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Background and Aim: Trial designs using multiple primary endpoints (MPEs) are increasing in phase III cancer trials. Our objectives were to describe the incidence of MPEs in recently published phase III trials testing systemic treatments in patients with advanced cancer; the main characteristics of trials adopting MPEs; the presence of mature results for all endpoints in the primary publication; consistency between results of each endpoint and authors' conclusions., Methods: Articles of randomised phase III trials conducted in patients with advanced cancer, published between 2017 and 2020, were retrieved from PubMed. The main outcome was the proportion of trials with MPEs. In principle, according to regulatory agencies, we considered two distinct cases: (i) MPEs correspond to 'multiple chances' for the success of experimental treatment, needing adjustment for multiplicity, and (ii) a positive result depends on the success in all MPEs ('co-primary' endpoints)., Results: Out of 235 eligible trials, 27 trials (12%) adopted MPE, mostly overall survival (OS) and progression-free survival (PFS). The proportion of trials with MPEs increased over time, from 6% in 2017 to 20% in 2020 (p = 0.025). MPEs were adopted in 16% of for-profit trials versus 4% of non-profit trials (p = 0.006). The proportion of trials adopting MPEs was particularly high with immunotherapy (53%, p < 0.00001). Out of 27 trials with MPEs, 10 (37%) adopted an explicit definition of 'co-primary' endpoints, but only 1/10 declared the positivity of both endpoints critical for interpretation. Most trials (23, 85%) planned correction for multiplicity. Of 21 publications with positive conclusions, only 12 had a statistically significant positive result in both primary endpoints. In four cases (15%), positive conclusions were based on PFS results alone., Conclusions: Adoption of MPEs in randomised trials in oncology is quite common. Only a minority of trials respect recommendations by regulatory agencies about the adoption of MPEs, definition of 'co-primary' endpoints and correction for multiplicity., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Maria Lucia Reale had a role as a consultant for Eli-Lilly, outside the submitted work. Francesco Perrone reports grants, personal fees and non-financial support from Bayer, personal fees from Sandoz, grants and personal fees from Incyte, personal fees from Celgene, grants and personal fees from Astra Zeneca, personal fees from Pierre Fabre, personal fees from Janssen Cilag, grants from Roche, grants from Pfizer, outside the submitted work.Massimo Di Maio received honoraria and had roles as consultant or advisor for AstraZeneca, Pfizer, Novartis, Roche, Takeda, Eisai, Janssen, Astellas; received institutional research grant by Tesaro – GlaxoSmithKline, outside the submitted work. All remaining authors declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600EBRAF- mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting., Methods: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests., Results: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001)., Conclusions: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies., Competing Interests: Conflict of interest statement The authors declare no conflict of interest regarding the publication of this article. Matteo Fassan received research grant from Astellas Pharma and QED Therapeutics and is a consultant/advisory board member for Astellas Pharma, Diaceutics, Tesaro and GSK. Fotios Loupakis received lecture fees from Amgen and F. Hoffmann-La Roche and advisory fees from Bayer and Genentech. Sara Lonardi received advisory board fees from Amgen, Bayer, Eli Lilly, and Merck Serono, received research grant from Amgen and Merck Serono and is part of the speakers' bureau of Lilly and BMS. Angelo Paolo Dei Tos declares personal fees for advisory boards/speaker's bureau from PharaMar, Lilly, Roche, Bayer and Pfizer. Filippo Pietrantonio declared honoraria/speaker's bureau from Roche, Amgen, Merck-Serono, Lilly, Sanofi, Bayer and Servier and research grant from BMS. Chiara Cremolini is a consultant/advisory board member for Roche, Amgen, Bayer, Merck Serono and Servier. Massimo Di Maio received honoraria, had roles as a consultant or advisor for AstraZeneca, Bristol Myears Squibb, MSD, Takeda and Janssen and received a research grant from Tesaro. Vittorina Zagonel received honoraria and had roles as a consultant or advisor for Bristol-Myears Squibb, Bayer, Roche, Pfizer, Janssen, Novartis, Astellas and Servier and had roles as a consultant or advisor for Celgene and Merck. Lorenza Rimassa reports personal fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, Celgene, Eisai, Eli Lilly, Exelixis, Hengrui, Incyte, Ipsen, Merck Sharp & Dohme, Nerviano Medical Sciences, Roches Sanofi, AbbViem Gilead and reearch grants from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Eli Lilly, Exelixis, FibroGen, Incyte, Ipsen, Merck Sharp & Dohme and Roche. Giuseppe Aprile reports receiving personal fees and has been a consultant for Merck Serono, Amgen, Roche and Servier., (Copyright © 2021 Elsevier Ltd. All rights reserved.)