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We describe the case of an 80-year-old man with sporadic right pheochromocytoma who developed metastatic disease six years after initial diagnosis. Despite adequate blood pressure control and initial biochemical cure criteria after surgery, elevated chromogranin A levels were detected during routine screening, which anticipated elevated 24-h urine metanephrines. Subsequent imaging tests revealed metastatic lesions in the lungs, liver, prostate and lymph nodes. The patient underwent systemic treatment with [131I] MIBG, which resulted in a decrease in chromogranin A levels, achieving radiological and clinical stability. This case highlights the importance of long-term follow-up and biochemical monitoring for early detection of tumor recurrence in patients with pheochromocytoma, emphasizing the need for individualized treatment strategies and interdisciplinary care., (Copyright © 2024. Publicado por Elsevier España, S.L.U.)

Medullary thyroid carcinoma (MTC) is a rare cancer derived from neuroendocrine C-cells of the thyroid. In contrast to other neuroendocrine tumors, a histological grading system was lacking until recently. A novel two-tier grading system based on the presence of high proliferation or necrosis is associated with prognosis. Transcriptomic analysis was conducted on 21 MTCs, including 9 high-grade tumors, with known mutational status, using the NanoString Tumor Signaling 360 Panel. This analysis, covering 760 genes, revealed upregulation of the genes EGLN3, EXO1, UBE2T, UBE2C, FOXM1, CENPA, DLL3, CCNA2, SOX2, KIF23, and CDCA5 in high-grade MTCs. Major pathways differentially expressed between high-grade and low-grade MTCs were DNA damage repair, p53 signaling, cell cycle, apoptosis, and Myc signaling. Validation through qRT-PCR in 30 MTCs demonstrated upregulation of ASCL1, DLL3, and SOX2 in high-grade MTCs, a gene signature akin to small-cell lung carcinoma, molecular subgroup A. Subsequently, DLL3 expression was validated by immunohistochemistry. MTCs with DLL3 overexpression (defined as ≥ 50% of positive tumor cells) were associated with significantly lower disease-free survival (p = 0.041) and overall survival (p = 0.01). Moreover, MTCs with desmoplasia had a significantly increased expression of DLL3. Our data supports the idea that DLL3 should be further explored as a predictor of aggressive disease and poor outcomes in MTC., (© 2024. The Author(s).)

The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m 2 /d iv on days 1-3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H 0 50%, H 1 72%, β 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile., (© 2024. The Author(s).)

Cancer therapy-related cardiac dysfunction (CTRCD), which commonly includes left ventricular dysfunction and heart failure, is the main adverse effect of anticancer therapy. In recent years several candidate genes studies and genome-wide association studies have identified common genetic variants associated with CTRCD, but evidence remains limited and few genetic variants are robust. A genome-wide meta-analysis of CTRCD was performed with 852 oncology patients receiving cancer therapy. DNA samples were genotyped and imputed to perform a GWAS meta-analysis for case-control (N = 852 (380 cases and 472 controls) and extreme phenotypes (N = 618 (78 cases and 472 controls) looking for genetic variants that predispose to CTRCD. The results were validated in a replicate cohort of 1,191 oncology patients (245 cases and 946 controls). Functional mapping of the replicated loci was then performed. The meta-analysis showed 9 and 17 loci suggestively associated (P-value < 1 × 10 -5 ) with CTRCD in case-control and extreme phenotypes analyses, respectively. The 3q28 locus (rs rs7652759, P = 5.64 × 10 -6 ) in the case-control analysis was the strongest signal, with up to 64 SNPs above the suggestive significance threshold. The rs7652759, an intergenic variant between TPRG1 and TP63 genes, was the only variant validated in the replication cohort (P-value = 0.01). Functional mapping of this significant locus revealed up to 5 new genes potentially involved in the CTRCD. We identified the intergenic region near TP63 as a novel CTRCD susceptibility locus. In the future, the genotyping of these markers could be considered in new CTRCD risk scores to improve preventive strategies in cardio-oncology., (© 2024. The Author(s).)

Thyroid cancer (TC) represents 3% of global cancer incidence. Recent changes have optimized treatment decisions based on risk assessment, molecular profiling, and imaging assessment, leading the development of targeted agents that have modified the natural history of this disease. This increasing complexity on treatment options requires careful assessment at the different stages of the disease to provide the most suitable approach from diagnosis to long-term follow-up. This guideline aims to offer a comprehensive and practical overview on the current status and last updates of TC management., (© 2024. The Author(s).)

Purpose: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%., Results: At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib., Conclusions: Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: This phase II nonrandomized study evaluated the efficacy and safety of AZD4635 in combination with durvalumab (Arm A) or durvalumab plus cabazitaxel (Arm B) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and ≥1 novel hormonal agent., Patients and Methods: The primary endpoint was radiographic progression-free survival (rPFS) per RECIST v1.1 (soft tissue) or the Prostate Cancer Clinical Trials Working Group 3 (bone). Secondary endpoints included safety, tolerability, overall survival, confirmed prostate-specific antigen (PSA 50 ) response, pharmacokinetics, and objective response rate. Enrollment in Arm A was stopped following a sponsor decision unrelated to safety. The study was stopped based on the planned futility analysis due to low PSA 50 response in Arm B., Results: In the final analysis (1 November 2021), 30 patients were treated (Arm A, n = 2; Arm B, n = 28). The median rPFS in Arm B was 5.8 months (95% confidence interval 4.2-not calculable). Median rPFS was 5.8 months versus 4.2 months for patients with high versus low blood-based adenosine signature. The most common treatment-related adverse events in Arm B were nausea (50.0%), diarrhea (46.4%), anemia and neutropenia (both 35.7%), asthenia (32.1%), and vomiting (28.6%). Overall, AZD4635 in combination with durvalumab or AZD4635 in combination with cabazitaxel and durvalumab showed limited efficacy in patients with mCRPC., Conclusions: Although the safety profile of both combinations was consistent with known safety data of the individual agents, the results of this trial do not support further development of the combinations., Competing Interests: Disclosure TAG: research funding, honoraria, and nonfinancial or other support from IPSEN, Adacap, Pfizer, Sanofi, EISAI, Lilly, Bayer, Janssen, BMS, Astellas, Novartis, Roche. MG: honoraria from Sanofi/Aventis and Alexion Pharmaceuticals for consulting or advisory role; travel, accommodations, expenses provided by AstraZeneca and Genentech; research funding paid to institution from Janssen, AstraZeneca, Genentech. CV: research funding paid to institution from Merck MSD; consulting fees from GSK, Astellas Pharma, Merck MSD, BMS, Leo-Pharma, Janssen, Cilag, Bayer, and AstraZeneca. GR: research funding paid to institution from Bayer; consulting fees from AAA, Astellas, Bayer, Sanofi, Janssen, AstraZeneca, and Pfizer. JZ: honoraria from AstraZeneca for advisory board and speaker bureau; advisory board for Bayer, Pfizer, and Dendreon; speaker bureau for Sanofi. MP: research funding paid to institution from Karyopharm; consulting fees from AstraZeneca, Exelixis, Oncocyte, Signatera, and Janssen. JMP: grants paid to institution from MSD, BMS, Janssen, Merk Serono, BeiGene; consulting fees from Novartis, Sanofi, Janssen, Astellas, BMS, MSD, and Roche. AA: employee of AstraZeneca and may own stock or stock options. GDJ: contractor for AstraZeneca. RC: employee of AstraZeneca and may own stock or stock options. ETG: employee of AstraZeneca and may own stock or stock options. JT: employee of AstraZeneca and may own stock or stock options. GP: employee of AstraZeneca and may own stock or stock options. RK: employee of AstraZeneca and may own stock or stock options. CS: research funding paid to institution by: Janssen, Astellas, Sanofi, Bayer, Sotio, and Dendreon; patents, consulting, or advisory role: Sanofi, Janssen, Astellas, Bayer, Genentech, Pfizer, Lilly; royalties and other intellectual property: Parthenolide (Indiana University); dimethylamino parthenolide (Leuchemix); Exelixis: abiraterone plus cabozantinib combination; FRAS1 SNP and tristetraprolin as biomarkers of lethal prostate cancer; stock or other ownership: Leuchemix., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is now a combination of androgen deprivation therapy plus an androgen receptor-targeted therapy (abiraterone, apalutamide, enzalutamide or darolutamide), with or without chemotherapy (docetaxel). The selection of suitable patients for each therapeutic approach has become a determining factor to ensure efficacy and minimize side effects. This article combines recent clinical evidence with the accumulated experience of experts in medical oncology, radiation oncology and urology, to provide a comprehensive view and therapeutic recommendations for mHSPC., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Purpose: The immunocytokine cergutuzumab amunaleukin (CEA-IL2v) showed manageable safety and favorable pharmacodynamics in phase I/Ib trials in patients with advanced/metastatic carcinoembryonic antigen-positive (CEA+) solid tumors, but this was accompanied by a high incidence of anti-drug antibodies (ADA). We examined B-cell depletion with obinutuzumab as a potential mitigation strategy., Experimental Design: Preclinical data comparing B-cell depletion with rituximab versus obinutuzumab are summarized. Substudies of phase I/Ib trials investigated the effect of obinutuzumab pretreatment on ADA development, safety, pharmacodynamics, and antitumor activity of CEA-IL2v ± atezolizumab in patients with advanced/metastatic or unresectable CEA+ solid tumors who had progressed on standard of care., Results: Preclinical data showed superior B-cell depletion with obinutuzumab versus rituximab. In clinical studies, patients received CEA-IL2v monotherapy with (n = 16) or without (n = 6) obinutuzumab pretreatment (monotherapy study), or CEA-IL2v + atezolizumab + obinutuzumab pretreatment (n = 5; combination study). In the monotherapy study, after four cycles (every 2 weeks treatment), 0/15 evaluable patients administered obinutuzumab pretreatment had ADAs versus 4/6 patients without obinutuzumab. Obinutuzumab pretreatment with CEA-IL2v monotherapy showed no new safety signals and pharmacodynamic data suggested minimal impact on T cells and natural killer cells. Conversely, increased liver toxicity was observed in the combination study (CEA-IL2v + atezolizumab + obinutuzumab pretreatment)., Conclusions: These preliminary findings suggest that obinutuzumab pretreatment before CEA-IL2v administration in patients with CEA+ solid tumors may be a feasible and potent ADA mitigation strategy, with an acceptable safety profile, supporting broader investigation of obinutuzumab pretreatment for ADA mitigation in other settings., (©2024 American Association for Cancer Research.)

