Mutation or Amplification: Who MET the Expectations?

Identification of driver oncogenes in NSCLC is leading the method for accurate patient selection and proper targeting of actionable alterations. Several molecular events have been described, and different biomarkers are now incorporated in clinical practice, with MET as one of the latest. 

Proto-oncogene MET is a tyrosine kinase transmembrane receptor for hepatocyte growth factor; it is deregulated in multiple malignancies, and its aberrant activation drives tumor growth and dissemination. Mechanisms resulting in MET deregulation include protein expression, gene copy number alteration, rearrangements, or gene mutations.¹ Available data demonstrated that MET overexpression, gene amplification, or mutation are negative prognostic factors in NSCLC.2-3 MET amplification has been described in patients not previously exposed to tyrosine kinase inhibitors (TKIs; de novo MET amplification) or as a mechanism of resistance to TKIs, mainly to EGFR TKIs.
During the past 10 years, a number of trials have evaluated different anti-MET agents in patients with advanced NSCLC, with conflicting results. Studies with monoclonal antibodies or with small molecules failed to demonstrate any benefit when given in combination with erlotinib in unselected pretreated individuals.⁴ 

Conversely, recent studies conducted in properly selected populations demonstrated that new anti-MET agents, including crizotinib, capmatinib, or tepotinib, induced tumor regression in a significant fraction of patients with MET-deregulated disease. The PROFILE 1001 phase I/II trial tested crizotinib in patients with MET exon 14–mutated NSCLC with overall response (ORR) as the primary endpoint. Among 65 patients who were response evaluable, ORR was 32% with a median PFS of 7.3 months.⁵ 

GEOMETRY mono-1 was a phase II trial of capmatinib in different cohorts of patients with MET exon 14 mutations or MET amplification, with the primary endpoint of ORR.⁶ In the cohort of patients with pretreated MET exon 14–mutated disease, ORR, median duration of response (DoR), and median PFS were 41%, 9.7 months, and 5.4 months, respectively. In the cohort of patients with untreated MET exon 14–mutated disease, response rate (RR) raised to 68%, DoR was 12.6 months, and PFS exceeded the year, suggesting that the greatest benefit is obtained when capmatinib is used early in the course of the disease. 

The phase II VISION trial aimed to investigate the activity of tepotinib in terms of RR in patients with advanced, MET-mutated NSCLC for whom up to two previous lines of therapy had failed.⁷ Interestingly, MET exon 14 skipping mutations were centrally tested using appropriate next-generation sequencing panels on circulating free DNA, in tissue samples, or in both, and patients were divided into three corresponding groups (liquid biopsy, tissue biopsy, and combined biopsy). Responses were similar in all groups (46% combined biopsy; 48% liquid biopsy; and 50% tissue biopsy), as was PFS (8.5 months, combined biopsy; 8.5 months, liquid biopsy; and 11.0 months, tissue biopsy). Furthermore, 67% of patients had matched liquid biopsies collected at baseline and during therapy, allowing comparison between molecular and RECIST response.  

These data clearly indicate that MET exon 14 mutations, detected in tissue or plasma, are the real drivers, and results previously described are in the range of activity of first-generation TKIs against other targeted populations.^8-10 Intriguingly, the same anti-MET agents produced only modest effects when given in patients with MET gene amplification,6, 11, 12 raising the question on the role of MET gene copy number as an actionable driver. 

In the MET-amplified cohort of the PROFILE 1001 trial, crizotinib induced a dramatic tumor shrinkage, confined to patients with high levels of MET amplification (ratio gene/centromere  2.5). This suggests that this value could discriminate responding patients.¹³ Additional preclinical studies reinforced the concept that efficacy of MET inhibition could be related to levels of gene amplification. Both gastric and lung cancer cell lines with high levels of MET amplification showed marked response to MET inhibition in preclinical studies.^14-15 Moreover, high levels of MET amplification found on MET-driven, gefitinib-resistant cells were rare in advanced NSCLC, and lower cutoffs did not demonstrate clinical significance.¹⁶ Nevertheless, subsequent trials failed to confirm the efficacy of crizotinib in MET-amplified NSCLC, with an RR of approximately 30% and median PFS of only few months.^11,12 In GEOMETRY, all the cohorts with low levels of amplification were closed for futility, and the efficacy of capmatinib in individuals with high MET gene copy number was lower than the prespecified threshold for clinically relevant activity.⁶ 

Beyond a limited drug efficacy, de novo MET amplification is a rare event, at least at high levels. In surgically resected NSCLC, among 435 screened patients, only 3 (0.6%) had high levels of amplification.¹⁶ The METROS trial screened more than 430 patients with advanced NSCLC, and only 0.4% displayed high levels of MET amplification, confirming the relative rarity of this molecular alteration. 

How can we put all these data into clinical practice? Available evidence indicates that new anti-MET agents are potentially effective in the presence of MET mutations, and this alteration should be routinely tested. Whether these agents are superior to other available first-line options remains a matter of investigation. By contrast, the absence of a defined cut-off, the rarity of the event, and the lack of effective therapies preclude the entry of MET gene copy number in our daily biomarkers list. Further studies and new agents are urgently needed in this group of patients with prognostically unfavorable disease. 

References:

1. Comoglio PM, Trusolino L, Boccaccio C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer. 2018;18(6):341-358.
2. 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(10):1667-1674. 
3. Tong JH, Yeung SF, Chan AWH, et al. MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non-Small Cell Lung Carcinoma with Poor Prognosis. Clin Cancer Res. 2016;22(12):3048-3056.
4. Scagliotti G, von Pawel J, Novello S, et al. Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2015;33(24):2667-2674.
5. Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020;26(1):47-51.
6. Wolf J, Seto T, Han J, et al. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383(10):944-957.
7. Paik PK, Felip E, Veillon R, et al. Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N Engl J Med. 2020;383(10):931-943.
8. Mok TS, Wu Y, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
9. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246.
10. Solomon BJ, Mok T, Kim D, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-2177.
11. Landi L, Chiari R, Tiseo M, et al. Crizotinib in MET-Deregulated or ROS1-Rearranged Pretreated Non-Small Cell Lung Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial. Clin Cancer Res. 2019;25(24):7312-7319.
12. Moro-Sibilot D, Cozic N, Pérol M, et al. Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial. Ann Oncol. 2019;30(12):1985-1991.
13. Camidge DR, Ignatius Ou SH, 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(15_suppl):8001.
14. 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(7):2316-2321.
15. 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(10):1624-1631.
16. 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(2):298-304.