Checkpoint inhibitor is active against large cell neuroendocrine carcinoma with high tumor mutation burden

Wang, Victoria E.; Urisman, Anatoly; Albacker, Lee A.; Ali, Siraj M.; Miller, Vincent A.; Aggarwal, Rahul; Jablons, David M.

doi:10.1186/s40425-017-0281-y

Cited by 54 publications

(46 citation statements)

References 24 publications

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“…To our knowledge, this is the first study that employed ctDNA sequencing in SCLC patients using a large gene panel capable of identifying sufficient mutations for subclonal analysis. Another foreseen advantage of a large gene panel is a more accurate estimation of tumor mutation burden (TMB), a potential biomarker for response to immune checkpoint blockade in many cancer types 37 – 41 . Recently presented early phase clinical trials have shown encouraging activity of immune checkpoint blockade in treatment of SCLC patients 42 – 44 , and high TMB has been demonstrated to be associated with superior response and prolonged survival in SCLC 45 .…”

Section: Discussionmentioning

confidence: 99%

Circulating tumor DNA analysis depicts subclonal architecture and genomic evolution of small cell lung cancer

et al. 2018

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Subclonal architecture and genomic evolution of small-cell lung cancer (SCLC) under treatment has not been well studied primarily due to lack of tumor specimens, particularly longitudinal samples acquired during treatment. SCLC is characterized by early hematogenous spread, which makes circulating cell-free tumor DNA (ctDNA) sequencing a promising modality for genomic profiling. Here, we perform targeted deep sequencing of 430 cancer genes on pre-treatment tumor biopsies, as well as on plasma samples collected prior to and during treatment from 22 SCLC patients. Similar subclonal architecture is observed between pre-treatment ctDNA and paired tumor DNA. Mean variant allele frequency of clonal mutations from pre-treatment ctDNA is associated with progression-free survival and overall survival. Pre- and post-treatment ctDNA mutational analysis demonstrate that mutations of DNA repair and NOTCH signaling pathways are enriched in post-treatment samples. These data suggest that ctDNA sequencing is promising to delineate genomic landscape, subclonal architecture, and genomic evolution of SCLC.

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Section: Discussionmentioning

confidence: 99%

Circulating tumor DNA analysis depicts subclonal architecture and genomic evolution of small cell lung cancer

et al. 2018

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“…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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“…reported a single case of pulmonary LCNEC in 2017 with an exceptional response to a first dose of pembrolizumab. The patient was continuing treatment at the time of publication of the case study so the duration of response cannot be determined [ 3 ].…”

Section: Resultsmentioning

confidence: 99%

Immune checkpoint inhibitors in large cell neuroendocrine carcinoma: current status

et al. 2018

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IntroductionLarge cell neuroendocrine carcinomas (LCNEC) are a group of rare high grade neuroendocrine tumors that often behave clinically like small cell carcinoma (SCLC) and are treated as such. No major advancement in the management of these tumors has occurred in the last 30 years.MethodsWe present a case series of three cases from Markey Cancer center along with a review of 13 published cases in the literature wherein immune-checkpoint inhibitors were utilized in the management of LCNEC.ResultsImmune-checkpoint inhibitors might have clinical activity in LCNEC.ConclusionRole of immune-checkpoint inhibitors should be explored in prospective LCNEC clinical trials. We summarize current evidence regarding use of immune checkpoint inhibitors in the treatment of LCNEC.

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Checkpoint inhibitor is active against large cell neuroendocrine carcinoma with high tumor mutation burden

Cited by 54 publications

References 24 publications

Circulating tumor DNA analysis depicts subclonal architecture and genomic evolution of small cell lung cancer

Circulating tumor DNA analysis depicts subclonal architecture and genomic evolution of small cell lung cancer

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

Immune checkpoint inhibitors in large cell neuroendocrine carcinoma: current status

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