Background: The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors., Main Body: Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8 + T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8 + and granzyme B + cells were observed., Conclusions: Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME., Trial Registration Number: NCT02671435., Competing Interests: Competing interests: SP: scientific advisory income from: Amgen, AstraZeneca, Bristol Myers Squibb, Certis, Eli Lilly, Genentech, Illumina, Merck, Pfizer, Rakuten, and Tempus; SP’s university receives research funding from: Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Eli Lilly, Fate Therapeutics, Iovance, Merck, Pfizer, Roche/Genentech, and SQZ Biotechnologies.TA-G has received research funding, honoraria, and non-financial or other support from IPSEN, Adacap, Pfizer, Sanofi, EISAI, Lilly, Bayer, Janssen, BMS, Astellas, Novartis, Roche, and Merck. SB: institutional grants: AstraZeneca and GlaxoSmithKline. Honoraria for Advisory boards: Amgen, AstraZeneca, Genmab, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Merck Sereno, Mersana Therapeutics, OncXerna, Seagen, and Shattuck Labs; Honoraria for lectures: Amgen, AstraZeneca, Clovis, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Mersana Therapeutics, Pfizer, and Roche. DW, JN, NES, DCP, L-YC, PK, MDH: employment by and stock ownership/options in AstraZeneca. MLA: former employment by and stock ownership/options in AstraZeneca. MD: employment by and stock ownership/options in AstraZeneca. JRD: institutional funds received from: AstraZeneca, Abbvie, Astellas, Gilead, Merck, Deciphera, Hutchison, BMS, Adlai Norte, Takeda, OnKure Therapeutics; Consulting: Gilead, OnKure Therapeutics; Equity Interest: OnKure Therapeutics. BAC: institutional research support: Astra Zeneca, Abbvie, Actuate Therapeutics, Astellas, Bayer, Dragonfly Therapeutics, Pfizer, Repare Therapeutics. Scientific advisory boards: Foundation Medicine, Tempus, Seattle Genetics, G1 therapeutics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The extent of tumor shrinkage has been deemed a predictor of survival for advanced/metastatic renal cell carcinoma (RCC), a disease with historically poor survival., Objective: To perform an exploratory analysis of overall survival (OS) by tumor response by 6 mo, and to assess the efficacy and survival outcomes in specific subgroups., Design, Setting, and Participants: CLEAR was an open-label, multicenter, randomized, phase 3 trial of first-line treatment of advanced clear cell RCC., Intervention: Patients were randomized 1:1:1 to lenvatinib 20 mg orally daily with pembrolizumab 200 mg intravenously once every 3 wk, lenvatinib plus everolimus (not included in this analysis), or sunitinib 50 mg orally daily for 4 wk on treatment/2 wk of no treatment., Outcome Measurements and Statistical Analysis: Landmark analyses were conducted to assess the association of OS with tumor shrinkage and progressive disease status by 6 mo. Progression-free survival, duration of response, and objective response rate (ORR) were analyzed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk subgroup and by the presence of target kidney lesions. Efficacy was assessed by an independent review committee as per Response Evaluation Criteria in Solid Tumors version 1.1., Results and Limitations: Landmark analyses by tumor shrinkage showed that patients enrolled to lenvatinib plus pembrolizumab arm with a confirmed complete response or >75% target-lesion reduction by 6 mo had a 24-mo OS probability of ≥91.7%. A landmark analysis by disease progression showed that patients with no progression by 6 mo had lower probabilities of death in both arms. Patients with an IMDC risk classification of intermediate/poor had longer median progression-free survival (22.1 vs 5.9 mo) and a higher ORR (72.4% vs 28.8%) with lenvatinib plus pembrolizumab versus sunitinib. Similarly, results favored lenvatinib plus pembrolizumab in IMDC-favorable patients and those with/without target kidney lesions. Limitations of the study are that results were exploratory and not powered/stratified., Conclusions: Lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with advanced RCC; landmark analyses showed that tumor response by 6 mo correlated with longer OS., Patient Summary: In this report of the CLEAR trial, we explored the survival of patients with advanced renal cell carcinoma by assessing how well they initially responded to treatment. We also explored how certain groups of patients responded to treatment overall. Patients were assigned to cycles of either lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 wk or sunitinib 50 mg daily for 4 wk (followed by a 2-wk break). Patients who either had a "complete response" or had their tumors shrunk by >75% within 6 mo after starting treatment with lenvatinib plus pembrolizumab had better survival than those with less tumor reduction by 6 mo. Additionally, patients who had more severe disease (as per the International Metastatic Renal Cell Carcinoma Database Consortium) at the start of study treatment survived for longer without disease progression with lenvatinib plus pembrolizumab than with sunitinib., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Thoracic and cervical paragangliomas (PGLs) are rare neuroendocrine tumors arising from chromaffin cells of the neural crest progenitors located outside the adrenal gland. We describe our current protocol as a multidisciplinary team for the management of cervical and thoracic PGLs. Surgery is generally considered the treatment of choice as it offers the best chance for cure. For resection of thoracic PGLs, video-assisted thoracoscopic surgery (VATS) is the main surgical approach, while open thoracotomy is preferred in case of tumors > 6cm, lacking confirmation of a plane of separation with adjacent structures, or with technical difficulties during VATS. In cervical PGLs, the surgical approach should be individualized according to location, mainly based on the Glasscock-Jackson and the Fisch-Mattox classifications. Surgery is the treatment of choice for most cervical and thoracic PGLs, but radiotherapy or observation could be more suitable options in unresectable cervical and thoracic PGLs or when resection has been incomplete., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice ( n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients ( n = 71) and women with breast cancer ( n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Introduction: The long-term clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) and a complete response (CR) to the tyrosine kinase inhibitor (TKI) sunitinib are poorly known. The characteristics of these patients could reveal previously undetected associations with clinical variables., Patients and Methods: This observational, retrospective study (ATILA) used data from a registry of patients with mRCC who had received first-line sunitinib and had achieved CR from 2007 to 2018 in Spain., Results: Sixty-two patients with CR were included; 48 patients (77.4%) received sunitinib in monotherapy and 14 (22.6%) combined with or followed by local treatment. Median age was 58.5 years (range, 32-81). Most patients (79.0%) had clear cell histology and had undergone previous nephrectomy (90.3%). The majority (70.2%) had an intermediate IMDC prognosis, 23% favorable and 7.0% poor. The median time on treatment with sunitinib was 28.2 months (IQR, 16.7-41.0) and the median time to CR was 10.9 months (IQR, 7.2-19.3). After a median follow-up of 8 years (range, 3-13 years), the median PFS was not reached. The overall median duration of complete response was 64.1 months (IQR, 32.2-99.4). The tolerance and safety profile of sunitinib was consistent with previous reports., Conclusion: Durable CR to sunitinib was observed in patients regardless the prognosis group, metastasis site or histology type, with 75% of patients remaining in CR after 10 years., Clinicaltrials: gov: NCT03916458., Competing Interests: Disclosures G.d.V. received research grants from Pfizer, Roche, and Ipsen; consulting or honoraria fees from Ipsen, Pfizer, Roche, Bayer, Astellas, BMS, MSD and Merck. T.A.G. received research grants from Pfizer, Roche, and Ipsen; consulting fees from Ipsen, Pfizer, Roche, Sanofi, Bayer, Astellas, Janssen-Cilag, BMS, and EISAI; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Pfizer, Eisai, and Merck; and support for attending meetings and/or travel from Pfizer, Sanofi, BMS, and IPSEN. A.R.-V. served in advisory boards for MSD, Pfizer, BMS, Astellas, Janssen, Bayer, Clovis and Roche; received honoraria or travel expenses from Pfizer, MSD, Astellas, BMS, Janssen, Astra Zeneca, Roche, Bayer, and Sanofi Aventis; and research funding from Takeda, Pfizer, and Merck. G.A.P. served in speaker bureaus for Ipsen, BMS, Roche, and Janssen. M.C. served in advisory or consultancy roles for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, EUSA Pharma, Lilly, Roche; received honoraria for lectures for Abbot, Bristol-Myers Squibb, EUSA Pharma, Ipsen, Novartis, Pfizer, Pierre Fabre, Roche; holds institutional financial interests in Astra Zeneca, Merck, Pfizer, Roche, and received travel expenses from Ipsen, Lilly, Merck, Pfizer, and Pierre Fabre. A.P. received research grants from Pfizer and BMS; advisory boards/speaker fees from Pfizer, BMS, Ipsen, Roche, Merck, MSD, Janssen, Astellas, Bayer, Sanofi; and travel expenses from Pfizer, BMS, Janssen and Roche. E.G. received grant support from Astellas, Janssen, Sanofi, Bayer, Ipsen, Ferrer, Pfizer, Roche, GSK and BMS; consulting fees from Sanofi, Janssen, Astellas, Bayer, Ipsen, Pfizer, Roche, Novartis, Eisai, EUSA Pharma, BMS, AstraZeneca, Merck, Rovi, Daiichi Sankyo and Techdow; payment or honoraria for lectures, presentations, speakers’ bureaus, man-uscript writing, or educational events from Astellas, Janssen, Sanofi, Bayer, Ipsen, Pfizer, Roche, BMS, Rovi, Daiichi Sankyo, Leo Pharma, Menarini, Eisai, MSD, Boehringer Ingelheim, Merck, EUSA Pharma and Novartis; support for attending meetings and/or travel from As-tellas, Janssen, Sanofi, BMS, Bayer, Ipsen, Roche, Novartis, Pierre Fabre, Pfizer and Eisai. N.F.N. received support from Roche, BMS, Boehringuer, Sanofi, Bayer, Astra Zeneca, Janssen, MSD, Lilly, Pfizer and IPSEN. I.C.-G. participated in advisory boards of Pfizer, EISAI and BMS. O.R. had consulting or advisory roles with BMS, EISAI, Ipsen; received travel and accommodations support from Ipsen and Pfizer. M.J.M. received honoraria and /or travel support from Janssen-Cilag, Bayer healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, EISAI, Novartis and Pfizer; advisory boards and speaking for: Pfizer, Astellas, Roche, Ipsen, BMS, Eusa Pharma, Sanofi, Novartis, Janssen andPierre Fabre. N.V.C. received consultant fees from Janssen; speaking fees from Sanofi, Astra Zeneca, Astellas, Janssen, Roche, MSD, Ipsen; and travel support from Pfizer, Pierre Fabre, BMS. A.L.M. received support for attending meetings from Roche and MSD. C.G.d.E. has held consultant or advisory roles with Janssen, Sanofi, Bayer, Astellas; speaking roles from Janssen, Sanofi, Bayer, Astellas, Roche, Ipsen, Pfizer; and other support from Janssen, Sanofi and Roche. M.A.C. has held consulting or advisory role with BMS, MSD, Bayer, EUNSA, Pfizer, Roche, Janssen, Pierre Fabre, Ipsen; received travel expenses from Janssen, Astellas, Roche, Ipsen, and MSD. A.R.S. held consulting or advisory roles for Roche, Bristol, Sanofi, Merck, Ipsen and Eisai. I.C.G. has served as consultant or advisory board to Pzifer, Bristol-Myers Squibb, Ipsen, Roche and EusaPharma; has served as speaker to Pfizer, Bristol-Myers Squibb and Ipsen; and received travel and/or accommodation grants from Pfizer. R.A. has participated in advisory boards for Pfizer, Roche, Sanofi and Servier. X.G.d.M. has participated in advisory boards or as invited speaker for Astellas, BMS, Ipsen, Roche, Eusa Pharma, Eisai, Pfizer and Pharmamar. J.C. reports support from Janssen, Roche, AstraZéneca, Astellas, BMS, Pfizer, Sanofi, and Novartis. J.A. received advisory boards/speaker fees from Novartis, Pfizer, Merck, Roche, BMS; and travel and accommodations from AstraZeneca, BMS, Pfizer, Astellas and Sanofi. S.H.P. participated in advisory boards and as speaker for GSK, Clovis, Astra-Zeneca/MSD and Pfizer. Ú.A. is an employee of Pfizer. All other authors report no conflicts of interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS., (© 2023. The Author(s).)

