C-MET Inhibitors as New Members of the NSCLC Treatment Armamentarium—A Pooled Analysis

Susanne Reuther,Michael F Murphy,Wolfram Dempke,Niccolo Bassani

doi:10.4236/alc.2022.111001

Abstract

Objective: Capmatinib and tepotinib, two recently FDA-approved and highly specific small-molecule inhibitors of c-MET exon 14 skipping mutations are new and important therapeutic options for the treatment of NSCLC patients harbouring c-MET alterations. However, the precise role of these molecules as a new treatment option is still not fully defined. Methods: In an attempt to further evaluate the contributions of c-MET inhibitors to the armamentarium of treatment options for advanced and metastatic NSCLCs, relevant phase II and III studies were retrospectively analyzed in terms of ORR and mPFS (mOS numbers are still not available for current c-MET trials and therefore not considered for statistical purposes). Results: Treatment of advanced and metastatic NSCLC patients harbouring c-MET exon 14 skipping mutations with the novel and highly selective c-MET inhibitors is significantly superior (p < 0.0001) when compared with standard chemotherapy. However, when c-MET inhibitors are compared with immunotherapy or the combination of immunotherapy and chemotherapy, no significant differences in terms of ORR and PFS were found, but treatment with c-MET reported be much more tolerable. Conclusion: The novel and highly selective c-MET inhibitors capmatinib and tepotinib are promising novel treatment options for patients with c-MET-dysregulated NSCLC primarily in the first-line setting, albeit a clear mOS benefit has not yet been established. Since immunotherapy did not appear to be particularly effective in NSCLC patients harbouring c-MET alterations, the vast majority of these patients are treated with immunotherapy plus chemotherapy. C-Met inhibitors appear to be equally effective and thereby sparing patients from the toxic effects of the chemotherapy. The routine testing of c-MET exon 14 skipping mutations should be performed as the GEOMETRY mono-1 data clearly showed higher response rates with capmatinib in treatment-naive than in pretreated patients, indicating that c-MET exon 14 skipping mutations should preferably be molecularly assessed at baseline. C-MET exon 14 skipping mutations are, therefore, clear biomarkers of response to c-MET inhibitors.

Highlights

First-line treatment of advanced or metastatic NSCLCs has changed dramatically during the last two decades, and novel treatment options such as tyrosine kinase inhibitors (e.g., EGFR, ALK, RET, Braf, c-MET) and immunotherapies (e.g., PD-1, PD-L1, CTLA-4) have demonstrated significant benefit for several NSCLC patients sparing them from the toxic effects of chemotherapy [1]
In an attempt to further evaluate the contributions of c-MET inhibitors to the armamentarium of treatment options for advanced and metastatic NSCLCs, relevant phase II and III studies were retrospectively analyzed in terms of ORR and mPFS
Mono-1 data clearly showed higher response rates with capmatinib in treatment-naive than in pretreated patients, indicating that c-MET exon 14 skipping mutations should preferably be molecularly assessed at baseline

Summary

Introduction

First-line treatment of advanced or metastatic NSCLCs (non-small cell lung cancers) has changed dramatically during the last two decades, and novel treatment options such as tyrosine kinase inhibitors (e.g., EGFR, ALK, RET, Braf, c-MET) and immunotherapies (e.g., PD-1, PD-L1, CTLA-4) have demonstrated significant benefit for several NSCLC patients sparing them from the toxic effects of chemotherapy [1]. Capmatinib and tepotinib, two recently FDA-approved [2] and highly specific small-molecule inhibitors of c-MET exon 14 skipping mutations are new and important therapeutic options for the treatment of NSCLC patients harbouring c-MET alterations. Both drugs showed substantial antitumour activity in patients with advanced NSCLC with a c-MET exon 14 skipping mutation, in those not been treated previously [3] [4]. Several lines of evidence have demonstrated that harbouring altered c-MET in NSCLC patients is associated with lower ORRs (overall response rates) and shorter mPFS (medium progression-free survival) and mOS (medium overall survial) than in tumours without such mutations [5]. C-MET alterations have been found to be positively correlated with enhanced expression of immune-inhibitory molecules (e.g., PD-L1), decreased expression of co-stimulatory markers (e.g., CD137, CD252 etc.), and c-MET obviously is implicated in controlling the inflamed TME (tumour microenvironment) [8] [9]

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Discussion

Conclusion