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Purpose: Approved systemic therapies for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown limited capacity to reduce tumor burden and no antitumor activity after progression to targeted agents (TAs). We investigated the efficacy and safety of lenvatinib in patients with previously treated advanced GEP-NETs., Patients and Methods: This was a multicenter, single-arm, open-label, phase II trial with two parallel cohorts (ClinicalTrials.gov identifier: NCT02678780) involving 21 institutions in 4 European countries. Eligible patients had histologically confirmed advanced grade 1-2 pancreatic (panNET) or GI (GI-NET) NETs with documented tumor progression after treatment with a TA (panNET) or somatostatin analogs (GI-NET). Patients were treated with lenvatinib 24 mg once daily until disease progression or treatment intolerance. The primary end point was overall response rate by central radiology review. Secondary end points included progression-free survival, overall survival, duration of response, and safety., Results: Between September 2015 and March 2017, a total of 111 patients were enrolled, with 55 (panNET) and 56 (GI-NET) patients in each cohort. The median follow-up was 23 months. The overall response rate was 29.9% (95% CI, 21.6 to 39.6): 44.2% (panNET) and 16.4% (GI-NET). The median (range) duration of response was 19.9 (8.4-30.8) and 33.9 (10.6-38.3) months in the panNET and GI-NET groups, respectively. The median progression-free survival was 15.7 months (95% CI, 14.1 to 19.5). The most common adverse events were fatigue, hypertension, and diarrhea; 93.7% of patients required dose reductions or interruptions., Conclusion: We report the highest centrally confirmed response reported to date with a multikinase inhibitor in advanced GEP-NETs, with a particularly strong response in the panNET cohort. This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other TAs, suggesting the potential value of lenvatinib in the treatment of advanced GEP-NETs., Competing Interests: Jaume CapdevilaConsulting or Advisory Role: Bayer, Eisai, Sanofi, Exelixis, Novartis, Ipsen, Pfizer, Merck Serono, Advanced Accelerator Applications, LillySpeakers' Bureau: Bayer, Eisai, Sanofi, Novartis, Ipsen, Pfizer, Merck Serono, LillyResearch Funding: Eisai, AstraZeneca, Advanced Accelerator Applications, Novartis, Ipsen, Bayer, PfizerTravel, Accommodations, Expenses: Pfizer, Ipsen, Eisai Nicola FazioHonoraria: Novartis, Ipsen, Merck, Sanofi, Advanced Accelerator ApplicationsConsulting or Advisory Role: Novartis/Ipsen, Advanced Accelerator Applications, Pfizer, Ipsen, Merck Serono, MSD OncologyResearch Funding: Novartis, Merck Serono, Ipsen, MSDOther Relationship: Springer, Il Pensiero Scientifico Editore Carlos Lopez LopezHonoraria: Roche, Merck, Sanofi, Novartis, Pfizer, Eisai, Ipsen, Bayer, AstraZeneca, Servier, Bristol Myers Squibb, MSD Oncology, Advanced Accelerator ApplicationsConsulting or Advisory Role: Amgen, Roche, Sanofi, Merck, Servier, Pfizer, Ipsen, Bayer, Eisai, AstraZenecaResearch Funding: Amgen, Roche, Merck, Merck Sharp & Dohme, AstraZeneca Spain, Sanofi, Bayer, Ipsen, Eisai, Bristol Myers Squibb, Boehringer IngelheimTravel, Accommodations, Expenses: Roche, Pfizer, Merck, Servier, Amgen, Ipsen Alex TeuleHonoraria: Ipsen, Novartis, AAA HealthCare, PfizerConsulting or Advisory Role: AAA HealthCare Juan ValleHonoraria: IpsenConsulting or Advisory Role: Ipsen, Novartis, AstraZeneca, Merck, Agios, Pfizer, PCI Biotech, Incyte, Keocyt, QED Therapeutics, Pieris Pharmaceuticals, Genoscience