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Sten Myrehaug, David L Chan, Victor Rodriguez-Freixinos, Hans Chung, Julie Hallet, Calvin Law, Chirag Patel, Laurent Milot, John Hudson, Hanbo Chen, and Simron Singh

Liver metastases are common in patients with neuroendocrine tumors. For patients, management must balance disease control with consideration of toxicity, given limited treatment options. Everolimus has demonstrated effectiveness in neuroendocrine neoplasms. Given emerging data of a synergistic effect with radiation therapy, we evaluated combined Everolimus and radiation for neuroendocrine liver metastases. This single-arm, single centre prospective pilot study evaluated the safety and efficacy of combined everolimus and radiotherapy for well-differentiated neuroendocrine liver metastases. Patients with unresectable liver metastases received everolimus for 30 days, followed by concurrent everolimus and liver radiotherapy, then a further 14 days of everolimus. Tolerability was evaluated using the CTCAE v.4.03. Individual metastasis response rate and local control were measured by RECIST v1.1. Overall survival, progression-free survival and freedom from change in systemic therapy were estimated by the Kaplan-Meier method. 40 metastases were treated in 14 patients. No Grade 3 or higher toxicities were identified in the concurrent treatment phase; 8 grade 2 toxicity and 1 patient develped grade 3 toxicity in the post-radiation phase. Overall response rate was 38%. One and 2-year local control was 97% and 71%. Median progression free survival was 12 months. One and 2-year overall survival were 100% and 92%. In conclusion, combined everolimus and radiation is well-tolerated for neuroendocrine liver metastases and is associated with excellent local control. The approach of selective local ablation of oligometastatic or oligoprogressive disease warrants further evaluation in this patient population.

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James Yao, Abhishek Garg, David Chen, Jaume Capdevila, Paul Engstrom, Rodney Pommier, Eric Van Cutsem, Simron Singh, Nicola Fazio, Wei He, Markus Riester, Parul Patel, Maurizio Voi, Michael Morrissey, Marianne Pavel, and Matthew Helmut Kulke

Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.

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James C Yao, Jonathan Strosberg, Nicola Fazio, Marianne E Pavel, Emily Bergsland, Philippe Ruszniewski, Daniel M Halperin, Daneng Li, Salvatore Tafuto, Nitya Raj, Davide Campana, Susumu Hijioka, Markus Raderer, Rosine Guimbaud, Pablo Gajate, Sara Pusceddu, Albert Reising, Evgeny Degtyarev, Mark Shilkrut, Simantini Eddy, and Simron Singh

Spartalizumab, a humanized anti-programmed death protein 1 (PD-1) MAB, was evaluated in patients with well-differentiated metastatic grade 1/2 neuroendocrine tumors (NET) and poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC). In this phase II, multicenter, single-arm study, patients received spartalizumab 400 mg every 4 weeks until confirmed disease progression or unacceptable toxicity. The primary endpoint was confirmed overall response rate (ORR) according to blinded independent review committee using response evaluation criteria in solid tumors 1.1. The study enrolled 95 patients in the NET group (30, 32 and 33 in the thoracic, gastrointestinal, and pancreatic cohorts, respectively), and 21 patients in the GEP-NEC group. The ORR was 7.4% (95% CI: 3.0, 14.6) in the NET group (thoracic, 16.7%; gastrointestinal, 3.1%; pancreatic, 3.0%), which was below the predefined success criterion of ≥10%, and 4.8% (95% CI: 0.1, 23.8) in the GEP-NEC group. In the NET and GEP-NEC groups, the 12-month progression-free survival was 19.5 and 0%, respectively, and the 12-month overall survival was 73.5 and 19.1%, respectively. The ORR was higher in patients with ≥1% PD-L1 expression in immune/tumor cells or ≥1% CD8+ cells at baseline. The most common adverse events considered as spartalizumab-related included fatigue (29.5%) and nausea (10.5%) in the NET group, and increased aspartate and alanine aminotransferases (each 14.3%) in the GEP-NEC group. The efficacy of spartalizumab was limited in this heterogeneous and heavily pre-treated population; however, the results in the thoracic cohort are encouraging and warrants further investigation. Adverse events were manageable and consistent with previous experience.