Background: There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC)., Methods: We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort., Results: Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort., Conclusions: TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers., (© 2022 The Authors. The Prostate published by Wiley Periodicals LLC.)

Background: In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up., Methods: This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial. Patients with clear-cell advanced renal cell carcinoma who had not received any systemic anticancer therapy for renal cell carcinoma, including anti-vascular endothelial growth factor therapy, or any systemic investigational anticancer drug, were eligible for inclusion from 200 sites (hospitals and cancer centres) across 20 countries. Patients were randomly assigned (1:1:1) to receive lenvatinib (20 mg per day orally in 21-day cycles) plus pembrolizumab (200 mg intravenously every 21 days; lenvatinib plus pembrolizumab group), lenvatinib (18 mg per day orally) plus everolimus (5 mg per day orally; lenvatinib plus everolimus group [not reported in this updated analysis]) in 21-day cycles, or sunitinib (50 mg per day orally, 4 weeks on and 2 weeks off; sunitinib group). Eligible patients were at least 18 years old with a Karnofsky performance status of 70 or higher. A computer-generated randomisation scheme was used, and stratification factors were geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint was progression-free survival assessed by independent imaging review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). In this Article, extended follow-up analyses for progression-free survival and protocol-specified updated overall survival data are reported for the intention-to-treat population. No safety analyses were done at this follow-up. This study is closed to new participants and is registered with ClinicalTrials.gov, NCT02811861., Findings: Between Oct 13, 2016, and July 24, 2019, 1417 patients were screened for inclusion in the CLEAR trial, of whom 1069 (75%; 273 [26%] female, 796 [74%] male; median age 62 years [IQR 55-69]) were randomly assigned: 355 (33%) patients (255 [72%] male and 100 [28%] female) to the lenvatinib plus pembrolizumab group, 357 (33%) patients (275 [77%] male and 82 [23%] female) to the sunitinib group, and 357 (33%) patients to the lenvatinib plus everolimus group (not reported in this updated analysis). Median follow-up for progression-free survival was 27·8 months (IQR 20·3-33·8) in the lenvatinib plus pembrolizumab group and 19·4 months (5·5-32·5) in the sunitinib group. Median progression-free survival was 23·3 months (95% CI 20·8-27·7) in the lenvatinib plus pembrolizumab group and 9·2 months (6·0-11·0) in the sunitinib group (stratified hazard ratio [HR] 0·42 [95% CI 0·34-0·52]). Median overall survival follow-up was 33·7 months (IQR 27·4-36·9) in the lenvatinib plus pembrolizumab group and 33·4 months (26·7-36·8) in the sunitinib group. Overall survival was improved with lenvatinib plus pembrolizumab (median not reached [95% CI 41·5-not estimable]) versus sunitinib (median not reached [38·4-not estimable]; HR 0·72 [95% CI 0·55-0·93])., Interpretation: Efficacy benefits of lenvatinib plus pembrolizumab over sunitinib were durable and clinically meaningful with extended follow-up. These results support the use of lenvatinib plus pembrolizumab as a first-line therapy for patients with advanced renal cell carcinoma., Funding: Eisai and Merck Sharp & Dohme., Competing Interests: Declaration of interests TKC reports research funding, paid to their institution, from AstraZeneca, Aveo, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda; consulting fees from AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Nuscan, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events; payment or honoraria for lectures, presentations, manuscript writing, or educational events from AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infiniti, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda, Tempest, Up-To-Date, and CME events; support for attending meetings or travel from Eisai, Merck, Exelixis, and Pfizer; patents planned, issued, or pending related to ctDNA and biomarkers of response to immune checkpoint inhibitors (no royalties as of April 12, 2022); participated on a data safety monitoring board or advisory board for Aravive; a leadership or fiduciary role in other board, society, committee, or advocacy group, for KidneyCan (unpaid), committees for American Society of Clinical Oncology, European Society for Medical Oncology, National Comprehensive Cancer Network®, and Genitourinary Steering Committee of the National Cancer Institute; stock or stock options from Pionyr, Tempest, Precede Bio, and Osel; and salary and research support from Dana-Farber and Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School, and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. ME reports research funding from Kissei, Sanofi, Astellas, ONO, Takeda, and Bayer; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from MSD, ONO, Chugai, Novartis, Pfizer, Bristol Myers Squibb, Takeda, Janssen, and Merck. RM reports research funding, paid to their institution from Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Merck, Pfizer, and Aveo Pharmaceuticals and consulting fees from AstraZeneca, Aveo Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly, Merck, Novartis, Pfizer, and Takeda. UDG reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis oncology, Eisai, Janssen, MSD, Pfizer, Ipsen, and Roche and support for attending meetings or travel from Janssen, Bristol-Myers Squibb, and Ipsen. TB reports research support, paid to their institution from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Merck, and Novartis; consulting fees from Bristol Myers Squibb, Astellas, Janssen, and Sanofi/Aventis; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol-Myers Squibb, Servier, and Pfizer; and receipt of equipment, materials, drugs, medical writing, gifts, or other services, paid to their institution from Bristol-Myers Squibb, AstraZeneca, Roche, and Servier. NSB reports consulting fees from Bristol-Myers Squibb, Ipsen, Eisai, Janssen, Pfizer, Roche, Merck, EMD Serono, AstraZeneca, and Bayer; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events (personal) from Bristol-Myers Squibb, Ipsen, and Merck; and support for attending meetings or travel from Eisai and Janssen. MJM-V reports consulting fees from Astellas Pharma, Bristol-Myers Squibb, EUSA Pharma, Ipsen, Eisai, Janssen-Cilag, Novartis, Pfizer, Roche, and Sanofi; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas Pharma, Bristol-Myers Squibb, Ipsen, EUSA Pharma, Janssen-Cilag, Pfizer, and Roche; and support for attending meetings or travel from Astellas Pharma, Bristol-Myers Squibb, Ipsen, Janssen-Cilag, Pfizer, and Roche. BM reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche, Pfizer, Bristol-Myers Squibb, Astellas, Novartis, Bayer, MSD, Merck Serono, Sanofi, Servier, AstraZeneca, Amgen, Janssen, Eisai, E Lilly, and Pierre Farbre; support for attending meetings or travel from Bristol-Myers Squibb and Merck Serono; and participation on a data safety monitoring board or advisory board for Roche, Pfizer, Bristol-Myers Squibb, Astellas, Novartis, Bayer, MSD, Merck Serono, Sanofi, Servier, AstraZeneca, Amgen, Janssen, Eisai, E Lilly, and Pierre Farbre. TH reports grants or contracts, paid to their institution, from Bristol-Myers Squibb, Eisai, Exelixis, Johnson & Johnson, and Pfizer; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas Pharma, Bristol-Myers Squibb, Eisai, Exelixis, Johnson & Johnson, and Pfizer; and participation on a data safety monitoring board or advisory board for Astellas Pharma, Bayer/Onyx, Bristol Myers Squibb, Exelixis, Johnson & Johnson, Novartis, and Pfizer. BMcG reports grants or contracts, paid to their institution from Exelixis, SeaGen, Pfizer, Bristol Myers Squibb and consulting fees from Astellas, Bristol-Myers Squibb, Calithera, Eisai, Exelixis, Pfizer, and SeaGen. TP reports research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; consulting fees from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; support for attending meetings or travel Astra Zeneca, Ipsen, MSD, Pfizer, and Roche. VG reports grants or contracts, paid to their institution, from AstraZeneca, Bristol-Myers Squibb, MSD, Pfizer, Ipsen; consulting fees from Bristol-Myers Squibb, Pfizer, Roche, MSD, Oncorena, PCI Biotech, Nanobiotix, Merck Serono, EUSA Pharm, Debiopharm, Eisai, and Apogepha; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Eisai, Ipsen, Janssen-Cilag, Merck Serono, MSD, Novartis, Pfizer, Roche, AstraZeneca, and Astellas; support for attending meetings or travel from Pfizer and Merck; participation on a data safety monitoring board or advisory board for Bristol-Myers Squibb, Ipsen, Eisai, PharmaMar, and PharmaMar; leadership or fiduciary role in other board, society, committee, or advocacy group from National Working Group AIO (Working Group on Internal Oncology in the German Cancer Society), German Cancer Society; and stock or stock options in AstraZeneca, Bristol-Myers Squibb, MSD, and SeaGen. BA reports grants or contracts from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; consulting fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events: Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, Roche; payment for expert testimony from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; and support for attending meetings or travel from Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche. SYR reports grants or contracts from Amgen, Merck, Bristol-Myers Squibb, MSD, Lilly, Daiichi Sankyo, Beigene, Eisai, and AstraZeneca; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen, Lilly, Bristol-Myers Squibb, MSD, and Eisai; and participation on a data safety monitoring board or advisory board from Amgen, MSD, Bristol-Myers Squibb, Merck, Indivumed, Beigene, Eisai, and Daiichi Sankyo. AK reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Merck, Bristol-Myers Squibb, Ipsen, Eisai, Janssen, AbbVie; leadership or fiduciary role in for Kidney Cancer Canada; and stock in Verity Pharma. TAG reports grants or contracts from Pfizer, Roche, and Ipsen; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Lilly, Pfizer, Roche, Bristol-Myers Squibb, MSD, Eisai, Bayer, Janssen, Sanofi, and Astellas. JCG reports consulting fees for an advisory board meeting from Merck Sharp & Dohme (Australia), Bristol-Myers Squibb, and GlaxoSmithKline; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Janssen–Cilag, Ipsen, Merck Sharp and Dohme (Australia), and AstraZeneca (Australia); and support for attending meetings or travel AstraZeneca (Australia), GlaxoSmithKline, and MSD. MS reports grants or contracts from Pfizer, GlaxoSmithKline, AVEO, Bristol Myers Squibb, Novartis, Bayer, Roche/Genentech, Immatics, Wilex, Ipsen, Exelixis, and Eisai; consulting fees from Pfizer, GlaxoSmithKline, Novartis, Bayer, Roche, Aveo, EUSA Pharm, Astellas, Ipsen, Exelixis, Pelloton, Eisai, Bristol-Myers Squibb, MSD, Apogepha, and Oncorena; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Pfizer, GlaxoSmithKline, AVEO, Novartis, Bayer, EUSA Pharma, Astellas, Ipsen, Exelixis, Pelloton, Eisai, Bristol-Myers Squibb, MSD, and Apogepha; and support for attending meetings or travel from Pfizer, EUSAPharm, Ipsen, Eisai, Bristol-Myers Squibb, MSD, and Apogepha. JRM reports grants or contracts, paid to their institution from Corvus Pharmaceuticals, Eisai, Genentech/Roche, Lilly, Merck, Novartis, Peloton Therapeutics, Pfizer, Replimune, Seattle Genetics/Astellas, Sillajen, Tizona Therapeutics, Tocagen, and Vyriad, and consulting fees from Exelixis. RX, KM, and JMcK are employees of Eisai. RFP is an employee of and holds stock in Merck, Rahway, NJ, USA. CGP reports consulting fees from Angelini Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, and MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Angelini Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, General Electric, Ipsen, and MSD; and participation on a data safety monitoring board or advisory board for Bristol-Myers Squibb, Eisai, MSD, the European Society of Medical Oncology, and the Italian Association for Medical Oncology. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: To describe our current protocol for surgical and postsurgical management of abdominal paragangliomas (PGLs) and pheochromocytomas, with a special focus on multidisciplinary management in centres with experience., Methods: The physicians involved in the management of patients with abdominal PGLs and pheochromocytomas of our hospital reviewed systematically current knowledge on the surgical management of abdominal PGLs and pheochromocytomas., Results: Currently, surgery is considered the treatment of choice for abdominal PGLs and pheochromocytomas. The choice of surgical approach is determined based on the location of the lesion, size, patient́s body habitus and the likelihood of malignancy. Laparoscopic surgery is usually considered the gold standard approach for pheochromocytomas, but open access should be considered in invasive and/or potentially malignant tumours >8-10 cm and for abdominal PGLs. Postsurgical management of pheochromocytomas and PGLs includes close hemodynamic monitoring and treatment of postsurgical complications, the pathological study of the surgical specimen, reassessment of hormonal and/or radiological status and planning of follow-up based on the risk of recurrence and malignancy., Conclusion: Surgery represents the treatment of choice of most abdominal PGLs and pheochromocytomas. Optimal postsurgical evaluation, including hemodynamic, pathological, hormonal, and radiological evaluation, should be performed by a multidisciplinary team specializing in PGL/pheochromocytoma management., (Copyright © 2022 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

