Genetic Heterogeneity of MET-Aberrant NSCLC and Its Impact on the Outcome of Immunotherapy

Kron, Anna; Scheffler, Matthias; Heydt, Carina; Ruge, Lea; Schaepers, Carsten; Eisert, Anna-Kristina; Merkelbach‐Bruse, Sabine; Riedel, Richard; Nogová, Lucia; Fischer, Rieke; Michels, Sebastian; Abdulla, Diana S.Y.; Koleczko, Sophia; Fassunke, Jana; Schultheis, Anne M.; Kron, Florian; Ueckeroth, Frank; Wessling, G.; Sueptitz, Juliane; Beckers, Frank; Braess, Jan; Panse, Jens; Grohé, Christian; Hamm, Michael W.; Kabitz, Hans-Joachim; Kambartel, Kato; Kaminsky, Britta; Krueger, Stefan; Schulte, Clemens; Lorenz, Joachim; Lorenzen, Johann; Meister, Wolfram; Meyer, Andreas; Kappes, Jutta; Reinmuth, Niels; Schaaf, Bernhard; Schulte, Wolfgang; Serke, Monika; Buettner, Reinhard; Wolf, Jürgen

doi:10.1016/j.jtho.2020.11.017

Cited by 47 publications

(38 citation statements)

References 29 publications

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“…In addition to our study, one registry-based study revealed that exposure to ICI therapy is associated with superior survival outcomes as opposed to chemotherapy among patients with MET -amplified NSCLC. 7 Another study similarly revealed that patients with MET -amplified NSCLCs treated with immunotherapy have longer PFS than the non– MET -amplified counterparts. 39 This study further revealed that MET amplification is related to immune response-related pathways, DNA damage response, and repair pathways.…”

Section: Discussionmentioning

confidence: 99%

“… 3 , 4 In contrast, it remains a matter of debate whether MET amplification is a true actionable driver of NSCLC and whether MET amplification is a definitive target of MET -directed therapies, 1 , 5 because MET amplification is more genetically heterogeneous than MET ex14, with a wide range of MET gene copy numbers and frequently observed comutations. 6 , 7 Accordingly, clinical trials have exhibited the inconsistent efficacy of MET inhibitors against MET -amplified tumors. 2 , 8 …”

Section: Introductionmentioning

confidence: 99%

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MET Amplification and Efficacy of Nivolumab in Patients With NSCLC

Yoshimura

Inoue

Inui

et al. 2021

JTO Clinical and Research Reports

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Introduction MET amplification is an important genetic alteration in NSCLC. Unlike in patients with EGFR and ALK alterations, the efficacy of immune checkpoint inhibitors in patients with MET -amplified NSCLC remains unknown. Methods An exploratory analysis of a prospective, multi-institutional cohort comprising 200 patients with advanced or recurrent NSCLC treated with nivolumab monotherapy was performed, and MET amplification was defined as a MET -to-CEP7 ratio of greater than or equal to 2 using fluorescent in situ hybridization. High-level and low-level MET gains were also defined as MET signals ≥10/nuclei and 10> MET signals ≥5/nuclei, respectively. Overall response rates (ORRs) and survival outcomes were evaluated on the basis of the MET gene copy number status. Results Among 175 patients eligible for analysis, MET amplification was detected in 13 tumors (7.4%). Four (2.3%) high-level and 14 (8.0%) low-level MET gains were also detected. There were no considerable differences in ORRs in accordance with the MET gene copy number status. Similarly, no significant differences in both progression-free survival (PFS) and overall survival (OS) were observed between patients with and without MET -amplified NSCLC (log-rank, p = 0.813 for PFS, and p = 0.855 for OS). Among 101 adenocarcinomas, ORRs in patients with high-level and low-level MET gains (50.0% for both, p = 0.049) were significantly higher than those without MET gains (17.6%), yet survival outcomes for both PFS and OS did not improve. Conclusions MET amplification was not associated with greater benefit of nivolumab treatment in patients with NSCLC. Further studies are warranted to prioritize immune checkpoint inhibitors in the treatment regimen for patients with MET amplification.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MET Amplification and Efficacy of Nivolumab in Patients With NSCLC

Yoshimura

Inoue

Inui

et al. 2021

JTO Clinical and Research Reports

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“…Therefore, it is not surprising that some retrospective studies showed that the expression of PD-L1, a potential biomarker used to predict the efficacy of ICIs, is high in NSCLCs with MET∆ex14 (43--91% if 1% ≧ PD-L1 is used as a cutoff) (Table 4). 23,[79][80][81][82][83][84][85] This high PD-L1 expression may be due not only to so-called adaptive immune resistance but also to activated MET signaling; a preclinical study showed that MET activation induced the expression of several immune checkpoints, including PD-L1, through a JAK2-independent pathway. 86 Therefore, the efficacy of ICIs in NSCLC patients with MET∆ex14 has received a great deal of attention.…”

Section: Immunotherapiesmentioning

confidence: 99%

Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges

Fujino¹,

Suda²,

Mitsudomi³

2021

LCTT

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MET exon 14 skipping mutation ( MET∆ex14) is present about 3% of non-small cell lung cancers (NSCLCs). NSCLC patients with MET∆ex14 are characterized by an average age of over 70 years at diagnosis, a smoking history and a higher frequency in pleomorphic carcinoma and adenosquamous cell carcinoma than in adenocarcinoma. It has also been reported that NSCLCs with MET∆ex14 often have codriver alterations such as EGFR amplification (6-28%), FGFR1 alterations (5-17%), KRAS alterations (~8%), BRAF alterations (~21%), or PIK3CA mutation/amplification (~14%). In 2020, the approval of two MET-tyrosine kinase inhibitors (TKIs), capmatinib and tepotinib, for NSCLCs carrying MET∆ex14 dawned a new era for MET-targeted therapy. These drugs yielded progressionfree survival of 5.4−12.4 months in clinical trials; however, it has also been reported that one-third to half of patients show inherent resistance to MET-TKIs. In addition, the emergence of acquired resistance to MET-TKIs is inevitable. In this review, we summarize the clinical and molecular characteristics of NSCLCs with MET∆ex14, the efficacy and safety of capmatinib and tepotinib, the inherent and acquired resistance mechanisms to MET-TKIs, and new treatment strategies for NSCLCs with MET∆ex14 in the near future.

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“…13,14 Importantly, the inhibition of MET signaling with MET inhibitor enhances T-cell mediated antitumor immunity in syngeneic mouse models. 15 Results of Kron et al 12 were consistent with the notion that in the METamp tumors, the suppressed tumor immune microenvironment might be associated with immunetolerance and poor prognosis, but how the ICI benefited the patients without modulating aberrant MET signaling required future validation and exploration.…”

mentioning

confidence: 63%

“…There is still a lot to be learned regarding heterogeneity in MET-aberrant NSCLC. In this issue of Journal of Thoracic Oncology, Kron et al 12 set out to understand the genetic and immune heterogeneity in the METex14 and METamp populations. The authors performed multilevel analyses, including evaluation of genetic features and programmed death-ligand 1 levels, and they performed clinical outcome association with different features.…”

mentioning

confidence: 99%

Heterogeneity in MET-Aberrant NSCLC

2021

Journal of Thoracic Oncology

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Genetic Heterogeneity of MET-Aberrant NSCLC and Its Impact on the Outcome of Immunotherapy

Cited by 47 publications

References 29 publications

MET Amplification and Efficacy of Nivolumab in Patients With NSCLC

MET Amplification and Efficacy of Nivolumab in Patients With NSCLC

Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges

Heterogeneity in MET-Aberrant NSCLC

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