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Background:Multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are known to cause cardiac toxicity, but the relative risk (RR) of QTc interval prolongation and serious arrhythmias associated with them are not reported.Methods:We conducted a trial-level meta-analysis of randomised phase II and III trials comparing arms with and without a US Food and Drug Administration-approved VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib and regorafenib). A total of 6548 patients from 18 trials were selected. Statistical analyses were conducted to calculate the summary incidence, RR and 95% CIs.Results:The RR for all-grade and high-grade QTc prolongation for the TKI vs no TKI arms was 8.66 (95% CI 4.92-15.2, P<0.001) and 2.69 (95% CI 1.33-5.44, P=0.006), respectively, with most of the events being asymptomatic QTc prolongation. Respectively, 4.4% and 0.83% of patients exposed to VEGFR TKI had all-grade and high-grade QTc prolongation. On subgroup analysis, only sunitinib and vandetanib were associated with a statistically significant risk of QTc prolongation, with higher doses of vandetanib associated with a greater risk. The rate of serious arrhythmias including torsades de pointes did not seem to be higher with high-grade QTc prolongation. The risk of QTc prolongation was independent of the duration of therapy.Conclusions:In the largest study to date, we show that VEGFR TKI can be associated with QTc prolongation. Although most cases were of low clinical significance, it is unclear whether the same applies to patients treated off clinical trials. [ABSTRACT FROM AUTHOR]

Background: Recombinant human erythropoietin (rhEPO) is effective for the treatment of anemia associated with multiple myeloma. Data from animal studies and case reports suggest that rhEPO has antineoplastic properties. Methods: Two hundred and ninety-two patients enrolled on different chemotherapy clinical trials at the Cleveland Clinic Myeloma Program between 1997 and 2003 were the subjects of this study. Information on erythropoietin use as well as baseline prognostic variables were collected retrospectively. Results: The population consisted of 257 patients with multiple myeloma treated at the Cleveland Clinic Foundation from 1997 to 2003 and followed for at least 1 month. Thirty-five patients were excluded from this analysis because information on erythropoietin use was not available. One hundred and twenty-seven patients received rhEPO for at least 1 month and the rest did not received rhEPO. On average, patients who received rhEPO were older, had a higher Southwest Oncology Group (SWOG) stage, higher serum creatinine, lower serum hemoglobin, higher β2-microglobulin, lower platelet counts, and a longer time from diagnosis to enrollment at the myeloma program (p < 0.001 for all). After adjusting for age, months from diagnosis to enrollment, serum creatinine, hemoglobin, platelet count, and β2-microglobulin, the use of rhEPO was associated with improved overall survival (hazard ratio = 0.6; 95% CI = 0.38–0.94) in patients with SWOG stages II, III and IV but not in patients with SWOG stage I. Conclusion: rhEPO was associated with improved overall survival in this population of anemic multiple myeloma patients with SWOG stages of II, III and IV. A prospective randomized trial is warranted to corroborate this finding. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

BACKGROUND: The concept behind cancer treatment has evolved over the past decade from systemic, nonspecific, high-dose chemotherapy to targeted therapy and the introduction of cancer vaccines. Advanced technology and a better understanding of the cellular mechanisms that control cancer biology have helped in the development of such targeted treatment. OBJECTIVE: The aim of this article was to review some of the new and commonly used targeted treatments in cancer, emphasizing their mechanisms of action, safety profiles, and clinical applications. METHODS: The terms cancer, chemotherapy, monoclonal antibodies, targeted treatment, tyrosine kinase, epidermal growth factors, epidermal growth factor receptor, and cancer vaccines were used to search MEDLINE for English-language studies in humans, published between 1966 and March 2003. Identified publications addressing the objectives of this article were selected for review. RESULTS: All-trans-retinoic acid, imatinib, gemtuzumab ozogamicin, rituximab, alemtuzumab, trastuzumab, cetuximab, and gefitinib are recently developed cancer therapies that target specific types of cells and receptors. They have been used in a variety of hematologic and solid tumors, and their tolerability makes them attractive for use even in elderly and extensively pretreated patients. Vaccines using dendritic cells, tumor cells, and fusions of tumor cells and antigen-presenting cells have also shown some promise in research, but further study is needed to obtain better, sustained results. CONCLUSIONS: Targeted treatment and cancer vaccines are novel approaches in the treatment of cancer. Both fields are expanding rapidly, with new technology and ongoing medical research. The clinical implications of such agents, administered either solely or in combination with established chemotherapeutic agents, may ultimately lead to better regimens and improved clinical responses. [ABSTRACT FROM AUTHOR]

Metastatic renal cell carcinoma (RCC) was, until recently, considered a challenging disease to treat with few therapeutic options of limited benefit. The past few years have seen spectacular advances in the treatment of this disease based on understanding the molecular pathways behind tumor growth and angiogenesis. This progress has led to the development of targeted therapies such as the receptor tyrosine kinase inhibitors sunitinib and sorafenib, the anti-vascular endothelial growth factor antibody bevacizumab, and a class of rapamycin analogues that includes temsirolimus and everolimus that have each demonstrated clinical efficacy in patients with metastatic RCC. The goal of this manuscript is to review the current evidence based on large randomized trials and propose a rationale paradigm for the treatment of this disease.