The androgen signaling pathway is the cornerstone in the treatment of high risk or advanced prostate cancer patients. However, in recent years, different mechanisms of resistance have been defined in this field, limiting the efficacy of the currently approved antiandrogen drugs. Different therapeutic approaches are under research to assess the role of combination therapies against escape signaling pathways or the development of novel antiandrogen drugs to try to solve the primary or acquired resistance against androgen dependent or independent pathways. The present review aims to summarize the current state of androgen inhibition in the therapeutic algorithm of patients with advanced prostate cancer and the mechanisms of resistance to those available drugs. In addition, this review conducted a comprehensive overview of the main present and future research approaches in the field of androgen receptor inhibition to overcome these resistances and the potential new drugs under research coming into this setting.

Renal cell carcinoma (RCC) is the seventh most frequently diagnosed tumor in adults in Europe and represents approximately 2.5 % of cancer deaths. In metastatic setting, clinical strategies including angiogenesis inhibition with tyrosine kinase inhibitors, as well as immunotherapy against immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. Unfortunately, most patients progress to anti angiogenic and immunotherapy treatment. Epigenetic aberrations are commonly found in RCC, showing that changes in epigenetic modifications, like promoter methylation or abnormal microRNA expression, are key in the development of RCC due to gene expression alterations without changes in the genome sequence. Nowadays, new drugs in the field of epigenetics are able to modify gene expression to induce antitumoral effect in the tumor cell. In kidney cancer, drugs targeting epigenetics are in early development, but could be promising in the near future. In this review, we summarize the main epigenetic alterations found in RCC and their involvement in pathological signaling pathways, being a new potential target that could potentially be added to the treatment flow of patients with advanced RCC., Competing Interests: Conflict of interest EG has received honoraria for speaker engagements, advisory roles or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, Thermo Fisher Scientific, and Zodiac. EG has received research grants from Pfizer, Merck, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals. JMC declares consultant, advisory or speaker roles for IPSEN, Roche, Pfizer, Sanofi, Janssen, and BMS. JMC has received research grants from Pfizer, IPSEN and Roche. TAG declares consultant, advisory or speaker roles for Ipsen, Pfizer, Roche, Bayer, Sanofi-Genzyme, Adacap, Janssen, Eisai, Bristol-Myers Squibb. TAG has received research grants from Pfizer, IPSEN and Roche. The other authors declare no conflicts of interest or state., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: We aimed to compare the efficacy and safety of maintaining or withdrawing abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer who had experienced cancer progression to this treatment and were beginning a docetaxel-based therapy., Patients and Methods: Phase II, randomised, open-label study conducted in patients with metastatic castration-resistant prostate cancer who were asymptomatic or mildly symptomatic. After open-label treatment with AAP, patients who had experienced cancer progression to AAP were randomised to 75 mg/m 2 of docetaxel plus AAP or to receive 75 mg/m 2 of docetaxel plus 10 mg of prednisone orally daily. The primary outcome was the radiographic progression-free survival rate at 12 months as evaluated by the investigators in all randomised patients., Results: A total of 148 patients were included in open-label treatment with AAP, and of them, 94 patients were randomised to receive either docetaxel plus AAP (intervention group; n = 47) or docetaxel plus prednisone (control group; n = 47). The 12-month radiographic progression-free survival rates did not differ between the intervention group (34.9%; 95% CI 20.7-49.2) and the control group (33.9%; 95% CI 19.5-48.3). There were no significant differences in the time to radiographic progression and the overall survival between the intervention and control groups. Grade 3-5 neutropenia with the combination of docetaxel plus prednisone and AA was more frequent than with docetaxel plus prednisone (59.6% versus 27.7%)., Conclusion: Our results indicate that the therapeutic strategy of maintaining AAP added to docetaxel in chemotherapy-naïve patients who have experienced cancer progression to AAP treatment should not be further evaluated and should be avoided in clinical practice., Clinical Trials: NCT02036060 https://clinicaltrials.gov/ct2/show/NCT02036060., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M-AC: advisory role from BMS, MSD, Bayer, EUSA, Pfizer, Merck, Roche, Janssen, Ipsen, Astellas, Astra Zeneca; has received honoraria from Ipsen, Astella, Janssen, BMS, MSD, Pfizer, Merck, Roche, EUSA, AstraZeneca. AF: research grants from Astra-Zeneca, Pierre-Fabre; consulting honorarium from Astellas; advisory honorarium from Janssen, Eusa, Astellas, Sanofi, Roche, Astra-Zeneca; and travel grants from Roche, Sanofi, Astellas. ID: Astellas, Invited Speaker, Personal, I have participated in compensated educational activities for this company in the last two years. ASTELLAS, Advisory Board, Personal, I have participated in different compensated advisory boards over the last two years. Bristol Myers Squibb, Advisory Board, Personal, I have served as an advisor for this company in the last two years. Bristol Myers Squibb, Invited Speaker, Personal, I have participated in different compensated educational activities sponsored by this company over the last two years. EUSA PHARMA, Invited Speaker, Personal, I have participated in educational activities sponsored by this company in the last two years. Immunomedics, Inc., Advisory Board, Personal, I have collaborated as an advisor for this company over the last two years. IPSEN, Invited Speaker, Personal, I have participated in different compensated educational activities sponsored by this company over the last two years. Ipsen, Advisory Board, Personal, I have collaborated as an advisor in different occasions over the last two years. Jansen, Invited Speaker, Personal, I have participated in different compensated educational activities sponsored by Jansen over the last two years. Merck, Advisory Board, Personal, I have collaborated as an advisor for this company in the last two year. MSD, Advisory Board, Personal, I have served as an advisor for this company in the last two years. MSD, Invited Speaker, Personal, I have participated in educational activities sponsored by this company in the last two years. Novartis, Invited Speaker, Personal, I have participated in educational activities sponsored by Novartis in the last 2 years. PFIZER, Invited Speaker, Personal, I have participated in different compensated educational activities sponsored by Pfizer over the last two years. Roche Genentech, Advisory Board, Personal, I have served as an advisor for this company in the last two years. Astra Zeneca, Research Grant, Personal and Institutional, Financial interest, AZ has funded research conducted in my institution related to a project where I am the PI. Immunomedics, Inc., Steering Committee Member, Personal, Financial interest, I serve as a member of a SC for a trial sponsored by this company. ROCHE GENENTECH, Research Grant, Personal and Institutional, Financial interest, Roche has funded research in my institution to projects under my coordination. Non-Financial Interests ASEICA, Member of Board of Directors, I belong as a external advisor to the board of directors of the Spanish Association of cancer research since 2021. GO NORTE, Leadership Role, I am the president of an independent cooperative group of GU Oncologist from the north of Spain. JP: Honoraria for speaker engagements, advisory roles or continuous medical education: Astellas, Astra Zeneca, Janssen, MSD, Bayer, Pfizer, Eisai, Ipsen, Sanofi, Roche, BMS, Pierre Fabre, Merck; Research Funding: Astellas, Pfizer; Consultant: Astellas, Roche. MJM-V: Invited speaker from Janssen-Cilag, Bayer healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, Novartis, Pfizer, MSD; Advisory role from Janssen-Cilag, Bayer healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, EISAI, Novartis, Pfizer, MSD; Travel support from Roche, Ipsen. JAAA: Advisory board: Janssen, Merck, MSD, BMS, Pfizer, Astellas; Speaker Honoraria: Merck, Pfizer, BMS; Travel accommodation: Merck, MSD, Janssen, Astellas. AG-D-A: has received research funding from Astellas, travel grants from Astellas, Jansen, Sanofi, BMS, Roche, Pfizer and Ipsen and honoraria for speaker engagements, advisory boards and continuous medical education from Janssen, Astellas, Sanofi, Bayer, Roche, Ipsen, BMS, MSD, Pfizer, Eusa Pharma, Eisai and Astra Zeneca. AS-H: Honoraria from