et al. published the results of a randomized phase II trial exploring the activity of the combination of erlotinib and onartuzumab (or MetMab), a monovalent monoclonal antibody directed against the extracellular domain of MET receptor, in 137 molecularly unselected NSCLC patients who failed at least one prior chemotherapy regimen (4). Archival tumor tissue was required to evaluate levels of MET expression by using immunohistochemistry (IHC) and considering as MET positive those samples having ≥50% of tumor cells with moderate (2+) or high (3+) staining intensity (MET diagnostic positive). Additional evaluation included MET gene copy number (GCN) assessed by fluorescent in situ hybridization (FISH) and adopting a cut-off of mean ≥5 copies per cell to define positivity. Co-primary end points of the trial were progression-free survival (PFS) in intent-to-treat (ITT) population and in IHC diagnostic positive population. In ITT population neither PFS (HR, 1.09; P=0.69) nor overall survival (OS; HR, 0.80; P=0.34) favored the experimental arm. However, in MET diagnostic positive disease the combination onartuzumab-erlotinib was superior to erlotinib-placebo in both PFS and OS (HR, 0.53; P=0.04; HR, 0.37; P=0.002, respectively), whereas a detrimental effect was noted in the MET diagnostic negative subgroup. Interestingly, MET GCN was not predictive for onartuzumab sensitivity.
Moving from these promising findings, the same authors conducted a large, randomized, confirmatory phase III trial aiming to demonstrate a survival improvement for the combination of onartuzumab and erlotinib in MET diagnostic positive NSCLC. The results of this study have been presented this year at the annual meeting of the American Society of Clinical Oncology (5). The study, enrolling a total of 490 subjects, failed to replicate the results observed in the phase II trial. Particularly, neither OS (6.8 vs. 9.1 months, HR, 1.27; P=0.07) nor PFS (2.7 vs. 2.6 months, HR, 0.99; P=0.92), the secondary end-point of this study, differed between the two arms. Notably, subset analyses for both OS and PFS confirmed the lack of superiority of onartuzumab-erlotinib combination, with similar results across all stratification factors, including histology (non-squamous versus squamous), number of previous therapy lines (1 versus 2), EGFR mutational status (mutated versus wild type) and MET status even when assessed by IHC (2+ versus 3+) or FISH (positive versus negative).
Although several factors could be responsible for the negative results of the study, it is possible that the potential benefit produced by the anti-MET agent was not detected because of a non-optimal patient selection. In fact, the cut-off of ≥5 MET copies per cell adopted for discriminating FISH positive versus FISH negative demonstrated a significant association with patient prognosis with no evidence of any predictive value (1). Recently, Camidge et al. presented the preliminary results of the ongoing phase I PROFILE 1001 study, in which the activity of crizotinib, a potent anti MET inhibitor, was evaluated exclusively in MET amplified NSCLC patients (6). In this study, MET FISH positivity was defined as a ratio of MET/centromere ≥1.8. By using this cut-off, patients were stratified on the base of levels of amplification within three categories as low (MET/CEP7 ratio ≥1.8-≤2.2) amplification, intermediate (MET/CEP7 ratio >2.2-<5) amplification and high (MET/CEP7 ratio ≥5) amplification. Interestingly, patients with intermediate and high levels of MET amplification were current smokers. Crizotinib did not result particularly effective in the small group of patients with low levels of amplification, whereas a marked anti-tumor activity was observed in both intermediate/high MET amplified groups (RR =50%). These findings are consistent with those reported in preclinical data (7,8). Indeed, in an in vitro model of gastric cancer, Japanese investigators demonstrated that only gastric cancer cell lines displaying high levels of amplification were sensitive to a potent anti MET inhibitor PF665752 (7). In another preclinical model, crizotinib induced apoptosis only in the two NSCLC cell lines with high levels of amplification (8). In addition, cell lines harboring EGFR mutations with acquired resistance to EGFR TKIs became MET addicted only in presence of high levels of MET amplification (3). Therefore, these data overall indicated that anti-MET strategies should be focused exclusively in patients which tumor display high levels of MET-amplification.