BACKGROUND Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P = 0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749). [ABSTRACT FROM AUTHOR]

Background: In 2012, the United States Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen (PSA) screening, despite evidence that Black men are at a higher risk of prostate cancer-specific mortality (PCSM). We evaluated whether Black men of potentially screening-eligible age (55-69 years) are at a disproportionally high risk of poor outcomes. Patients and methods: The SEER database was used to study 390 259 men diagnosed with prostate cancer in the United States between 2004 and 2011. Multivariable logistic regression modeled the association between Black race and stage of presentation, while Fine-Gray competing risks regression modeled the association between Black race and PCSM, both as a function of screening eligibility (age 55-69 years versus not). Results: Black men were more likely to present with metastatic disease (adjusted odds ratio [AOR] 1.65; 1.58-1.72; P < 0.001) and were at a higher risk of PCSM (adjusted hazard ratio [AHR] 1.36; 1.27-1.46; P < 0.001) compared to non-Black men. There were significant interactions between race and PSA-screening eligibility such that Black patients experienced more disproportionate rates of metastatic disease (AOR 1.76; 1.65-1.87 versus 1.55; 1.47-1.65; Pinteraction < 0.001) and PCSM (AHR 1.53; 1.37-1.70 versus 1.25; 1.14-1.37; Pinteraction = 0.01) in the potentially PSA-screening eligible group than in the group not eligible for screening. Conclusions: Racial disparities in prostate cancer outcome among Black men are significantly worse in PSA-screening eligible populations. These results raise the possibility that Black men could be disproportionately impacted by recommendations to end PSA screening in the United States and suggest that Black race should be included in the updated USPSTF PSA screening guidelines. [ABSTRACT FROM AUTHOR]

Background: Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.Methods: In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more.Results: The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).Conclusions: Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .). [ABSTRACT FROM AUTHOR]

Background: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.Methods: A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.Results: The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).Conclusions: Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.). [ABSTRACT FROM AUTHOR]

Background: Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC.Methods: This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary end point was the objective response rate (ORR). Secondary end points included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives.Results: Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had>10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with≤10% sarcomatoid histology (P = 0.04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7).Conclusions: These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation. [ABSTRACT FROM AUTHOR]

Background: The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology study in patients with aRCC (FRACTION-RCC) was designed to assess new immuno-oncology (IO) combinations in patients with advanced renal cell carcinoma (aRCC). We present results in IO-naive patients treated with nivolumab (NIVO) + relatlimab (RELA) or NIVO + ipilimumab (IPI) in track 1., Methods: The open-label, randomised, phase II FRACTION-RCC trial enrolled patients with aRCC from 32 hospitals and cancer centres across six countries. Patients were enrolled in track 1 (IO-naive) or track 2 (IO-experienced). IO-naive patients were stratified by previous tyrosine kinase inhibitor therapy and randomised to NIVO (240 mg) + RELA (80 mg) intravenously once every 2 weeks or NIVO (3 mg/kg) + IPI (1 mg/kg) intravenously once every 3 weeks for four doses, followed by NIVO (480 mg) once every 4 weeks, each up to ∼2 years. The primary endpoints were objective response by investigator (RECIST version 1.1), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Safety was a secondary endpoint; biomarker analyses were exploratory., Results: FRACTION-RCC enrolled patients between 2 February 2017 and 23 January 2020. In track 1, 30 patients each were treated with NIVO + RELA or NIVO + IPI (clinical database lock, 1 November 2021). With NIVO + RELA [median follow-up, 48.6 months; interquartile range (IQR) 46.9-51.7 months], objective response was 30% [95% confidence interval (CI) 15% to 49%], with 33 weeks (95% CI 16-53 weeks) median DOR. The PFS rate at 24 weeks was 43% (95% CI 25% to 60%). With NIVO + IPI (median follow-up, 48.7 months; IQR 47.1-52.0 months), the objective response was 20% (95% CI 8% to 39%), with the median DOR not reached (95% CI 33 weeks-not estimable). The PFS rate at 24 weeks was 49% (95% CI 29% to 66%). Higher baseline lymphocyte activation gene 3 (LAG-3) and programmed death-ligand 1 (PD-L1) expression levels were detected among track 1 NIVO + RELA responders. Grade 3-4 treatment-related adverse events were reported in 4/30 (13%) patients treated with NIVO + RELA and 10/30 (33%) patients treated with NIVO + IPI. No deaths were attributed to study treatments., Conclusions: Results showed antitumour activity and manageable safety with NIVO + RELA. Findings also support NIVO + IPI as an effective combination regimen in IO-naive patients with aRCC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Renal cell carcinoma (RCC) is characterized by recurrent somatic mutations in epigenetic regulators, which stratify patients into clinically significant subgroups with distinct prognoses and treatment responses. However, the cell type-specific epigenetic landscape of RCC-broadly and in the context of these mutations-is incompletely understood. To investigate these open questions, we integrated single nucleus ATAC sequencing data from RCC tumors across four independent cohorts. In clear cell RCC tumors, we identified four shared malignant epigenetic programs related to angiogenesis, proximal tubule-like features, interferon (IFN) signaling, and one that lacked distinct genomic regions with increased accessibility. Among the mutated epigenetic regulators, BAP1 mutation exhibited the most significant impact on chromatin accessibility in tumor cells, and the associated epigenetic changes were linked to IFN response. We identify multiple potential sources of elevated IFN signaling in these lesions, such as increased immune infiltration and increased accessibility and expression of an IFN-associated ERV, ERV3-16A3&#95;LTR. We find that the expression of ERV3-16A3&#95;LTR may itself be a negative prognostic biomarker in ccRCC. Our findings highlight the convergence of malignant epigenetic programs across ccRCC tumors and suggest that BAP1 loss, potentially through ERV3-16A3&#95;LTR dysregulation, is associated with an IFN response-high epigenetic program.