BMS, MSD, AstraZeneca, Roche, Janssen, Sanofi, Pfizer, Lilly and Novartis; Consulting or advisory accommodations and expenses from BMS, MSD, AstraZeneca, Roche, Janssen, Sanofi, Pfizer, Lilly and Novartis; Speakers’ bureau from BMS, MSD, AstraZeneca, Roche, Janssen, Sanofi, Pfizer, Lilly and Novartis. MJJF: Advisory member from Janssen, BMS; Speaker honorarium from Janssen, Sanofi, BMS, GPPharm, Pierre-Fabre; Advisory honorarium from Novartis, Janssen, BMS. TA-G: Scientific Consultancy Role (speaker and advisory role) and travel grant: IPSEN, Pfizer, Roche, Bayer, Sanofi, Janssen, Astellas, Eisai, Adacap, Lilly, Novartis, BMS; Research grants: Roche, Pfizer, IPSEN. BMG: Speakers’ Bureau: Roche, Sanofi, Janssen, Astellas, Pfizer, Novartis, Bristol-Myers Squibb and Ipsen; Research Funding: Roche, Bayer and Janssen. PM: Research grant from Roche, Bayer; Speaker honorarium from Janssen; Advisory honorarium from Janssen, Bayer, Astellas, Pfizer, BMS. ML-Q: Consultant or Advisory Role: BMS, MSD, Takeda, Roche, Pfizer, Roche, Ipsen, Astra-Zéneca, Boehringer, Pierre-Fabré, Bayer; Speaking: Roche, Ipsen, Lilly, Astellas, Janssen, Novartis, Boehringer, BMS; Grant or travel support: MSD, Ipsen, Roche, Janssen, Pfizer, Astellas, Pierre-Fabré; Participation in clinical trials: Merck, Astellas, Pfizer, Ipsen, Roche, Mirati. JC-E: Advisory board member for ASTELLAS, JANSSEN, ASTRAZÉNECA, BRISTOL-MYERS, MSD; Speaker honorarium from ASTELLAS, JANSSEN, ASTRAZÉNECA, BRISTOL-MYERS, MSD IPSEN, PFIZER. BP-V: Consultancy from Astellas Parma; honoraria from Pierre Fabre; travel/accommodations expenses covered or reimbursed from Janssen-Cilag and Pfizer. CG: Speaker honorarium from Janssen, Pfizer, BMS, Astellas, Bayer; Consulting honorarium from Janssen, Pfizer, BMS, Astellas, Bayer; Advisory honorarium from Janssen, Astellas, Bayer, Sanofi, Roche; Travel grants from Pfizer, Roche. DC: ASTELLAS, Advisory Board, Personal; ASTRA ZENECA, Advisory Board, Personal; BMS, Advisory Board, Personal; GSK, Advisory Board, Personal; IPSEN, Advisory Board, Personal; JANSSEN, Advisory Board, Personal; MSD, Advisory Board, Personal; NOVARTIS, Advisory Board, Personal; Pfizer, Advisory Board, Personal; ROCHE, Advisory Board, Personal. ASTELLAS, Local PI, Institutional, No financial interest; ASTRA ZENECA, Local PI, institutional, No financial interest; BAYER, Local PI, Institutional, No financial interest; BMS, Local PI, Institutional, No financial interest; CLOVIS, Local PI, Institutional, No financial interest; EISAI, Local PI, Institutional, No financial interest; EXELISIS, Local PI, Institutional, No financial interest; GSK, Local PI, Institutional, No financial interest; IPSEN, Local PI, Institutional, No financial interest; JANSSEN, Local PI, Institutional, No financial interest. LILLY, Local PI, Institutional, No financial interest; MSD, Local PI, Institutional, No financial interest; PFIZER, Local PI, Institutional, No financial interest; QED Therapeutics, Local PI, Institutional, No financial interest; ROCHE, Local PI, Institutional, No financial interest. MIS, CSL and EE report no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: As management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer., Methods: In a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19., Findings: The study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR 30 ) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR 30 (4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, p<0.0001), requirement of oxygen therapy (15.8% vs 41.5%, p=0.0030), COVID-19 complication rate (11.9% vs 34.6%, p=0.0040), with a reduced need for COVID-19-specific therapy (26.3% vs 57.9%, p=0.0004) compared with unvaccinated patients. Inverse probability of treatment weighting (IPTW)-fitted multivariable analysis, following a clustered-robust correction for the data source (OnCovid vs ESMO CoCARE), confirmed that vaccinated patients experienced a decreased risk of death at 30 days (adjusted OR, aOR 0.08, 95% CI 0.01 to 0.69).Overall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13-48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR 30 (10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 10 9  cells/L, p=0.0098)., Conclusion: Anti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2., Competing Interests: Competing interests: KJH declares research funding from AstraZeneca, Boehringer-Ingelheim, MSD, Replimune and advisory board fees/honoraria from Arch Oncology, AstraZeneca, BMS, Boehringer-Ingelheim, Codiak Biosciences, Inzen Therapeutics, Merck-Serono, MSD, Pfizer, Replimune. DA reports consultation/advisory role for AstraZeneca, Bristol Myers Squibb, Merck Sharp reports speaker’s engagement from AstraZeneca, Bristol Myers Squibb, Merck Sharp reports serving as local PI for Bristol Myers Squibb, Pierre Fabre Pharma and coordinating PI for OncoLytics; reports grant funding from AbbVie; reports being/been DSMB chair of Sanofi (Genzyme); reports being/been a steering committee member of Roche. Olivier Michielin reports personal fees from Bristol-Myers Squibb, MSD, Novartis, Roche, Amgen, NeraCare, outside the submitted work. JR received speaker or advisory fees from Roche, Astra Zeneca, Merck, Ferrer, Persan Farma, Teva Pharma, Leo Pharma, Fresenius kabi, MSD, BMS. Travel expenses support from BMS, MSD, RocheUrania Dafni reports honorarium as Member of the Tumor Agnostic Evidence Generation Working Group of Roche, outside the submitted work. GP reports grants from Amgen, Lilly; grants, personal fees and nonfinancial support from Merck; grants and non-financial support from AstraZeneca; grants and personal fees from Roche, Bristol Myers Squibb, MSD, Novartis, outside the submitted work. Solange Peters reports consultation/advisory role for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol- Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody; talk in a company’s organized public event for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda; receipt of grants/research supports from being a (sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. Emanuela Rromano reports investigator-initiated trial (funds paid to the institution) supported by Astra-Zeneca, BMS; serves on the consultancy/advisory board for Astra-Zeneca, Merck, Roche, Pierre Fabre. ML acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen and Sandoz outside the submitted work.Alessandra Gennari has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. CMV has received travel grants and other honoraria from BMS, MSD, Novartis and Roche. Joan Brunet has declared consulting/advisory role for MSD and Astra Zeneca. Aleix Prat has declared personal honoraria from Pfizer, Roche, MSD Oncology, Eli Lilly, and Daiichi Sankyo; travel, accommodations, and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; and consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb. Mark Bower received speakers’ fee from EISAI pharma, Gilead Sciences, Merck and ViiV. JT reports consulting fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; speaker’s fees from Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource; and institutional research support from Amgen, Array Biopharma, AstraZeneca Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX, Hutchison MediPharma International, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp and has had leadership roles in the European AIDS Clinical Society, UNAIDS, WHO, and The European Hematology Association/ European Society of Medical Oncology. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, EISAI, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra and Astra Zeneca; research funding (to institution) from MSD and BMS. AC received consulting fees from MSD, BMS, AstraZeneca, Roche; speakers’ fee from AstraZeneca, MSD, Novartis and Eisai. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Radionuclide imaging tests with [ 123 I] Metaiodobenzylguanidine (MIBG), [ 18 F] -fluorodeoxyglucose, [ 18 F]-fluorodopa, or 68 Ga-DOTA(0)-Tyr(3)-octreotate are useful for the diagnosis, staging and follow-up of pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs). In addition to their ability to detect and localize the disease, they allow a better molecular characterization of the tumours, which is useful for planning targeted therapy with iodine-131 ( 131 I) -labelled MIBG or with peptide receptor radionuclide therapy (PRRT) with [ 177 Lu]-labelled DOTATATE or other related agents in patients with metastatic disease. In this review we detail the main characteristics of the radiopharmaceuticals used in the functional study of PPGLs and the role of nuclear medicine tests for initial evaluation, staging, selection of patients for targeted molecular therapy, and radiation therapy planning. It also offers a series of practical recommendations regarding the functional imaging according to the different clinical and genetic scenarios in which PPGLs occur, and on the indications and efficacy of therapy with [ 131 I]-MIBG and 177 Lu-DOTATATE., (Copyright © 2021 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