Identification of patients potentially sensitive to anti-MET agents is of crucial relevance. In 2009 we analyzed a cohort of more than 430 surgically resected NSCLC, aiming to evaluate the prognostic impact of MET amplification, and we found that an increase GCN of >5 copies per cell discriminated patients with different prognosis (1). By applying the same criteria adopted in the study by Camidge et al., we observed that among patients included onto the analysis only a small percentage had intermediate (3%) or high levels (0.6%) of MET amplification, clearly indicating that the proportion of patients population potentially sensitive to anti-MET agents is relatively small. In addition, we observed that MET amplified patients are generally former or current smokers and approximately one third of them have squamous histology. Moreover, clinical characteristics of MET amplified patients do not reflect the typical population of NSCLC generally screened for biomarkers in clinical practice. In the MetMab trial, the main method used for selecting patients was IHC (5). Several evidences indicated that such method is not optimal for patient selection. Looking at mechanisms of MET deregulation, it is clear that even restricting the analysis to patients with high expression (MET 3+), they represent approximately 10% of all NSCLC, while patients with MET amplification are only 3-4% of cases. Recently, Arriola et al. showed that although MET amplified NSCLC invariably displayed high levels of protein expression (3+), a consistent proportion of MET 3+ by IHC was FISH negative (9). That implies that presence of MET amplification should be confirmed by FISH, even in MET 3+ patients.
In conclusion, MET remains a relevant target driving tumor growth in NSCLC but realistically in a small fraction of patients with gene amplification. In addition, as MET amplification have been identified mainly in individuals with smoking history and also in squamous cell histology, looking for patients potentially sensitive to anti MET agents means to focus on a category of patients that is normally less considered for biomarkers assessment. All available data clearly demonstrated that IHC or MET GCN are not optimal for identify patients potentially sensitive to anti-MET agents. Furthermore, as IHC is less expensive and less time-consuming than FISH test, its use could be proposed to screen on a large scale those individuals more likely to have MET amplification. At the present time, a phase II Italian trial (METROS trial, Eudract number 2014-001263-12) is ongoing with the aim of assessing crizotinib sensitivity in patients with intermediate or high levels of MET amplification. The results of this study will provide evidence on the role of anti-MET agents in selected NSCLC and will define the best cut-off of MET amplification discriminating sensitive versus resistant population. If sensitivity is not confined to individuals with high levels of amplification, more than one needle could be found in the haystack.
This manuscript is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2012-13157, Fondazione Ricerca Traslazionale (FoRT) and Istituto Toscano Tumori (ITT) Project F13/16.
Disclosure: The authors declare no conflict of interest.
- Cappuzzo F, Marchetti A, Skokan M, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 2009;27:1667-74. [PubMed]
- Engelman JA, Jänne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2008;14:2895-9. [PubMed]
- Cappuzzo F, Jänne PA, Skokan M, et al. MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol 2009;20:298-304. [PubMed]
- Spigel DR, Ervin TJ, Ramlau RA, et al. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2013;31:4105-14. [PubMed]
- Spigel DR, Edelman MJ, O’Byrne K, et al. Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb and IV NSCLC: results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial. J Clin Oncol 2014;32:abstr 8000.
- Camidge DR, Ou SHI, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). J Clin Oncol 2014;32:abstr 8001.
- Smolen GA, Sordella R, Muir B, et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci U S A 2006;103:2316-21. [PubMed]
- Tanizaki J, Okamoto I, Okamoto K, et al. MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations. J Thorac Oncol 2011;6:1624-31. [PubMed]
- Arriola E, Casadevall D, Gimeno J, et al. Met heterogeneity evaluation by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in nonsquamous non-small cell lung cancer (nsNSCLC). J Clin Oncol 2014;32:abstr 11005.