Background: Nivolumab plus ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years of median follow-up from CheckMate 214., Patients and Methods: Patients with aRCC (N = 1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. The endpoints included OS, independent radiology review committee (IRRC)-assessed progression-free survival (PFS), and IRRC-assessed objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients., Results: With 8 years (99.1 months) of median follow-up, the hazard ratio [HR; 95% confidence interval (CI)] for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). The median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1 months-not estimable (NE) versus 19.8-33.2 months] in ITT patients, 82.8 versus 19.8 months (54.1 months-NE versus 16.4-26.4 months) in I/P patients, and 61.5 versus 33.2 months (27.8 months-NE versus 24.8-51.4 months) in FAV patients. The incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time., Conclusions: Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only., Methods: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or T any N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual., Findings: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related., Interpretation: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma., Funding: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb., Competing Interests: Declaration of interests VM reports support for attending meetings or travel from American College of Surgeons; and participation on the Advisory Board on Diversity, Equity, and Inclusion at Exelixis. VM also reports a leadership role (unpaid) on Society of Urologic Oncology Clinical Trials Consortia. DFM received payment or honoraria from Bristol Myers Squibb, Pfizer, Merck, Eisai, Xilio, Aveo, Genentech, Cullinan, and Exelixis; and support for attending meetings or travel from Bristol Myers Squibb, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes. LCH reports ownership of stock in Coherus and previous employment at Surface Oncology. SS reports grants or contracts from Bristol Myers Squibb and Exelixis to their institution; and royalties or licenses from Biogenex. SS also reports consulting fees from AstraZeneca, Merck, and CRISPR Therapeutics; and a leadership or fiduciary role at American Association for Cancer Research as Senior Editor at Clinical Cancer Research and at the NCI National Cancer Institute as Renal Task Force Co-Chair. HE reports consulting fees for Janssen and Aveo advisory boards. NA reports grants or contracts from Exelixis, Genentech, Merck, and Bristol Myers Squibb; and consulting fees from Exelixis, Bristol Myers Squibb, Aveo, Merck, EMD Serono, and Sanofi. MAB reports institutional grants from Merck, Xencor, Bayer, Bristol Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer; and payment or honoraria for Advisory Board participation from Exelixis, Bayer, Bristol Myers Squibb, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi. TMM reports payment to their institution for clinical trials from Merck, Curium, and ECOG; consulting fees from Impact Network and Aptitude Health; and honoraria from Exelixis and Blue Earth Diagnostics. TC reports support from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work. TC also reports institutional research funding related to clinical trials from AstraZeneca, Aveo, Arcus, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, and Takeda. TC also reports consulting fees from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work. TC also reports payment or honoraria from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work. TC also reports support for attending meetings or travel in relation to meetings, lectures, and advisory boards; and participates in the Aravive Data and Safety Monitoring Board or advisory board. TC also reports a patent related to ctDNA and biomarkers of response to immune checkpoint inhibitors (no royalties as of current date). TC also reports a leadership or fiduciary role in KidneyCan (unpaid) and committees for American Society of Clinical Oncology, European Society of Medical Oncology, National Comprehensive Cancer Network, and Genitourinary Steering Committee of the NCI. TC also reports stock ownership (for being an advisor) of Pionyr, Tempest, Precede Bio, Osel, Curesponse, Immdura, and Primium. TC also reports no receipt of equipment, materials, drugs, medical writing, gifts, or other services, except for travel and accommodation (flights, hotel, and meals) related to advisory or consulting when travel needed. TC also reports to be 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, Pan-Mass Challenge, Hinda and Arthur Marcus Fund, and Loker Pinard Funds for Kidney Cancer Research at Dana Farber Cancer Institute. MDD reports participation on the Scientific Advisory Boards (honoraria received) at Merck, Eisai, Exelixis, and Janssen. DYH reports compensation from consulting work from Bristol Myers Squibb, Merck, Ipsen, Exelixis, Pfizer, and Eisai. BS reports consulting fees from Merck, Veracyte, Telix, and Johnson and Johnson; payment or honoraria from Merck; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Telix. BCL reports a leadership or fiduciary role at Kidney Cancer Association as Chair of Board of Directors. JM reports participation on the NCI Central Institutional Review Board and has been recused from all discussions of this study. RU reports participation and financial support on a Data Safety Monitoring Board at Pfizer and other financial support on a steering committee at Merck. RU also reports a leadership or fiduciary role (non-financial support) at Haymarket Media as a board member. GB reports a leadership role during the study as President of the Society of Urologic Oncology–Clinical Trial Consortium. NBH reports participation in the Data and Safety Monitoring Committee atezolizumab at Roche Genentech and advisory boards at Bristol Myers Squibb and Eisai. NBH also reports a non-financial leadership role as ECOG ACRIN Genitourinary Committee Co-Chair. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Lymphocytes are closely linked to mechanisms of action of immuno-oncology (IO) agents. We aimed to assess the prognostic significance of absolute lymphocyte count (ALC) in patients with metastatic renal cell carcinoma (mRCC)., Patients and Methods: Using the International mRCC Database Consortium (IMDC), patients receiving first-line IO-based combination therapy were analysed. Baseline patient characteristics, objective response rates (ORRs), time to next treatment (TTNT), and overall survival (OS) were compared., Results: Of 966 patients included, 195 (20%) had lymphopenia at baseline, and they had a lower ORR (37% versus 45%; P < 0.001), shorter TTNT (10.1 months versus 24.3 months; P < 0.001), and shorter OS (30.4 months versus 48.2 months; P < 0.001). Among 125 patients with lymphopenia at baseline, 52 (42%) experienced ALC recovery at 3 months, and they had longer OS (not reached versus 30.4 months; P = 0.012). On multivariable analysis for OS, lymphopenia was an independent adverse prognostic factor (hazard ratio 1.68; P < 0.001). Incorporation of lymphopenia into the IMDC criteria improved OS prediction accuracy (C-index from 0.688 to 0.707)., Conclusions: Lymphopenia was observed in one-fifth of treatment-naive patients with mRCC and may serve as an indicator of unfavourable oncologic outcomes in the contemporary IO era., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: This research explores the impact of the COVID-19 pandemic on psychotherapists' practices and their ability to maintain a framework despite a shared reality with their patients. The specific focus in this article is on the Lebanese context, which is characterized by a series of crises including economic collapse, the COVID-19 pandemic, and the Beirut blast. The objective of this study was to examine how the destabilization of the meta-frame due to crises necessitates adaptations in theoretical knowledge, practice, and setting., Methods: We conducted a qualitative study among a population consisting of mental health professionals, which were recruited in Lebanon through associations and societies of psychologists, psychotherapists, and psychoanalysts. Data was collected using semi-structured individual interviews. The interviews were analyzed using interpretative phenomenological analysis (IPA), which allowed for a dynamic exploration of the participants' experiences., Results: Our study revealed four superordinate themes: (1) The strained frontiers; (2) The cumulative traumatic reality and its impact; (3) A challenged professional identity; (4) The creativity stemming from collective trauma., Conclusions: Our results highlight the insecurity caused by external reality infiltrating the therapeutic setting. Online therapy allowed for continued work, but uncertainty about the online environment's impact on therapeutic relationships was observed. The study underscores the importance of adaptability, containment, and support for therapists navigating crises, particularly in the online setting., (© 2024. The Author(s).)

Background: Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score., Patients and Methods: Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability., Results: Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71]; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN [56% (50% to 62%) versus 28% (23% to 33%)]; 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN., Conclusions: After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC., Trial Registration: ClinicalTrials.gov, NCT03141177., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018)., Patients and Methods: Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints., Results: Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months., Conclusions: The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted., Competing Interests: Disclosure BAM reports consulting fees from BMS, Eisai, Exelixis, Gilead, Pfizer, SeaGen and research funding to institution from BMS, Exelixis, Pfizer, SeaGen. GPS reports consulting fees from, Genentech, EMD Serono, Merck, Astrazeneca, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse, Tempus, Ellipses Pharma, PrecisCa, Primum. He serves on scientific advisory board for Suba Therapeutics, Syapse, Servier, Merck, Syncorp and reports research support to institution from Sanofi, Astrazeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono, Jazz Therapeutics. He is a paid speaker for BIO – INFORMAÇÃO BRASILEIRA DE ONCOLOGIA Ltda, OLE Forum (Mexico), Seagen, Gilead, Natera, Exelixis, Janssen, Bayer, Aveo and serves on data safety monitoring committee honorarium for Mereo. His spouse is employed by Myriad. XG reports consulting fees from Bayer, Flare Therapeutics, Myovant, PathAI, PureTech Bio, Silverback Therapeutics. CMM reports consulting fees from Aadi Bioscience, Synthekine and research funding to institution from BMS. XXW reports consulting fees from Novartis and research funding to institution from BMS. JEB reports speaker honoraria from Guardant Health with consulting fees from Guardant Health, Genome Medical, Oncotect, Precede, TracerDx, Musculo, JucaBio. He has equity in Cityblock Health, Genome Medical, Oncotect, Precede, TracerDx, Musculo and institutional patent filed on methods to detect neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis. SAB reports consulting fees from BMS, Eisai, Exelixis, Seagen. PKR reports research funding to institution from Bayer, Telix, and Lilly. MDM reports scientific advisory boards for Merck and Janssen. TKC reports consulting fees from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO and others), outside the submitted work. He has institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA and equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium. He 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, Pan Mass Challenge, Hinda, Arthur Marcus Fund, and Loker Pinard Funds for Kidney Cancer Research at DFCI. JB reports personal and institutional financial interests with Genentech, Pfizer, Bristol-Myers Squibb, AstraZeneca, Merck, Takeda, Eisai, Scholar Rock, Surface Oncology, Gilead, Ipsen, and Pierre-Fabre, trial sponsorship through Associació per a la Recerca Oncológia (APRO), royalties from UpToDate, stocks from Rainier Therapeutics, and a nonfinancial interest as President of APRO. All other authors have declared no conflicts of interest., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: In the phase III JAVELIN Renal 101 trial, first-line avelumab + axitinib improved progression-free survival (PFS) and objective response rate versus sunitinib in patients with advanced renal cell carcinoma across all International Metastatic RCC Database Consortium (IMDC) risk groups (favorable, intermediate, and poor); analyses of overall survival (OS) remain immature. Here, we report post hoc analyses of efficacy