The diagnosis of central nervous system metastases in patients with radioiodine refractory differentiated thyroid cancer is a late and rare event that occurs in less than 1% of patients. Definitive conclusions on the overall clinical management cannot be drawn due to the limited number of patients included in retrospective series or post hoc analysis from clinical trials. However, most data show a trend to an increased benefit from a multimodal approach. Local treatment based on surgical and/or radiation techniques is highly encouraged for symptom control and to reduce tumor burden in this location despite a high risk of clinical complications. In addition, systemic treatment with novel tyrosine kinase inhibitors has demonstrated activity in this subgroup of patients, improving an otherwise unfavorable prognosis., (© 2022 The Author. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: The paper aims to evaluate the efficacy and safety of 223 Ra in patients who progressed after first-line androgen deprivation therapy., Patients and Methods: EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223 Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety., Results: Median rPFS was 5.5 months (95% CI 5.3-5.5). Median rPFS of patients with AR-V7(-) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2-not reached) and was significantly greater for AR-V7(-) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223 Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively)., Conclusions: 223 Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bayer, Johnson & Johnson, Bristol-Myers Squibb, Astellas Pharma, Pfizer, Sanofi, MSD, Roche, AstraZeneca, Asofarma, Ipsen, AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, Aveo Pharmaceuticals INC, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim España, S.A., , Clovis Oncology INC, Cougar Biotechnology INC, Deciphera Pharmaceuticals LLC, Exelixis INC, F. Hoffmann-La Roche LTD, Genentech INC, GlaxoSmithKline, Incyte Corporation, -Cilag, International NV, Karyopharm Therapeutics INC., EISAI, Merck Serono, Lilly, Novartis Pharmaceutical, S.A, Janssen, Eusa Pharma, Sanofi-Genzyme, Beigene, VCN biotech, and VCN biotech; Leurquin Mediolanum SAS, Pierre Fabre, Rovi, Daiichi Sankyo, Techdow, Leo Pharma, Menarini, Ferrer, Millennium Pharmaceuticals, INC, Medimmune, Nanobiotix SA, S.L.U, Puma Biotechnology, FJ Pharma LTD. II, Teva Pharma S.L.U., MEDSIR., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous malignancies with distinct prognosis based on primary tumor localization, grade, stage and functionality. Surgery remains the only curative option in localized tumors, but systemic therapy is the mainstay of treatment for patients with advanced disease. For decades, the therapeutic landscape of GEP-NETs was limited to chemotherapy regimens with low response rates. The arrival of novel agents such as somatostatin analogues, peptide receptor radionuclide therapy, tyrosine kinase inhibitors or mTOR-targeted drugs, has changed the therapeutic paradigm of GEP-NETs. However, the efficacy of these agents is limited in time and there is scarce knowledge of optimal treatment sequencing. In recent years, massive parallel sequencing techniques have started to unravel the genomic intricacies of these tumors, allowing us to better understand the mechanisms of resistance to current treatments and to develop new targeted agents that will hopefully start an era for personalized treatment in NETs. In this review we aim to summarize the most relevant genomic aberrations and signaling pathways underlying GEP-NET tumorigenesis and potential therapeutic strategies derived from them., Competing Interests: Declaration of Competing Interest EG has received honoraria for speaker engagements, advisory roles or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, Thermo Fisher Scientific, and Zodiac. EG has received research grants from Pfizer, Merck, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals. JMC declares consultant, advisory or speaker roles for IPSEN, Roche, Pfizer, Sanofi, Janssen, and BMS. JMC has received research grants from Pfizer, IPSEN and Roche. TAG declares consultant, advisory or speaker roles for Ipsen, Pfizer, Roche, Bayer, Sanofi-Genzyme, Adacap, Janssen, Eisai, Bristol-Myers Squibb. TAG has received research grants from Pfizer, IPSEN and Roche. The other authors declare no conflicts of interest or state. The manuscript do not present other disclaimers, any prior presentations or acknowledgements., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The aim of our study was to describe the epidemiology, diagnosis, and treatment of the most complex pheochromocytoma and paraganglioma (PGL) cases, including pheochromocytoma/PGL during pregnancy, in cyanotic congenital heart diseases (CCHDs), and metastatic pheochromocytoma. The English and Spanish literature was thoroughly evaluated searching for articles reporting clinical studies, case reports, or reviews of pheochromocytoma/PGL in pregnancy and in CCHD and metastatic pheochromocytoma/PGL. Particular settings in the diagnosis and management of pheochromocytoma and PGLs remain challenging. Those special situations include the diagnosis during pregnancy or in the context of CCHD since the typical clinical features of pheochromocytoma may be confounded with preeclampsia during pregnancy and with the complications commonly observed in CCHD. In addition, although some clinical and genetic features have been associated with higher risk of metastatic pheochromocytoma, the detection and prediction of the development of metastatic disease involve another complex situation that may require special hormonal determinations as plasmatic 3-methoxytyramine and nuclear medicine studies including 18 FDG PET-CT or 18 F-FDOPA PET-CT, among others. Furthermore, the selection of the most appropriate treatment in these situations, as well as the moment to carry it out, requires special care as limited evidence is available. This article reviews the epidemiology, diagnosis, and treatment of the pheochromocytoma/PGL during pregnancy, metastatic pheochromocytoma/PGL, and pheochromocytoma/PGL in CCHD. The diagnosis, and especially the treatment, of metastatic pheochromocytomas and pheochromocytoma/PGL during pregnancy and in CCHD is challenging. Thus, these cases should be management in reference centres by multidisciplinary teams specialized in the pheochromocytoma/PGL treatment., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Opinion Statement: Neuroendocrine tumors (NET) represent a complex and heterogeneous group of malignancies arising from the diffuse endocrine cells and other cells derived from the neural crest. Advanced disease is observed at diagnosis in more than one-third of patients. Somatostatin analogs (SSA) are the cornerstone in advanced well-differentiated NET treatment. Unfortunately, most patients will eventually develop resistance to SSA treatment by different mechanisms that are not fully understood. In some cases of refractory carcinoid syndrome or progressive disease, the increase of SSA dose may help to reach out a symptomatic and/or tumor growth control. The clinical evidence behind above-label SSA administration is limited and should be individualized and discussed patient by patient. Some questions regarding high-dose SSA use are unsolved, such as the optimal dose to use, the frequency of administration, or the need of deepen molecular understanding that could help to adequately select patients for this approach., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: ESMO COVID-19 and CAncer REgistry (ESMO-CoCARE) is an international collaborative registry-based, cohort study gathering real-world data from Europe, Asia/Oceania and Africa on the natural history, management and outcomes of patients with cancer infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)., Patients and Methods: ESMO-CoCARE captures information on patients with solid/haematological malignancies, diagnosed with coronavirus disease 2019 (COVID-19). Data collected since June 2020 include demographics, comorbidities, laboratory measurements, cancer characteristics, COVID-19 clinical features, management and outcome. Parameters influencing COVID-19 severity/recovery were investigated as well as factors associated with overall survival (OS) upon SARS-CoV-2 infection., Results: This analysis includes 1626 patients from 20 countries (87% from 24 European, 7% from 5 North African, 6% from 8 Asian/Oceanian centres), with COVID-19 diagnosis from January 2020 to May 2021. Median age was 64 years, with 52% of female, 57% of cancer stage III/IV and 65% receiving active cancer treatment. Nearly 64% patients required hospitalization due to COVID-19 diagnosis, with 11% receiving intensive care. In multivariable analysis, male sex, older age, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, body mass index (BMI) <25 kg/m 2 , presence of comorbidities, symptomatic disease, as well as haematological malignancies, active/progressive cancer, neutrophil-to-lymphocyte ratio (NLR) ≥6 and OnCovid Inflammatory Score ≤40 were associated with COVID-19 severity (i.e. severe/moderate disease requiring hospitalization). About 98% of patients with mild COVID-19 recovered, as opposed to 71% with severe/moderate disease. Advanced cancer stage was an additional adverse prognostic factor for recovery. At data cut-off, and with median follow-up of 3 months, the COVID-19-related death rate was 24.5% (297/1212), with 380 deaths recorded in total. Almost all factors associated with COVID-19 severity, except for BMI and NLR, were also predictive of inferior OS, along with smoking and non-Asian ethnicity., Conclusions: Selected patient and cancer characteristics related to sex, ethnicity, poor fitness, comorbidities, inflammation and active malignancy predict for severe/moderate disease and adverse outcomes from COVID-19 in patients with cancer., Competing Interests: Disclosure MS was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers ‘Digital biodesign and personalized healthcare’ number 075-15-2020-926. DV reports travel, accommodations and expenses from Merk; honoraria for speakers bureau from Servier. RL reports speaker fee Astra Zeneca and institutional funding from BMS. ACr reports consulting or advisory role with Ipsen, Astellas, Pfizer, MSD Oncology Research (funding to self and hospital), Bristol-Myers Squibb, Merck (only hospital), Astellas, Amgen, Exelixis, Merck KGaA; and travel accommodations from Merck and Servier. SŠ reports honoraria and/or advisory fees from Roche, Pfizer, Novartis, Astra Zeneca and Amicus. MR received travel and personal fees from Novartis and Ipsen. TAG reports honoraria and/or advisory fees from IPSEN, Pfizer, Bayer, Sanofi, Janssen, Astellas, Adacap, Eisai, Lilly, Novartis, BMS. TKC reports institutional and personal, paid and unpaid support for research, advisory boards, consultancy and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, NiKang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (PeerView, OncLive, MJH and others), outside the submitted work; institutional patents filed on molecular mutations and immunotherapy response and ctDNA; equity in Tempest, Pionyr, Osel, Nuscan; serves on committees for NCCN, GU Steering Committee and ASCO/ESMO; Medical writing and editorial assistance support may have been funded by communications companies in part; no speaker’s bureau; has mentored several non-United States citizens on research projects with potential funding (in part) from non-United States sources/Foreign components; the institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. TKC is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham and Loker Pinard Funds for Kidney Cancer Research at DFCI. s provided upon request for scope of clinical practice and research. DA reports consultation/advisory role for AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi (Genzyme), Bayer, Terumo, Roche, Hexal, Samsung Bioepis, Pierre Fabre Pharma, CRA International, Ketchum, IQVIA; reports speaker’s engagement from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi (Genzyme), Bayer, Eli Lilly, Terumo, Boston Scientific, Amgen, Roche, Ipsen, Merck (Serono), Samsung Bioepis, Pierre Fabre Pharma, Servier, PharmaCept, PRMA Consulting, Tactics MD LLC, WebMD Health Corp, From Research to Practice, Aptitude Health, art tempi media, ACE Oncology, Imedex, streamitup Germany, MedAhead (Austria), Clinical Care Options (CCO); reports serving as local PI for Bristol Myers Squibb, Pierre Fabre Pharma and coordinating PI for OncoLytics; reports grant funding from AbbVie; reports being/been DSMB chair of Sanofi (Genzyme); reports being/been a steering committee member of Roche. KH declares research funding from AstraZeneca, Boehringer-Ingelheim, MSD, Replimune and advisory board fees/honoraria from Arch Oncology, AstraZeneca, BMS, Boehringer-Ingelheim, Codiak Biosciences, Inzen Therapeutics, Merck-Serono, MSD, Pfizer, Replimune. OM reports personal fees from Bristol-Myers Squibb, MSD, Novartis, Roche, Amgen, NeraCare GmbH, outside the submitted work. UD reports honorarium as Member of the Tumor Agnostic Evidence Generation Working Group of Roche, outside the submitted work. GP reports grants from Amgen, Lilly; grants, personal fees and nonfinancial support from Merck; grants and non-financial support from AstraZeneca; grants and personal fees from Roche, Bristol Myers Squibb, MSD, Novartis, outside the submitted work. SPe reports consultation/advisory role for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody; talk in a company’s organized public event for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda; receipt of grants/research supports from being a (sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. ER reports investigator-initiated trial (funds paid to the institution) supported by Astra-Zeneca, BMS; serves on the consultancy/advisory board for Astra-Zeneca, Merck, Roche, Pierre Fabre. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours with a diverse behaviour, biology and prognosis, whose incidence is gradually increasing. Their diagnosis is challenging and a multidisciplinary approach is often required. The combination of pathology, molecular biomarkers, and the use of novel imaging techniques leads to an accurate diagnosis and a better treatment approach. To determine the functionality of the tumour, somatostatin receptor expression, differentiation, and primary tumour origin are the main determining tumour-dependent factors to guide treatment, both in local and metastatic stages. Until recently, little was known about the biological behaviour of these tumours. However, in recent years, many advances have been achieved in the molecular characterization and diagnosis of NENs. The incorporation of novel radiotracer-based imaging techniques, such as 68 Gallium-DOTATATE PET-CT, has significantly increased diagnostic sensitivity, while introducing the theragnosis concept, offering new treatment strategies. Here, we will review current knowledge and novelties in the diagnosis of NENs, including molecular biology, pathology, and new radiotracers.

