PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers

Sabari, Joshua K.; Leonardi, Giulia C.; Shu, Catherine A.; Umeton, Renato; Montecalvo, Joseph; Ni, Ai; Chen, R.; Dienstag, Jordan; Mrad, Chebli; Bergagnini, Isabella; Lai, W. Victoria; Offin, Michael; Arbour, Kathryn C.; Plodkowski, Andrew J.; Halpenny, Darragh; Paik, Paul K.; Li, B.T.; Riely, Gregory J.; Kris, Mark G.; Rudin, Charles M.; Sholl, Lynette M.; Nishino, Mizuki; Hellmann, Matthew D.; Rekhtman, Natasha; Awad, Mark M.; Drilon, Alexander

doi:10.1093/annonc/mdy334

Cited by 247 publications

(237 citation statements)

References 26 publications

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“…In this study, we show that with our custom-made DNA-based NGS approach, we prospectively find METex14del mutations in 2 % (32/ 1497) of non-squamous NSCLC, in line with previous studies [5,[8][9][10][11][12][13][14].…”

Section: Discussionsupporting

confidence: 91%

“…However, in contrast to previous studies, we describe a predominantly male population, which may reflect the uncertainty whether there is any sex predominance in the METex14del population. Several studies have shown that non-squamous NSCLC patients with METex14del seem to exhibit an impressive response to cMET TKIs [10,[16][17][18][19][20][32][33][34], in contrast to the response to PD-(L)1 inhibition [13]. In this study, 11/36 received cMET inhibition in either a phase I/II clinical trial or in named patient base program of which 5 were treated with crizotinib in a named patient base program, resulting in 3 partial responses and 1 stable disease for 4, 6, 12 and 14 months, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of exon 14 skipping is the expression of a constitutively active cMET receptor with impaired degradation and consequently induction of cell proliferation and tumor growth [6][7][8]. METex14del is shown in 1.3 %-5.7 % of NSCLC patients based on both RNA and DNA tests using RT-PCR or Next Generation Sequencing (NGS) [5,[8][9][10][11][12][13][14]. This alteration has been described as a potential oncogenic driver, showing mostly mutual exclusiveness with other oncogenic driver mutations [5,12,15].…”

Section: Introductionmentioning

confidence: 99%

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Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

et al. 2020

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The oncogenic MET exon 14 skipping mutation (METex14del) is described to drive 1.3 %-5.7 % of non-small-cell lung cancer (NSCLC) and multiple studies with cMET inhibitors show promising clinical responses. RNA-based analysis seems most optimal for METex14del detection, however, acquiring sufficient RNA material is often problematic. An alternative is DNA-based analysis, but commercially available DNA-based panels only detect up to 63 % of known METex14del alterations. The goal of this study is to describe an optimized DNA-based diagnostic test for METex14del in NSCLC, including clinical features and follow-up of patients treated with cMET-targeted therapy and consequent resistance mechanisms. Material and methods: Routinely processed diagnostic pathology non-squamous NSCLC specimens were investigated by a custom-made DNA-based targeted amplicon-based next generation sequencing (NGS) panel, which includes 4 amplicons for METex14del detection. Retrospectively, histopathological characteristics and clinical follow up were investigated for advanced non-squamous NSCLC with METex14del. Results: In silico analysis showed that our NGS panel is able to detect 96 % of reported METex14 alterations. METex14del was found in 2 % of patients with non-squamous NSCLC tested for therapeutic purposes. In total, from May 2015-Sep 2018, METex14del was found in 46 patients. Thirty-six of these patients had advanced nonsquamous NSCLC, they were predominantly elderly (76.5 years [53-90]), male (25/36) and (ex)-smokers (23/ 36). Five patients received treatment with crizotinib (Pfizer Oncology), in a named patient based program, disease control was achieved for 4/5 patients (3 partial responses, 1 stable disease) and one patient had a mixed response. Two patients developed a MET D1228N mutation during crizotinib treatment, inducing a resistance mechanism to crizotinib. Conclusions: This study shows that METex14del can be reliably detected by routine DNA NGS analysis. Although a small cohort, patients responded well to targeted treatment, underlining the need for routine testing of METex14del in advanced non-squamous NSCLC to guarantee optimal personalized treatment.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

et al. 2020

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“…Defects in these molecules and an increased canonical signaling have recently been shown to be associated with intrinsic and/or acquired resistance to PD-1/PD-L1 inhibition [121][122][123][124]. A systematic meta-analysis revealed that a high TMB could also predict the improved efficacy of iCPI in cancers suggesting that targeted next generation sequencing for estimating TMB might be standardized to eliminate heterogeneity [125,126].…”

Section: State Of the Art Pd-1/pd-l1 Based Immunotherapy And Therapy mentioning

confidence: 99%

Basis of PD1/PD-L1 Therapies

Seliger

2019

JCM

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It is obvious that tumor cells have developed a number of strategies to escape immune surveillance including an altered expression of various immune checkpoints, such as the programmed death-1 receptor (PD-1) and its ligands PD-L1 and PD-L2. The interaction between PD-1 and PD-L1 results in an activation of self-tolerance pathways in both immune cells as well as tumor cells. Thus, these molecules represent excellent targets for T cell-based immunotherapies. However, the efficacy of therapies using checkpoint inhibitors is variable and only a limited number of patients receive a long-term response, while others develop resistances. Therefore, a better insight into the constitutive expression levels and their control as well as the predictive and prognostic value of PD-1/PD-L1, which are controversially discussed due to the methodological assessment, the dynamic and time-related variable expression of these molecules, is urgently required. In this review, the current knowledge of the PD-L1 and PD-1 genes, their expression in immune and tumor cells, the underlying molecular mechanisms of their regulation and their association with clinical parameters and therapy responses are summarized.

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“…This may be important in tumors with MET exon 14 alternations as they response more poorly to immune check point inhibitors. However, in a study where tumor samples with MET exon 14-alterations were available for assessment of PD-L1 status, outcomes with PD-1 blockade were poorer than for unselected patients (33). The authors also found treatment outcomes were not better in tumors with higher PD-L1 expression.…”

Section: C-met and Immune Evasionmentioning

confidence: 95%

The Emerging Role of the c-MET-HGF Axis in Non-small Cell Lung Cancer Tumor Immunology and Immunotherapy

et al. 2020

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Study of the c-Met-HGF axis in non-small cell lung cancer (NSCLC) has focused on the roles of c-MET signaling in neoplastic epithelial cells and the secretion of its ligand hepatocyte growth factor (HGF) by tumor stromal cells. However, there is increasing evidence that some leukocyte subsets also express c-MET raising the possibility of an immunomodulatory role for this axis. Consequently, the role of the c-MET-HGF axis in immunoncology is an active area of ongoing research. This review summarizes current knowledge of c-MET expression in NSCLC, the prognostic significance of these findings and the mechanisms by which the c-MET-HGF axis might act in NSCLC, focusing on the emerging evidence for an immunoregulatory role.

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PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers

Abstract: A substantial proportion of MET exon 14-altered lung cancers express PD-L1, but the median TMB is lower compared with unselected NSCLCs. Occasional responses to PD-1 blockade can be achieved, but overall clinical efficacy is modest.

Cited by 247 publications

References 26 publications

Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

Basis of PD1/PD-L1 Therapies

The Emerging Role of the c-MET-HGF Axis in Non-small Cell Lung Cancer Tumor Immunology and Immunotherapy

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