from the third interim analysis (data cut-off, April 2020) by the numbers of IMDC risk factors and target tumor sites at baseline., Methods: Efficacy endpoints assessed were PFS, objective response, and best overall response per investigator assessment (RECIST v1.1) and OS. Best percentage change and percentage change from baseline in target tumor size over time during the study were also assessed., Results: In patients with 0, 1, 2, 3, or 4-6 IMDC risk factors, hazard ratios [HRs; 95% confidence interval (CIs)] for OS with avelumab + axitinib versus sunitinib were 0.660 (0.356-1.223), 0.745 (0.524-1.059), 0.973 (0.668-1.417), 0.718 (0.414-1.248), and 0.443 (0.237-0.829), and HRs (95% CIs) for PFS were 0.706 (0.490-1.016), 0.709 (0.540-0.933), 0.711 (0.527-0.960), 0.501 (0.293-0.854), and 0.395 (0.214-0.727), respectively. In patients with 1, 2, 3, or ≥4 target tumor sites, HRs (95% CIs) for OS with avelumab + axitinib versus sunitinib were 0.912 (0.640-1.299), 0.715 (0.507-1.006), 0.679 (0.442-1.044), and 0.747 (0.346-1.615), and HRs (95% CIs) for PFS were 0.706 (0.548-0.911), 0.552 (0.422-0.723), 0.856 (0.589-1.244), and 0.662 (0.329-1.332), respectively. Across all subgroups, analyses of objective response rate and complete response rate favored avelumab + axitinib versus sunitinib, and a greater proportion of patients treated with avelumab + axitinib had tumor shrinkage., Conclusions: In post hoc analyses, first-line treatment with avelumab + axitinib was generally associated with efficacy benefits versus treatment with sunitinib in patients with advanced renal cell carcinoma across subgroups defined by different numbers of IMDC risk factors or target tumor sites., Competing Interests: Disclosure YT has participated in consulting or advisory roles for Eisai, Merck Sharp & Dohme (MSD), and Ono Pharmaceutical; has received honoraria from Astellas Pharma, Bristol Myers Squibb Japan, Chugai Pharma, Novartis, Ono Pharmaceutical, and Pfizer; and has received research funding from Astellas Pharma, AstraZeneca, Chugai Pharma, Eisai, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Takeda. RJM has participated in consulting or advisory roles for AstraZeneca, Aveo, Calithera Biosciences, Eisai, Exelixis, Genentech/Roche, Incyte, Pfizer, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA; has received travel, accommodations, and expenses from Bristol Myers Squibb; and has received research funding from Aveo, Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Novartis, Pfizer, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. TKC reports institutional and personal, paid and/or unpaid support for research, advisory boards, consultancy, and honoraria from Aravive, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, CME events (Peerview, OncLive, MJH and others), Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, MSD, NiKang, Novartis, Nuscan, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, and Up-To-Date, outside the submitted work; reports institutional patents filed on molecular alterations and immunotherapy response/toxicity, and circulating tumor DNA; reports equity Osel, Pionyr, Precede Bio, and Tempest; has served in committees for ACCRU, ASCO/ESMO, GU Steering Committee, KidneyCan, and NCCN; reports that medical writing and editorial assistance support may have been funded by communications companies in part; has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components; reports that 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; and 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, Pan Mass Challenge, and Loker Pinard Funds for Kidney Cancer Research at DFCI. BIR has participated in consulting or advisory roles for 3D Medicines, Aravive, Arrowhead Pharmaceuticals, Aveo, Bristol Myers Squibb, Corvus Pharmaceuticals, Eisai, GlaxoSmithKline, Pfizer, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Shionogi, Surface Oncology, and Synthorx; reports leadership with MJH Life Sciences; has received travel, accommodations, and expenses from Bristol Myers Squibb, Pfizer, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA; reports stock and other ownership interests from PTC Therapeutics; and has received research funding from Aravive, Arrowhead Pharmaceuticals, AstraZeneca/MedImmune, Bristol Myers Squibb, Dragonfly Therapeutics, Immunomedics, Incyte, Exelixis, Pfizer, Roche/Genentech, Seagen, Surface Oncology, Taris, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. HM has received honoraria, consulting or advisory fees, and research funding from Pfizer. MO has participated in consulting or advisory roles for Bayer; has received honoraria from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb Japan, Chugai Pharma, Janssen, MSD, Novartis, Ono Pharmaceutical, Pfizer, Sanofi, and Takeda; and has received research funding from Astellas Pharma. LA has participated in consulting or advisory roles for Astellas Pharma, AstraZeneca, Bellerophon Therapeutics, Bristol Myers Squibb, Corvus Pharmaceuticals, Eisai, Janssen, Ipsen, Merck, MSD, Novartis, Pfizer, and Roche; has received travel, accommodations, and expenses from Bristol Myers Squibb and MSD; and has received research funding from Bristol Myers Squibb. MA is an employee of Pfizer R&D Japan. YU is an employee of Pfizer R&D Japan and holds stock in Pfizer. JW is an employee and reports stock and other ownership interest with Pfizer. AdiP reports employment, stock, and other ownership interest with Pfizer, and has received honoraria from Pfizer. MS has participated in consulting or advisory roles for Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, MSD, and Roche; has received travel, accommodations, and expenses from Bristol Myers Squibb, Ipsen, and Roche; and has received honoraria from Alkermes, Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, Janssen Oncology, and MSD., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Molecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR-Cas9 genome editing, we generated somatic mosaic genetically engineered models that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect of the interferon receptor genes cluster as an adaptive mechanism to deleterious chromosomal instability in metastatic progression. This work provides critical knowledge on drivers of renal cell carcinoma progression and defines the primary role of interferon signaling in constraining the propagation of aneuploid clones in cancer evolution., (© 2023. The Author(s).)