Introduction: Patients with cancer (PC) are at high risk of acquiring COVID-19 and can develop more serious complications. Deeper understanding of vaccines immunogenicity in this population is crucial for adequately planning vaccines programs. The ONCOVac study aimed to comprehensively assess the immunogenicity of mRNA-1273 vaccine in terms of humoral and cellular response., Methods: We conducted a prospective, single-center study including patients with solid tumours treated with cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), immunotherapy (IT) or chemotherapy (CT). Patients were enrolled previously to vaccination with mRNA-1273. We also involved health care workers (HCW) to serve as a control group. We took blood samples before first dose administration (BL), after first dose (1D), and after second dose (2D). The primary objective was to compare the rate and magnitude of T cell response after second dose whereas safety and humoral response were defined as secondary objectives. We also collected patient reported outcomes after both the first and second vaccine dose and a six-month follow-up period to diagnose incident COVID-19 cases was planned., Results: The rate of specific anti-S serologic positivity (anti-S IgG cut-off point at 7,14 BAU/mL) was significantly higher in HCW compared to PC after 1D (100% versus 83.8%; p = 0.04), but similar after 2D (100% versus 95.8%; p = 0.5). This difference after 1D was driven by PC treated with CT (100% versus 64.5%; p = 0.001). Cellular response after 2D was significantly lower in PC than in HCW for both CD4+ (91.7% versus 59.7%; p = 0.001) and CD8+ (94.4% versus 55.6%; p < 0.001) T cells. We found a difference on pre-existing CD4+ T cell response in HCW comparing to PC (36% and 17%, p = 0.03); without difference in pre-existing CD8+ T cell response (31% and 23%, p = 0.5). After excluding patients with pre-existing T cell response, PC achieved even lower CD4+ (50.9% versus 95.5%, p < 0.001) and CD8+ (45.5% versus 95.5%, p < 0.001) T cell response compared with HCW. Regarding safety, PC reported notably more adverse events than HCW (96.6% versus 69.2%, p < 0.001)., Conclusion: We demonstrated that PC showed a similar humoral response but a lower T cell response following two doses of mRNA-1273 vaccination. Further studies are needed to complement our results and determine the implication of low T cell response on clinical protection of PC against COVID-19., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alfonso Cortes declares the payment for presentations/speaker bureaus/manuscript-writing/educational events from GSK, AstraZeneca, Roche, MSD and Eisai. Alfonso Cortes declares consulting fees from Clovis, Lilly, Pfizer, GSK, Ferrer and Roche. Alfonso Cortes has received research grants from Pfizer. Alfonso Cortes declares support for attending meetings from Roche, Daiichi and Pfzer. Alfonso Cortes is co-founder of ONCARE. Jose Luis Casado and Federico Longo have not conflict of interest to declare. Juan José Serrano declares speaker bureau from Pierre-Fabre and travel/accomodation/expenses from Novartis. Cristina Saavedra declares travel/accomodation/expenses from Lilly and Pfizer. Hector Velasco, Alejandro Vallejo and Adrian San Miguel have not conflict of interest to declare. Jesus Chamorro and Diana Rosero have not conflict of interest to declare. María Fernandez, María Gion and Noelia Martinez have not conflict of interest to declare. Ainara Soria has not conflict of interest to declare. Teresa Alonso declares: Scientific Consultancy Role (speaker and advisory role) and travel grant from IPSEN, Pfizer, Bayer, Sanofi, Janssen, Astellas, Adacap, Eisai, Lilly, Novartis, BMS, Roche. Teresa Alonso declares the participation in Clinical trials from Roche, BMS, MSD, Pfizer, Novartis, IPSEN, Exelixis, Astrazeneca-Medimmune, Janssen, Lilly, Eisai, Astellas. Teresa Alonso declares research support from Roche, Pfizer, IPSEN. Iñigo Martinez and Yolanda Lage have not conflict of interest to declare. Elena López declares to receive advisory/consultancy honorarium from AstraZeneca, Pfizer, Roche, Novartis. Elena López has received speaker bureau/expert testimony honorarium from Roche, Novartis , Eisai, Astra Zeneca; and has received travel/accommodation/expenses from Roche, Novartis. María Eugenia Olmedo has not conflict of interest to declare. Pablo Reguera has not conflict of interest to declare. Pablo Gajate declares travel and educational support from BMS, MSD, Pfizer, Ipsen, Sanofi-Genzyne, Roche and Jansen. Pablo Gajate declares advisor and delivered lectures for BMS, MSD, Merck Serono, Pfizer, Ipsen, Roche, Adacap, Eisai, Sanofi-Genzyme, Novartis and Jansen. Javier Molina declares consultant, advisory or speaker roles for IPSEN, Roche, Pfizer, Sanofi, Janssen, and BMS. Javier Molina has received research grants from Pfizer, IPSEN and Roche. Eva Guerra declares: advisory/consultancy honorarium from AstraZeneca-MSD, Clovis Oncology, GSK-Tesaro, PharmaMar, Roche. Eva Guerra has received speaker bureau/expert testimony honorarium from AstraZeneca, PharmaMar, Roche, GSK; and has received travel/accommodation/expenses from Roche, TESARO, and Baxter. Raquel Fuentes, Beatriz Romero and Mario J Rodriguez-Dominguez have not conflict of interest. Alfredo Carrato has not conflict of interest to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies., Patients and Methods: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate., Results: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib., Conclusion: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens., Competing Interests: Disclosure EG has received honoraria for speaker engagements, advisory roles, or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, GSK, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, Thermo Fisher Scientific. TAG has received support for the present manuscript (protocol review and manuscript review); has received research grants from Pfizer, Roche, and Ipsen; has received consulting fees from Ipsen, Pfizer, Roche, Sanofi, Bayer, Astellas, Janssen-Cilag, BMS, and EISAI; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Pfizer, Eisai, and Merck; has received support for attending meetings and/or travel from Pfizer, Sanofi, BMS, and IPSEN. OR has received personal payment from Eusapharma, BMS, Pfizer, and Ipsen; has received support for attending meetings and/or travel from Ipsen and Pfizer; has participated in the Advisory Board of BMS and Bayer. XGdM has received consulting fees from Roche, Pharmamar, BMS, Ipsen, Lilly, Eusapharma, Pfizer, Merck, and Astellas; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from BMS, Astellas, Pharma, Eisai, Pfizer, and EusaPharma; has received support for attending meetings and/or travel from Pfizer and Roche; and has received research funding from AstraZeneca. MJM has received payment or honoraria as invited speaker from Janssen-Cilag, Bayer Healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, EISAI, Norvartis, Pfizer, and MSD; has received travel support from Roche and Ipsen; has participated on Data Safety Monitoring Board or Advisory Board of Janssen-Cilag, Bayer Healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, EISAI, Novartis, Pfizer, and MSD. JGD has received grants or contracts from Eusapharma, Bristol Myers, Novartis, GSK, Merck, MSD, Sanofi, Janssen, Astellas, Astra Zeneca, and Ipsen; has received support for attending meetings and/or travel from Roche; has participated on a Data Safety Monitoring Board or Advisory Board from Pfizer and Pharmamar. MGR has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche; has received support for attending meetings and/travel from Roche, Ipsen, AstraZeneca, MSD, and Jansen. JAAA has received grants or contracts from Bristol-Myers Squibb (grant to Spanish GU Oncology Group for research in prostate cancer); has received consulting fees from Janssen, Cilag, Pfizer, MSD, and Bristol-Myers Squibb; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas, Pfizer, and MSD; has received support for attending meetings and/or travel from MSD, Bristol-Myers Squibb, and Astra Zeneca. PLC has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from MSD and Bristol; has participated on a Data Safety Monitoring Board or Advisory Board from Sanofi and Roche. JMC has received support for the present manuscript (protocol review and manuscript review); has received grants or contracts from Pfizer and Ipsen; has received consulting fees from Ipsen, Pfizer, Roche, Sanofi, Astellas, Janssen Cilag, BMS, and EISAI; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Pfizer, and BMS; and has received support for attending meetings and/or travel from Pfizer, BMS, and Ipsen. BM has received research grant/funding (self) from Jansen, Roche, Astellas, Sanofi, and Bayer; has received payment or honoraria for speaker bureau from Pfizer, Ipsen, Jansen, Roche, Astellas, Sanofi, BMS, and Bayer; has received support for travel accommodation from Pfizer, Ipsen, Janssen, and Roche; other financial or non-financial interests: advisory and speaker bureau rom Pfizer, Ipsen, Jansen, Roche, Astellas, Sanofi, BMS, and Bayer; travel accommodation from Pfizer, Ipsen, Jansen, and Roche; and research grant/funding (self) from Roche, Astellas, Sanofi Jansen, BMS, and Bayer. CAF has received consulting fees from Ipsen, Boehringer Ingelheim, and Astra Zeneca; has received support for attending meetings and/or travel from Roche, Pfizer, and Astellas. GDV has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from BMS, Pfizer, Roche, Merk, MSD, Bayer, Eusapharma, Astellas, and Ipsen; has received support for attending meetings and/or travel from Roche; has participated on a Data Safety Monitoring Board or Advisory Board from BMS, Pfizer, Roche, Merck, MSD, Bayer, and Astellas. JFRM has received support for the present manuscript from Pfizer; has received grants or contracts from HM Hospitales; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Pfizer, BMS, Novartis, and MSD; has received support for attending meetings from Pfizer, BMS, Novartis, and MSD; has participated on a Data Safety Monitoring Board or Advisory Board from BMS and Novartis; and has participated in corporate-sponsored research in his institution from AstraZeneca, BMS, Amgen, Roche, Novartis, MSD, Janssen, Pfizer, Astellas, GSK, PharmaMar, Ipsen, Tesaro, Abbvie, Aprea Therapeutics, Eisai, Bayer, and Merck. CSR has received grants or contracts from AB Science, Aragon Pharmaceuticals, Astellas Pharma, Astra Zeneca AB, Bayer, Blueprint Medicines Corporation, Boehringer Ingelheim España SA, BMS, Clovis Oncology, Exelixix Inc F, Genentech Inc, GlaxoSmithKline SA, Hoffman-La Roche LTD, Novartis Farmaceutica SA, Pfizer SLU, and Sanofi-Aventis; has received payment or honoraria for speakers’ bureau from Astellas Pharma, BMS, Hoffmann-La Roche LTD, Ipsen, Pfizer SLU; has participated on a Data Safety Monitoring Board or Advisory Board from Astellas Pharma, Bayer, BMS, Eusapharma, Hoffmann-La Roche LTD, Ipsen, MSD, Novartis, Pfizer, and Sanofi-Aventis E. All other authors have declared no conflicts of interest. Data sharing The clinical trial data are available from the corresponding author upon reasonable request., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Thyroid cancer is the most frequently diagnosed endocrine malignancy, with an increasing incidence over the last decades. The recent advances in understanding the molecular mechanisms underlying the carcinogenesis of thyroid cancer have led to a better therapeutic approach of these tumors. This has allowed the development and approval of several drugs during the past decade. The rearranged during transfection [RET] protooncogene encodes a transmembrane receptor tyrosine kinase, which is activated by chromosomal rearrangements or point mutations in multiple malignancies, including thyroid cancer. Selective RET inhibitors have proved their value in the treatment algorithm in molecularly selected patients with significantly high response rates and duration of response. Notwithstanding, there are patients who experiment rapid progression or tumor recurrence after an early response to those targeted therapies, which suggest the existence of primary and acquired mechanisms of resistance that have been largely unknown to date. In the present review, we attempt to provide a comprehensive analysis of the most relevant mechanisms of resistance to RET inhibitors which could help in the development of next generation MKI and RET inhibitors, along with combination strategies with different targeted therapies that could potentially overcome these resistances., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A better understanding of the genetic and molecular background of bronchial carcinoids (BCs) would allow a better estimation of the risk of disease progression and the personalization of treatment in cases of advanced disease. Molecular studies confirmed that lungs neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are different entities; thus, no progression of NET to NEC is expected. In BCs, MEN1 gene mutations and deletions and decreased gene expression have been associated with a poor prognosis. ATRX mutation has also been linked to a shorter disease-specific survival. In terms of therapeutic targets, PI3K/AKT/mTOR pathway mutations have been described in 13% of typical carcinoids (TCs) and 39% of atypical carcinoids (ACs), representing a targetable mutation with kinase inhibitors. Regarding treatment, surgical resection is usually curative in localized BCs and adjuvant treatment is not routinely recommended. Multiple options for systemic therapy exist for patients with advanced BCs, although limited by a heterogeneity in the scientific evidence behind their use recommendation. These options include somatostatin analogues, everolimus, peptide receptor radionuclide therapy, chemotherapy, radiotherapy, antiangiogenic agents, and immunotherapy. In this article, we provide a comprehensive review about the molecular and genetic background of BCs, and about the treatment of local and metastatic disease, as well as the main paraneoplastic syndromes that have been associated with this tumor.

