Sustained partial remission of a metastatic NEN using off-label immunotherapy with pembrolizumab

Stüven, Anna Kathrin; Wiedenmann, Bertram

doi:10.18632/oncotarget.26906

Cited by 6 publications

(5 citation statements)

References 49 publications

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“…We have already reported [ 34 ] about a 55-year-old male patient, who was diagnosed with a non-functional SSR-positive NET G2 of the pancreatic tail with invasion of the spleen and synchronous SSR negative bilobar liver metastases, which progressed into a NEC (Ki-67 > 50%) with additional metastasis to kidney, adrenals, peritoneum, and lymph nodes.…”

Section: Individual Case Presentationmentioning

confidence: 99%

PD-L1 – inhibitors in neuroendocrine neoplasia

et al. 2021

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Immune check-point inhibitors (ICIs) have changed our view on how to treat cancer. Despite their approval in treatment of many different cancers, efficacy of immune check-point inhibitors (ICI) in neuroendocrine neoplasia is limited and poorly understood. Established treatment options of neuroendocrine tumors (NET) and neuroendocrine carcinomas (NECs) are based on surgery, tumor-targeted medical treatments, Peptide Receptor Radionuclide Therapy (PRRT), and locoregional therapies. However, in many patients these treatments lose efficacy over time, and novel therapies are urgently needed. We report on 8 patients diagnosed with neuroendocrine neoplasms (NEN) that were treated with ICI (pembrolizumab, avelumab, nivolumab plus ipilimumab) as salvage therapy. In this cohort, we observed tumor response with partial remission in 3 patients and stable disease in 1 patient. Four patients showed progressive disease. Of note, responses were observed both in PD-L1 positive and PD-L1 negative patients. Here, we discuss clinical courses of these patients in the context of available literature to highlight limitations and drawbacks currently preventing the use of ICI in routine management of patients with NEN.

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Section: Individual Case Presentationmentioning

confidence: 99%

PD-L1 – inhibitors in neuroendocrine neoplasia

et al. 2021

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“…If so, this might also explain why first clinical trials with checkpoint inhibitors in NEN failed but significant benefit has been reported in individual patients. Incidentally, one of the patients with high FLT3LG tissue mRNA expression benefited substantially from treatment with a checkpoint inhibitor started 13 months after surgery [22]. In addition, high circulating Flt3L was detected in a blood sample of this patient obtained during the remission phase that followed treatment initiation.…”

Section: Discussionmentioning

confidence: 89%

“…While much-anticipated first clinical trials with immune checkpoint inhibitors in NEN have been disappointing [17], subgroup analyses have suggested more favorable response profiles in high grade NEN [18,19]. Furthermore, a growing number of case reports suggest that individual patients benefit substantially [20][21][22], creating an urgent need to better understand NEN immune control and evasion, especially in patients with advanced aggressive disease, who have otherwise run out of established therapeutic options [23].…”

Section: Introductionmentioning

confidence: 99%

Elevated Flt3L Predicts Long-Term Survival in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

Detjen

Otto

Giesecke

et al. 2021

Cancers

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Background: The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features. Methods: We evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN. Results: We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients’ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue. Conclusions: We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.

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“…Cases of activity of PD-1/PD-L1 immune checkpoint inhibition are mainly reported in NECs [89][90][91]. The phase II spartalizumab trial also includes a cohort of patients with well-differentiated gastrointestinal (N = 30) and pancreatic NET (N = 30) and a cohort of patients with poorly differentiated GEP-NEC (N = 20).…”

Section: Immunotherapy In Gastroenteropancreatic Nensmentioning

confidence: 99%

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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Sustained partial remission of a metastatic NEN using off-label immunotherapy with pembrolizumab

Cited by 6 publications

References 49 publications

PD-L1 – inhibitors in neuroendocrine neoplasia

PD-L1 – inhibitors in neuroendocrine neoplasia

Elevated Flt3L Predicts Long-Term Survival in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia

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