Background: We report updated data for avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma from the third interim analysis of the phase III JAVELIN Renal 101 trial., Patients and Methods: Progression-free survival (PFS), objective response rate (ORR), and duration of response per investigator assessment (RECIST version 1.1) and overall survival (OS) were evaluated in the overall population and in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups; safety was also assessed., Results: Overall, median OS [95% confidence interval (CI)] was not reached [42.2 months-not estimable (NE)] with avelumab plus axitinib versus 37.8 months (31.4-NE) with sunitinib [hazard ratio (HR) 0.79, 95% CI 0.643-0.969; one-sided P = 0.0116], and median PFS (95% CI) was 13.9 months (11.1-16.6 months) versus 8.5 months (8.2-9.7 months), respectively (HR 0.67, 95% CI 0.568-0.785; one-sided P < 0.0001). In patients with IMDC favorable-, intermediate-, poor-, or intermediate plus poor-risk disease, respectively, HRs (95% CI) for OS with avelumab plus axitinib versus sunitinib were 0.66 (0.356-1.223), 0.84 (0.649-1.084), 0.60 (0.399-0.912), and 0.79 (0.636-0.983), and HRs (95% CIs) for PFS were 0.71 (0.490-1.016), 0.71 (0.578-0.866), 0.45 (0.304-0.678), and 0.66 (0.550-0.787), respectively. ORRs, complete response rates, and durations of response favored avelumab plus axitinib overall and across all risk groups. In the avelumab plus axitinib arm, 81.1% had a grade ≥3 treatment-emergent adverse event (TEAE), and incidences of TEAEs and immune-related AEs were highest <6 months after randomization., Conclusions: Avelumab plus axitinib continues to show improved efficacy versus sunitinib and a tolerable safety profile overall and across IMDC risk groups. The OS trend favors avelumab plus axitinib versus sunitinib, but data remain immature; follow-up is ongoing., Trial Registration: ClinicalTrials.govNCT02684006; https://clinicaltrials.gov/ct2/show/NCT02684006., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: COVID-19 has significantly affected patients with cancer and revealed unanticipated challenges in securing optimal cancer care across different disciplines. The European Society for Medical Oncology COVID-19 and CAncer REgistry (ESMO-CoCARE) is an international, real-world database, collecting data on the natural history, management, and outcomes of patients with cancer and SARS-CoV-2 infection., Methods: This is the 2nd CoCARE analysis, jointly with Belgian (Belgian Society of Medical Oncology, BSMO) and Portuguese (Portuguese Society of Medical Oncology, PSMO) registries, with data from January 2020 to December 2021. The aim is to identify significant prognostic factors for COVID-19 hospitalization and mortality (primary outcomes), as well as intensive care unit admission and overall survival (OS) (secondary outcomes). Subgroup analyses by pandemic phase and vaccination status were carried out., Results: The cohort includes 3294 patients (CoCARE: 2049; BSMO: 928, all hospitalized by eligibility criteria; PSMO: 317), diagnosed in four distinct pandemic phases (January to May 2020: 36%; June to September 2020: 9%; October 2020 to February 2021: 41%; March to December 2021: 12%). COVID-19 hospitalization rate was 54% (CoCARE/PSMO), ICU admission 14%, and COVID-19 mortality 22% (all data). At a 6-month median follow-up, 1013 deaths were recorded with 73% 3-month OS rate. No significant change was observed in COVID-19 mortality among hospitalized patients across the four pandemic phases (30%-33%). Hospitalizations and ICU admission decreased significantly (from 78% to 34% and 16% to 10%, respectively). Among 1522 patients with known vaccination status at COVID-19 diagnosis, 70% were non-vaccinated, 24% had incomplete vaccination, and 7% complete vaccination. Complete vaccination had a protective effect on hospitalization (odds ratio = 0.24; 95% confidence interval [0.14-0.38]), ICU admission (odds ratio = 0.29 [0.09-0.94]), and OS (hazard ratio = 0.39 [0.20-0.76]). In multivariable analyses, COVID-19 hospitalization was associated with patient/cancer characteristics, the first pandemic phase, the presence of COVID-19-related symptoms or inflammatory biomarkers, whereas COVID-19 mortality was significantly higher in symptomatic patients, males, older age, ethnicity other than Asian/Caucasian, Eastern Cooperative Oncology Group performance status ≥2, body mass index <25, hematological malignancy, progressive disease versus no evident disease, and advanced cancer stage., Conclusions: The updated CoCARE analysis, jointly with BSMO and PSMO, highlights factors that significantly affect COVID-19 outcomes, providing actionable clues for further reducing mortality., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Sarcomatoid differentiation in patients diagnosed with renal cell carcinoma (sRCC) imply aggressive behavior and often metastatic disease at the time of diagnosis. We aim to examine the overall survival (OS) in patients with sRCC using the National Cancer Database (NCDB)., Materials and Methods: We identified patients