Background and Aims: Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives., Methods: Formalin-fixed paraffin-embedded samples of mUC patients ( n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n = 11) or responders (R: response ≥ 6 months; n = 12)., Results: Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment., Conclusions: Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.

Introduction: Somatostatin analogs (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NENs., Methods: We identified patients with well-differentiated (Ki-67% ≤20%), metastatic GEP-NENs treated in first line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real-world clinical practice versus RCTs., Results: The dataset contained 535 patients with a median age of 62 years (range: 26-89). The median Ki-67% was 4 (range: 0-20). The most common primary tumor sites were as follows: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n = 266) and half, lanreotide autogel (n = 269). The median PFS was 28.0 months (95% CI: 22.1-32.0) for octreotide versus 30.1 months (95% CI: 23.1-38.0) for lanreotide. The overall hazard ratio for lanreotide versus octreotide was 0.90 (95% credible interval: 0.71-1.12). The probability of effect sizes >30% with lanreotide versus octreotide was 2 and 6% for midgut and foregut NENs, respectively., Conclusion: Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data). Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs., (© 2021 S. Karger AG, Basel.)

Objective: To offer a practical guide for the presurgical and anesthetic management of pheochromocytomas and sympathetic paragangliomas (PGLs)., Methods: This protocol was based on a comprehensive review of the literature and on our own multidisciplinary team's experience from managing pheochromocytoma and sympathetic PGLs at a referral center., Results: Patients with pheochromocytomas and sympathetic paragangliomas (PGLs) may develop potentially life-threatening complications, especially during surgical procedures. A complete biochemical, radiological, genetic, and cardiological assessment is recommended in the preoperative stage as it provides an evaluation of the risk of surgical complications and malignancy, allowing individualization of the presurgical treatment. Treatment with α-blockade and proper volume expansion in the preoperative stage significantly reduces the perioperative morbidity. During surgery, the anesthesiologist should look for a deep anesthetic level that inhibits the cardiovascular effects of catecholamines to minimize the risk of intraoperative complications., Conclusions: An optimal presurgical evaluation of pheochromocytomas/ sympathetic PGL requires a multidisciplinary approach, including a complete hormonal, radiological, cardiac, genetic, and functioning evaluation in most cases. A proper preoperative evaluation in combination with strict blood pressure and heart rate control, and blood volume status optimization, will significantly reduce the risk of intraoperative and perioperative complications. In those patients who unfortunately develop intraoperative complications, the role of the anesthesiologist is essential since the selection of the appropriate management has a direct impact on morbimortality reduction., (© 2021. Italian Society of Endocrinology (SIE).)

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.

Background: Sunitinib (SUN)-induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo-isophosphoramide mustard. SUNEVO, a phase II, open-label, single-arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs)., Methods: Systemic treatment-naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m 2 on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1., Results: From 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow-up of 15.7 months, 17.6% of patients achieved a complete (n = 1) or partial response (n = 2), and 11 patients had stable disease (64.7%). The median progression-free survival was 10.4 months (95% confidence interval, 2.6-18.0). Treatment-related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX, ATRX, MEN1, SETD2, and PTEN gene mutations., Conclusion: SUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. (Clinical trial identification number: NCT02402062) IMPLICATIONS FOR PRACTICE: Addition of hypoxia-activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression-free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs' resistance to antiangiogenic agents with other therapies with a safer profile., (© 2021 AlphaMed Press.)

Introduction: Androgenic deprivation therapies have been linked to the development of metabolic syndrome (MS) and cardiovascular diseases, which may lead to a poorer survival in patients with metastatic Castration-Resistant Prostate Cancer (mCRPC). We aimed to analyze whether some cardiovascular or neurological disorders, together with other medical and urological complications, may have an effect on survival outcomes, at baseline and during treatment from patients treated with androgen pathway inhibitors (API)., Material and Methods: A retrospective study of a consecutive series of patients diagnosed with mCRPC between 2010 and 2018 treated with API in the first line setting in a single center., Results: Seventy-three patients met the inclusion criteria. Baseline prognostic factors associated with worse survival were diabetes mellitus (DM) with insulin needs compared to patients without DM [hazard ratio (HR) = 0.19, p  = 0.025], hypertension (HTN) (HR = 0.46, p  = 0.035), and a history of stroke (HR = 0.16, p  < 0.001). However, previous history of hypercholesterolemia, arrythmias, and cognitive disorders did not result in a significant worsening on survival. During treatment, patients who developed de novo HTN had the best progression free survival (PFS) (HR = 0.38, p  = 0.048) and overall survival (OS) (HR 0.08, p  = 0.012) compared with patients with previous HTN. Other factors related to worse outcomes included the presence of heart failure (HR = 0.31, p  = 0.001), the requirement for major opioids for pain relief (HR = 0.33, p  = 0.023), and the presence of bilateral ureterohydronephrosis (HR = 0.12, p  = 0.008)., Conclusions: Some comorbidities may be strongly involved in patient outcomes when receiving API for mCRPC. In this sense, collaborative networking between specialists and caregivers treating prostate cancer (PC) patients should be recommended, focusing on MS features, cardiovascular and neurological disorders in order to anticipate medical and surgical complications., Competing Interests: Conflict of interest statement: Juanjo Serrano Domingo declares Travel expenses from Janssen. Teresa Alonso Gordoa declares Advisory Boards: Bayer, Janssen, Sanofi, Astellas; Speaker: Janssen, Astellas; Travel expenses: Sanofi Javier Lorca Álvaro declares Travel expenses from Astellas. Arantza Barquín García declares no conflicts of interest Javier Molina Cerrillo declares Advisory Boards: Sanofi; Speaker: Janssen. Olga Martínez Sáez declares no conflicts of interest. Javier Burgos Revilla declares Advisory Boards and Honoraria from Astellas, Janssen and Sanofi and Travel Grants from Astellas and Janssen. Alfredo Carrato declares Advisory Boards: Bayer. Sara Álvarez Rodriguez has received honoraria from Janssen, Astellas and Bayer., (© The Author(s), 2021.)

There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from the duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1 = 74; L2 = 52) included alkylating-based (n = 32), etoposide-platinum (n = 22) or adenocarcinoma-like (n = 20) chemotherapy, somatostatin analogs (n = 21), targeted therapies (n = 22) and liver-directed therapies (n = 7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI (1.5-12.2); P = 0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (P < 0.001 and P = 0.008, respectively). The longest median PFS was obtained with adenocarcinoma-like chemotherapy (16.5 months (9.0-24.0)) and targeted therapies (12.0 months (8.2-15.8)), while the shortest PFS was observed with somatostatin analogs (6.2 months (3.8-8.5)) and etoposide-platinum chemotherapy (7.2 months (5.2-9.1)). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 (1.61-8.44), P = 0.002) and alkylating-based chemotherapies (multivariable HR 1.95 (1.01-3.78), P = 0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.

Background: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear., Methods: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated., Results: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels., Conclusions: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown., Materials and Methods: We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells., Results: Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months; p = 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemotherapy arm [46/57 (81%) vs 44/74 (59%)]., Conclusion: Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab.

Background: Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited., Materials and Methods: To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014-2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints., Results: A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6-173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6-16.2) and 11.9 months (95% CI, 8.6-14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2-16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1-4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8-86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2-10; p = .01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea., Conclusion: SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%., Implications for Practice: The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population., (© 2020 AlphaMed Press.)

Purpose: Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported., Methods: In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1., Results: In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent., Conclusion: Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

Background: Somatostatin analogues are an established first-line therapy for well differentiated small bowel neuroendocrine tumours (Wd-SBNETs), while and peptide receptor radionuclide therapy (PRRT) is frequently used as a second-line therapy. Adequate treatment selection of third-line treatment remains challenging due to the limited prospective data currently available on the best therapeutic sequence., Aim: To understand current practice and rationale for decision-making by physicians in the 3 rd -line setting by building an online survey., Methods: Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored., Results: Replies from representatives of 28 centers were received (5/8/2020-21/9/2020); medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from European Neuroendocrine Tumor Society (ENETS) Centres of Excellence (57.1%), who followed ENETS guidelines (82.1%). Generally speaking, 3 rd -line treatment for Wd-SBNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon-alpha (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%), or personal experience (22.2%). EVE was most likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3 rd -line setting (WA 3.23/4); regardless of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was mainly utilised only if rapid progression (within 6 mo) (WA 3.35/4), Ki-67 10%-20% (WA 2.77/4), negative somatostatin receptor imaging (WA 2.65/4) or high tumour burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-fluorouracil (5-FU) (57.7%), FOLFOX (5-FU combined with oxaliplatin) (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4)., Conclusion: Everolimus was the most frequently used therapeutic option in the third-line setting. The most important factors for decision-making included Ki-67, rate of progression, functionality and tumour burden; since this decision is based on multiple factors, it highlights the need for a multidisciplinary assessment., Competing Interests: Conflict-of-interest statement: Dr Angela Lamarca received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen, Incyte and AAA; advisory honoraria from EISAI, Nutricia Ipsen, QED and Roche. Dr. Mauro Cives received travel support from Ipsen, Novartis, Pfizer and AAA; speaker honoraria from Ipsen, Novartis and AAA; advisory honoraria from AAA. Dr. Joakim Crona received educational honoraria from Novartis., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)