Pharma, Mundipharma EDO GmbH, Wren Laboratories, Nucana, Servier, Debiopharm Group, Imaging Equipment Limited, Hutchison MediPharma, Zymeworks, Aptitude Health, Sirtex Medical, BaxterSpeakers' Bureau: Novartis, Ipsen, Nucana, Imaging Equipment Limited, Mylan, IncyteTravel, Accommodations, Expenses: Nucana, Pfizer, Lilly Nicholas ReedHonoraria: Novartis, Ipsen, Eisai, Roche, LillyConsulting or Advisory Role: Novartis, Ipsen, EisaiSpeakers' Bureau: RocheResearch Funding: Novartis, Ipsen, Exelixis, Lilly Enrique GrandeHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, Roche, Eisai, Eusa Pharma, MSD, Genzyme, Advanced Accelerator Applications, Novartis, Pierre Fabre, Lexicon, Celgene, Janssen-Cilag, Astellas Pharma, AstraZeneca, Lilly, EUSA PharmaConsulting or Advisory Role: MSD, Pfizer, Ipsen, Roche, Bristol Myers SquibbResearch Funding: Roche, Pfizer, AstraZeneca, Ipsen, Molecular Templates, Lexicon, Astellas PharmaTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche/Genentech, Pfizer, Janssen-Cilag, Ipsen Rocio Garcia-CarboneroHonoraria: Ipsen, Roche, Sanofi, Servier, Novartis, Pfizer, Merck, PharmaMar, Advanced Accelerator Applications, Bristol Myers Squibb, AstraZeneca, Lilly, Boehringer Ingelheim, Gilead Sciences, Sysmex, Pierre Fabre, Midatech Pharma, Advanz Pharma, HMP, Bayer, MSDConsulting or Advisory Role: Ipsen, Novartis, Pfizer, HMP, Advanced Accelerator Applications, Bayer, PharmaMar, Merck, MSD, Pierre FabreResearch Funding: Pfizer, Bristol Myers Squibb, MSDTravel, Accommodations, Expenses: Roche, Merck Paula J FonsecaOther Relationship: Ipsen Jorge HernandoSpeakers' Bureau: Eisai, Ipsen, Roche, Acraf, Advanced Accelerator ApplicationsTravel, Accommodations, Expenses: Ipsen, Novartis, Advanced Accelerator Applications, Roche, AstraZeneca, Eisai Francesca SpadaConsulting or Advisory Role: Ipsen, Novartis, Advanced Accelerator ApplicationsSpeakers' Bureau: Ipsen, Novartis, Advanced Accelerator ApplicationsTravel, Accommodations, Expenses: Ipsen, Novartis, Advanced Accelerator Applications Vicente AlonsoConsulting or Advisory Role: Amgen, Sanofi/Regeneron, Ipsen, Servier, Merck SeronoTravel, Accommodations, Expenses: Merck Serono, Roche, Novartis, Amgen, Sanofi/Regeneron, Ipsen, Servier Alfredo BerrutiConsulting or Advisory Role: Janssen-Cilag, Astellas Pharma, AmgenSpeakers' Bureau: Janssen-Cilag, Astellas PharmaResearch Funding: Astellas Pharma, Janssen-CilagTravel, Accommodations, Expenses: Janssen-Cilag, Sanofi, Sanofi Adelaida La CastaTravel, Accommodations, Expenses: Amgen, Roche, MSD Oncology Sevilla IsabelConsulting or Advisory Role: Ipsen, Pfizer, AmgenSpeakers' Bureau: Ipsen, PharmaMar, Sanofi, AAA HealthCareTravel, Accommodations, Expenses: Ipsen Patrizia KumpResearch Funding: Bristol Myers SquibbTravel, Accommodations, Expenses: Ipsen Pablo GajateConsulting or Advisory Role: Ipsen, Roche, EisaiSpeakers' Bureau: IPSEN, Pfizer, Novartis, EisaiTravel, Accommodations, Expenses: Ipsen, Pfizer Ignacio MatosSpeakers' Bureau: MSDResearch Funding: ESMO Angela LamarcaConsulting or Advisory Role: EISAI, Nutricia, Ipsen, QED Therapeutics, RocheSpeakers' Bureau: Merck, Ipsen, Pfizer, Novartis, Incyte, Advanced Accelerator ApplicationsResearch Funding: Ipsen, RocheTravel, Accommodations, Expenses: Abbott Nutrition, Ipsen, Pfizer, Celgene, Novartis, Advanced Accelerator Applications, Sirtex Medical, Bayer, Delcath Systems, Mylan, NanoString Technologies Toni IbrahimConsulting or Advisory Role: EISAI, Novartis, SanofiTravel, Accommodations, Expenses: Ipsen, Pharmamar, NovartisNo other potential conflicts of interest were reported.

Competing Interests: The authors have declared that no competing interests exist.

Purpose: To evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA)., Patients and Methods: HALO 109-301 was a phase III, randomized, double-blind, placebo-controlled study. Patients ≥ 18 years of age with untreated, metastatic, hyaluronan-high PDA were randomly assigned 2:1 to PEGPH20 plus AG or placebo plus AG. Treatment was administered intravenously in 4-week cycles (3 weeks on, 1 week off) until progression or intolerable adverse events: PEGPH20 3.0 µg/kg twice per week for cycle 1 and once per week thereafter; nab-paclitaxel 125 mg/m 2 once per week; and gemcitabine 1,000 mg/m 2 once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1., Results: At data cutoff, 494 patients were randomly assigned, with 492 (327 for PEGPH20 and 165 for placebo) included in intention-to-treat analyses. Baseline characteristics were balanced for PEGPH20 plus AG versus placebo plus AG. There were 330 deaths, with a median OS of 11.2 months for PEGPH20 plus AG versus 11.5 months for placebo plus AG (hazard ratio [HR], 1.00; 95% CI, 0.80 to 1.27; P = .97); median PFS was 7.1 months versus 7.1 months (HR, 0.97 [95% CI, 0.75 to 1.26]); ORR was 47% versus 36% (ORR ratio, 1.29 [95% CI, 1.03 to 1.63]). Grade ≥ 3 adverse events with a ≥ 2% higher rate with PEGPH20 plus AG than with placebo plus AG included fatigue (16.0% v 9.6%), muscle spasms (6.5% v 0.6%), and hyponatremia (8.0% v 3.8%)., Conclusion: The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.

In recent years, there have been important scientific advances in the biologic characterization of neuroendocrine neoplasms and in their treatment. This review will describe these scientific advances, the evolving systemic treatment approaches, and important topics to be addressed in future research.

Purpose: Knowledge of clinical course of pancreatic endocrine carcinomas (PECs) is poor. This study aimed to determine the time to progression of advanced PECs, and to identify predictors capable of selecting subgroups with higher risk of progression., Patients and Methods: In this multicenter retrospective analysis, patients with advanced PECs were enrolled. Staging was according to European Neuroendocrine Tumors Society guidelines. Grading was based on proliferation index using Ki67 immunohistochemistry. The primary end point was progression-free survival (PFS), which was assessed using the Kaplan-Meier method. The Cox regression proportional hazard model was used to identify predictors for tumor progression., Results: Two hundred two patients with PECs were enrolled, including 172 with well-differentiated and 30 with poorly differentiated endocrine carcinomas. There were 34 patients with stage III and 168 with stage IV tumors. G1 tumors were present in 19.7% of patients, whereas 60.1% of patients had G2 tumors, and the remaining 20.2% had G3 tumors. Disease progression occurred in 166 patients (82.2%), at a median interval of 10 months (interquartile range, 5 to 22) from diagnosis. Median PFS was 14 months. Different PFS were observed depending on G grade (P < .001) and tumor differentiation (P < .001) and in patients who did not receive any antitumor treatment (P = .002). The major risk factor for progression was the proliferation index Ki67 (hazard ratio, 1.02 for each increasing unit; P < .001). Overall 5-year survival was 44.1%., Conclusion: The vast majority of patients with advanced PECs undergo disease progression. The major risk factor for progression is Ki67 index, which should lead physicians dealing with PECs to plan appropriate follow-up programs and therapeutic strategies.

Purpose: This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy., Patients and Methods: Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric carcinoma, a performance status