diagnosed with sRCC between 2010-2015. We employed Kaplan-Meier curves and multivariable Cox proportional hazards regression models to examine the impact of several potential risk factors on OS in patients diagnosed with sRCC., Results: In total, 8582 patients with renal cancer were found to have sarcomatoid differentiation, with 4105 patients (47.8%) being diagnosed with AJCC stage IV disease. The median OS was 17.2 months (IQR 5.4, 68.7 months). Compared to patients who did not undergo surgery, OS was significantly longer in patients undergoing partial or total nephrectomy across all stages. This result remained consistent on multivariable Cox proportional hazards regression adjusting for patient and tumor characteristics (Surgery: Hazard ratio 0.54, 95%Confidence interval 0.43 - 0.68, P < .001)., Conclusion: In our cohort sRCC was found to have an unfavorable median OS, which was mainly caused by the high number of cases diagnosed with late-stage disease. Additionally, surgery was associated with favorable OS across all stages. This study supports the notion that surgical therapy, even in the setting of cytoreductive surgery, provides a survival benefit in patients with sRCC., (Copyright © 2022. Published by Elsevier Inc.)

Background: C-reactive protein (CRP) is an important prognostic and predictive factor in advanced renal cell carcinoma (aRCC). We report the association of CRP levels at baseline and early after treatment with efficacy of avelumab plus axitinib or sunitinib from the phase III JAVELIN Renal 101 trial., Patients and Methods: Patients were categorized into normal (baseline CRP <10 mg/l), normalized (baseline CRP ≥10 mg/l and ≥1 CRP value decreased to <10 mg/l during 6-week treatment), and non-normalized (CRP ≥10 mg/l at baseline and during 6-week treatment) CRP groups. Progression-free survival and best overall response from the second interim analysis and overall survival (OS) from the third interim analysis were assessed., Results: In the avelumab plus axitinib and sunitinib arms, respectively, 234, 51, and 108 patients and 232, 36, and 128 patients were categorized into normal, normalized, and non-normalized CRP groups. In respective CRP groups, objective response rates [95% confidence interval (CI)] were 56.0% (49.4% to 62.4%), 66.7% (52.1% to 79.2%), and 45.4% (35.8% to 55.2%) with avelumab plus axitinib and 30.6% (24.7% to 37.0%), 41.7% (25.5% to 59.2%), and 19.5% (13.1% to 27.5%) with sunitinib; complete response rates were 3.8%, 11.8%, and 0.9% and 3.0%, 0%, and 1.6%, respectively. Median progression-free survival (95% CI) was 15.2 months (12.5-21.0 months), not reached (NR) [11.1 months-not estimable (NE)], and 7.0 months (5.6-9.9 months) with avelumab plus axitinib and 11.2 months (8.4-13.9 months), 11.2 months (6.7-13.8 months), and 4.2 months (2.8-5.6 months) with sunitinib; median OS (95% CI) was NR (42.2 months-NE), NR (30.4 months-NE), and 23.0 months (18.4-33.1 months) and NR (39.0 months-NE), 39.8 months (21.7-NE), and 19.1 months (16.3-25.3 months), respectively. Multivariate analyses demonstrated that normalized or non-normalized CRP levels were independent factors for the prediction of objective response rate or OS, respectively, with avelumab plus axitinib., Conclusions: In patients with aRCC, CRP levels at baseline and early after treatment may predict efficacy with avelumab plus axitinib., Competing Interests: Disclosure YT has received honoraria from Pfizer, Astellas Pharma, Novartis, Ono Pharmaceutical, Bristol Myers Squibb, and Chugai Pharma; has served in a consulting or advisory role for Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical; and has received research funding from Pfizer, Ono Pharmaceutical, Takeda, Astellas Pharma, AstraZeneca, Novartis, Chugai Pharma, MSD, and Eisai. JLhas received personal fees from Eisai, GlaxoSmithKline, Kymab, Roche/Genentech, Secarna, Pierre Fabre, and EUSA Pharma, and has received grants and personal fees from MSD, Pfizer, and Novartis. BVhas served in a consulting or advisory role for Pfizer, Merck, Ipsen, and MSD; has provided speaker services for MSD, Ipsen, and EUSA Pharma; has received honoraria from Pfizer, Bristol Myers Squibb, and EUSA Pharma; and has received research funding from Pfizer, Merck, Calithera Biosciences, and MSD. JHhas served in a consulting or advisory role for Achilles Therapeutics, AIMM Therapeutics, Bristol Myers Squibb, Immunocore, Ipsen, MSD, Neogene Therapeutics, Neon Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, and Third Rock Ventures, and has received research funding from Amgen, Bristol Myers Squibb, MSD, Neon Therapeutics, and Novartis. HK has received research funding from Taiho Pharmaceutical, Takeda, MSD, Astellas Pharma, Ono Pharmaceutical, Nihon Medi-Physics, Fujifilm, and Kissei Pharmaceutical. ME has served in a consulting or advisory role for Pfizer, Eisai, Ono Pharmaceutical, AstraZeneca, Chugai Pharma, Olympus, Johnson & Johnson, Bristol Myers Squibb, and Merck; has provided speaker services for MSD, Ono Pharmaceutical, Chugai Pharma, Novartis, Pfizer, Bristol Myers Squibb, Takeda, and Janssen; and has received research funding from Kissei Pharmaceutical, Sanofi, Astellas Pharma, Ono Pharmaceutical, Takeda, and Bayer. M-OG has served in a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, Ipsen, MSD, Ono Pharmaceutical, Pfizer, Astellas Pharma, and EUSA Pharma; has received travel and accommodations expenses from Bristol Myers Squibb and Merck; has received honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Medac, MSD, Ono Pharmaceutical, Novartis, Pfizer, Ipsen, Merck, and EUSA Pharma; and has received research funding from Bristol Myers Squibb and Intuitive Surgical. YF is an employee of Pfizer R&D Japan G. K. YU is an employee of Pfizer R&D Japan G. K. and also holds Pfizer stock. BH is an employee of Pfizer. MM is an employee of Pfizer. AdP is an employee of Pfizer and also holds Pfizer stock. TKC has received support for the present manuscript from Pfizer and Merck; has received institutional research funding from AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Eisai, Exelixis, GlaxoSmithKline, Lilly, MSD, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda, and Merck; holds patents, royalties, and other intellectual properties related to biomarkers of immune checkpoint blockers and ctDNA; has served in a consulting role or received honoraria from Alexion, Analysis Group, Aravive, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Cerulean, Corvus, Eisai, Exelixis, Foundation Medicine, Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, IQVIA, Janssen Oncology, Lilly, MSD, National Comprehensive Cancer Network, NiKang, Novartis, Nuscan, Peloton, Pfizer, Prometheus, Roche, Sanofi/Aventis, Surface Oncology, Tempest, Merck, and UpToDate; has served in CME-related events for OncLive, PVI, and MJH Life Sciences; is member of the National Cancer Institute Genitourinary Steering Committee, ASCO, ESMO, and National Comprehensive Cancer Network; has received travel expenses for meetings, lectures, and advisory boards; and holds stock with Pionyr and Tempest. Data sharing Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct., Patients and Methods: This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations., Results: The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P < 0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded., Conclusions: Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial., Competing Interests: Disclosure The authors report the following conflicts of interest: ZB non-financial support, Bristol Myers Squibb (BMS); research support, Genentech/imCore. Honoraria from UpToDate. CL research support, Genentech/imCore. AS educational travel support, Pfizer and Astellas. MMA research support, BMS Lilly, AstraZeneca, and Genentech; consulting/advisory role, BMS, Lilly, AstraZeneca, Genentech, Merck, Achilles, and Abbvie. RH consulting/advisory role, BMS, Merck, Pfizer, Genetech, AstraZeneca, and GSK; research grant/funding, Merck, BMS, Pfizer, Genentech, GSK, and AstraZeneca. ST institutional research funding from AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Exelixis, BMS, Eisai, Nanostring, Cyclacel, Odonate, and Seattle Genetics; has served as an advisor/consultant to AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, BMS, Eisai, Nanostring, Puma, Sanofi, Celldex, Paxman, Puma, Silverback Therapeutics, G1 Therapeutics, AbbVie, Athenex, OncoPep, Outcomes4Me, Kyowa Kirin Pharmaceuticals, Daiichi-Sankyo, and Samsung Bioepsis Inc. MDG reports: Stock, Rappta Therapeutics; consulting/advisory role, BioMotiv, Janssen, Dendreon, Merck, GlaxoSmithKline, Lilly, Astellas, Genentech, BMS, Novartis, Pfizer, EMD Serono, AstraZeneca, Seattle Genetics, Incyte, Alleron Therapeutics, Dracen, Inovio Pharmaceuticals, Numab, Dragonfly Therapeutics; institutional research funding, Janssen, Dendreon, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca, Genentech/Roche. TKC research support, AstraZeneca, Alexion, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda; honoraria, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc. (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly Oncology; consulting or advisory role, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest, Lilly Ventures; Stocks: Pionyr, Osel, and Tempest; leadership role, Director of Genitourinary Oncology Division at Dana-Farber and past President of Medical Staff at Dana-Farber, member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee, KidneyCan Advisory board, Kidney cancer Research Summit co-chair (2019-); patents, royalties or other intellectual properties related to checkpoint inhibitors biomarkers and ctDNA (no royalties made as to date); travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria; medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others). TKC’s 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 has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. DD Consulting/Advisory role, Mirati, Ipsen, Boehringer Ingelheim, Atheneum Partners, Boston Healthcare Associates, Dedham Group, Guidepoint Global Advisors; travel expenses, