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Incidence rates of Merkel cell carcinoma (MCC), an uncommon skin cancer with an aggressive disease course, have increased in recent decades. Limited treatment options are available for patients with metastatic MCC (mMCC). Avelumab, an anti-programmed cell death-ligand 1 monoclonal antibody, became the first approved treatment for mMCC after the results of the phase 2 JAVELIN Merkel 200 study. Prior to its regulatory approval, an expanded access program (EAP) enabled compassionate use of avelumab in patients with mMCC. Here we report findings from patients enrolled in the EAP in Europe and the Middle East. Efficacy and safety data were provided at the discretion of treating physicians. Between March 2, 2016, and December 22, 2018, 403 requests for avelumab were received from 21 countries, and avelumab was supplied to 335 patients. Most patients (96.7%) received avelumab as second-line or later treatment. In 150 patients for whom response data were available, the objective response rate was 48.0%, and in responding patients, median duration of treatment was 7.4 months (range, 1.0-41.7 months). The most common treatment-related adverse events were infusion-related reaction (2.4%) and pyrexia (2.1%), and no new safety signals were observed. Overall, results from European and Middle Eastern patients enrolled in this EAP confirm the efficacy and safety of avelumab treatment observed in previous studies in patients with mMCC., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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.

Background and Purpose: Combined mTORC1 inhibition with everolimus (EVE) and phosphatidylinositol 3-kinase catalytic subunit p110α blockade with alpelisib (ALP) has demonstrated synergistic efficacy in preclinical models and supports testing the combination of ALP and EVE in the clinical setting. The primary objective was to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of ALP in combination with EVE and in combination with EVE and exemestane (EXE) and subsequently assess safety, preliminary efficacy and effect of ALP on the pharmacokinetics of EVE and determine the magnitude of the drug-drug interaction., Patients and Methods: Dose escalation phases were conducted in patients with advanced solid tumours and in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). The dose expansion phase was conducted in patients with pancreatic neuroendocrine tumour and renal cell carcinoma (RCC) (both mechanistic target of rapamycin inhibitor [mTORi]-naive), in patients with mTORi-pretreated solid tumours and in postmenopausal women with HR+, HER2- ABC., Results: During the doublet escalation phase, dose-limiting toxicities (DLTs) were reported in 5 of 10 (50%) patients: one patient had grade (Gr) 2 hyperglycemia and one patient had Gr 3 diarrhoea in the 300 mg dose group, one patient had Gr 2 hyperglycemia and one patient had Gr 4 hypocalcaemia in the 250 mg dose group, and one patient in the 200 mg dose group had Gr 3 diarrhoea and Gr 3 stomatitis. The combination of ALP 250 mg + EVE 2.5 mg was declared as the MTD/RDE in subjects with advanced solid tumours. In the triplet escalation phase, one patient who received ALP 200 mg + EVE 2.5 mg + EXE 25 mg had a DLT of Gr 3 acute kidney injury. This dose combination was declared as the MTD and RDE in subjects with advanced HR-positive HER2-negative BC. The common adverse events (≥30% patients), occurring across all phases, were hyperglycaemia, stomatitis, diarrhoea, nausea, asthenia, decreased appetite and fatigue. The sixteen-week progression-free survival rate was 52.4% (90% confidence interval [CI]: 32.8, 71.4) in the RCC cohort, 35.3% (90% CI: 16.6, 58.0) in the prior pNET cohort and 30.0% (90% CI: 8.7, 60.7) in the prior mTORi cohort. The pharmacokinetics of 2.5 mg of EVE was largely unchanged in the presence of ALP, independent of the dose (250 mg or 300 mg). There were no clinically relevant drug-drug interactions observed between ALP and EVE., Conclusion: The overall safety profile of ALP with EVE and EXE is manageable and reversible; no unexpected safety signals were noted compared with the individual safety profiles. Pharmacokinetics of ALP, EVE and EXE was largely unchanged in combination with each other., Competing Interests: Conflict of interest statement G.C. reports personal fees from Pfizer, personal fees from Novartis, personal fees from Lilly, personal fees from Seagen, personal fees from Amgen, personal fees from Roche, personal fees from AstraZeneca and personal fees from Daiichi Sankyo, outside the submitted work. M.M. reports personal fees from AstraZeneca, grants and personal fees from Roche, personal fees from Lilly, grants and personal fees from Puma, grants and personal fees from Novartis, personal fees from Taiho Oncology, personal fees from Pfizer, personal fees from PharmaMar and personal fees from Daiichi Sankyo, outside the submitted work. K.J. reports grants and personal fees from Novartis, personal fees from Spectrum Pharmaceuticals, grants and personal fees from ADC Therapeutics, grants and personal fees from Pfizer, personal fees from Bristol Myers Squibb, personal fees from Jounce Therapeutics, personal fees from Taiho Oncology, grants and personal fees from Genentech, personal fees from Synthon, personal fees from AbbVie, personal fees from Eisai, grants from Clovis Oncology, grants from AstraZeneca, grants from Novita Pharmaceuticals, grants from Debiopharm, grants from Lilly, grants from Zymeworks, grants from Immunomedics and grants from Puma Biotechnology, outside the submitted work. J.T.B. reports grants from AbbVie, grants from Alliance, grants from Amgen, grants from Ascentage Pharma Group, grants from AstraZeneca, grants from Bayer, grants from Boston Biomedical, grants from Bristol Myers Squibb, grants from Celgene, grants from Eli Lilly, grants from Genentech-Roche, grants from Hutchison, grants from Immunomedics, grants from Janssen, grants from MT Group, grants from Nektar, grants from Pfizer, grants from Polynoma, grants from Seattle Genetics, grants from EMD Serono, grants from Tesaro, grants from TG Therapeutics, grants from Biodesix and grants from Exact Sciences, during the conduct of the study. G.T. declared no conflict of interest. N.F. reports honoraria from Novartis, Ipsen, Merck, Sanofi-Aventis and Advanced Accelerator Applications; consulting or advisory role in Novartis/Ipsen, Advanced Accelerator Applications, Pfizer, Ipsen, Merck Serono, MSD Oncology and Wren Laboratories, Europe; research funding from Novartis (Inst), Merck Serono (Inst), Ipsen (Inst) and MSD (Inst) and other relationship with Springer and II Pensiero Scientifico Editore. M.M. and R.A.H. declared no conflict of interest. H.L. reports grants, personal fees and non-financial support from Novartis, personal fees and non-financial support from Ipsen and personal fees and non-financial support from Pfizer, during the conduct of the study. V.D. is a Novartis employee and declared no conflict of interest. O.A. is a Novartis employee and declared no conflict of interest. Z.L. is a Novartis employee and declared no conflict of interest. L.B. is a Novartis employee and declared no conflict of interest. F.A. reports grants from Novartis, during the conduct of the study, grants from Pfizer, grants from Roche, grants from Daiichi, grants from Eli Lilly and grants from Astra Zeneca, outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To review the therapeutic strategy in Merkel cell carcinoma (MCC) treated with radiotherapy (RT) discussed in a multidisciplinary tumour board., Methods: Clinical records of patients with a diagnosis of MCC and with an indication to undergo RT at the European Institute of Oncology between 2003 and 2018 were reviewed retrospectively., Results: Twenty-six patients were included in the analysis (median age 65 years, range 42-87). Nineteen received adjuvant RT, 4 exclusive RT, and the remainder palliative RT. Intensity-modulated RT was used in 13 cases, a 3D conformal technique in 11 cases, and stereotactic RT in 2 cases. No major toxicities were recorded. The median relapse-free survival (RFS) after adjuvant RT was 20.5 months, while for unknown primary MCC, it was 23 months. In the adjuvant setting, median polyomavirus-positive RFS was 21.5 months (range 1-49) and median polyomavirus-negative RFS was only 14 months (range 4-45). Overall, RFS of polyomavirus-positive and polyomavirus-negative patients was 10.5 and 8 months, respectively. After adjuvant RT, only 1 out of 10 patients had a recurrence in the RT field. At the time of data collection, 16 patients were alive with no evidence of disease, 1 patient was alive with advanced status of disease, 8 patients died of disease progression, and 1 patient died of other causes., Conclusions: The management of unknown primary and polyomavirus-positive cases, which had a better prognosis in our series, may benefit from a multidisciplinary approach, given the limited data available regarding optimal treatment.

Purpose: Peptide receptor radionuclide therapy (PRRT) for the treatment of neuroendocrine tumours (NET) has been explored for almost two decades, but there are still few trials that have exclusively investigated well-differentiated and moderately differentiated NET arising from the respiratory tree. Thus, the aim of this study was to explore the outcome in patients affected by bronchopulmonary carcinoid (BPC) following PRRT., Methods: We retrospectively analysed 114 patients with advanced stage BPC consecutively treated with PRRT at the European Institute of Oncology, Milan, from 1997 to 2012 and followed until October 2014. The objective responses, overall survival (OS) and progression-free survival (PFS) were rated, and three different PRRT protocols ((90)Y-DOTATOC vs. (177)Lu-DOTATATE vs. (90)Y-DOTATOC + (177)Lu-DOTATATE) were compared with regard to their efficacy and tolerability., Results: The median OS (evaluated in 94 of the 114 patients) was 58.8 months. The median PFS was 28.0 months. The (177)Lu-DOTATATE protocol resulted in the highest 5-year OS (61.4%). Morphological responses (partial responses + minor responses) were obtained in 26.5% of the cohort and were associated with longer OS and PFS. The (90)Y-DOTATOC + (177)Lu-DOTATATE protocol provided the highest response rate (38.1%). Adverse events were mild in the majority of patients. However, haematological toxicity negatively affected survival. No severe (grade 3/4) serum creatinine increase was observed. Patients treated with (90)Y-DOTATOC alone more frequently showed a mild/moderate decrease in renal function. In patients treated with chemotherapy before PRRT had a shorter OS and PFS, and a higher risk of developing nephrotoxicity., Conclusion: In a large cohort of patients with advanced BPC treated in a "real-world" scenario and followed up for a median of 45.1 months (range 2-191 months), PRRT proved to be promising in prolonging survival and delaying disease progression. Despite the potential selection biases, considering the risk-benefit ratio, (177)Lu-DOTATATE monotherapy seems the best option for PRRT. Our results indicate that the use of PRRT in earlier stages of the disease could provide a more favorable outcome.