P1.07-012 Efficacy of Immune Checkpoint Inhibitors in Large Cell Neuroendocrine Lung Cancer: Results from a French Retrospective Cohort

Levra, Matteo Giaj; Mazières, Julien; Valette, C. Audigier; Molinier, Olivier; Planchard, David; Frappat, V; Ferrer, L.; Toffart, Anne Claire; Moro‐Sibilot, D.

doi:10.1016/j.jtho.2016.11.923

Cited by 41 publications

(26 citation statements)

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“…In LCNEC, checkpoint blockade therapy showed encouraging results on a retrospective multicenter cohort involving 10 patients (five of them receiving third-line treatment, all in good performance [0-1]), with six partial responses and a long progression-free survival for the overall cohort (median 57 weeks [range ). 85 PD-L1 in a study on early-stage LCNEC was expressed in up to 34% of tumors (n ¼ 72), 86 but this frequency is much lower in other cohorts (10.4% and 0% in two series of 106 and 11, respectively). 81,82 The mutational burden is very high in LCNEC (>8 mutations/Mb) and is related to PD-L1 expression.…”

Section: Lcnecmentioning

confidence: 89%

New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management

Derks

Leblay

Lantuéjoul

et al. 2018

Journal of Thoracic Oncology

117

103

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Carcinoids and large cell neuroendocrine carcinomas (LCNECs) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g., menin 1 gene [MEN1]), and few affect genes of the phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin gene pathway. Aggressive disease has been related to chromothripsis, DNA-repair gene mutations, loss of orthopedia homeobox/CD44, and upregulation of ret proto-oncogene gene (RET) gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with biallelic inactivation of tumor protein p53 gene (TP53) and retinoblastoma gene (RB1), a hallmark of SCLC; and the other one with biallelic inactivation of TP53 and serine/threonine kinase 11 gene (STK11)/kelch like ECH associated protein 1 gene (KEAP1), genes that are frequently mutated in NSCLC. These data, together with the identification of common mutations in the different components of combined LCNEC tumors, provide further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mechanistic target of rapamycin pathway mutations and response to mechanistic target of rapamycin inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, delta like Notch canonical ligand 3 inhibitors and immunotherapy may provide alternative options for patient-tailored therapy in LCNEC.

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Section: Lcnecmentioning

confidence: 89%

New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management

Derks

Leblay

Lantuéjoul

et al. 2018

Journal of Thoracic Oncology

117

103

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“…The mPFS was 57 weeks. These data seem to demonstrate a promising activity of immunotherapy in this setting [73].…”

Section: Lcnec Typical and Atypical Carcinoidmentioning

confidence: 63%

Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia

Maggio

Manuzzi

Ricci

et al. 2020

Cancers

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Background: Neuroendocrine neoplasms are rare entities consisting of a heterogeneous group of tumors that can originate from neuroendocrine cells present in the whole body. Their different behavior, metastatic potential, and prognosis are highly variable, depending on site of origin, grade of differentiation, and proliferative index. The aim of our work is to summarize the current knowledge of immunotherapy in different neuroendocrine neoplasms and its implication in clinical practice. Results: Several studies evaluated the efficacy and safety of immunotherapy in neuroendocrine neoplasms, in any setting of treatment, alone or in combination. Studies led to approval in neuroendocrine neoplasia of the lung, in combination with chemotherapy as first-line treatment or as a single-agent in a third-line setting, and Merkel cell carcinoma as a single agent. Results in other settings have been disappointing so far. Conclusions: Immunotherapy seems a valid treatment option for high grade, poorly differentiated neoplasms. Future trials should explore the combination of immunotherapy with other agents, such as anti-angiogenic or other immunotherapy agents, in order to evaluate potential efficacy in low and intermediate grades, well differentiated tumors.

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“…Patients with large-cell lung NEC (LCNEC) at stage IIIB-IV were treated with nivolumab (n = 9) or pembrolizumab (n = 1) after platinum-based first-line therapy [44]. After a median of 16 cycles, 6 (60%) patients showed a PR, 1 (10%) had stable disease (SD).…”

Section: Clinical Experience With Checkpoint Inhibitors In Nensmentioning

confidence: 99%

“…The median PFS was 57 (interquartile range, 24-57) weeks. Most of the patients stopped treatment due to disease progression, 1 due to pulmonary interstitial pneumonia [44]. A case report described a heavily pretreated patient with PD-L1-positive LCNEC stage IB who achieved a significant and durable response with pembrolizumab [45].…”

Section: Clinical Experience With Checkpoint Inhibitors In Nensmentioning

confidence: 99%

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

Weber

Fottner²

2018

Oncol Res Treat

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Background: Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. Method: Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. Results: Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. Conclusion: Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load.

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P1.07-012 Efficacy of Immune Checkpoint Inhibitors in Large Cell Neuroendocrine Lung Cancer: Results from a French Retrospective Cohort

Cited by 41 publications

References 0 publications

New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management

New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management

Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

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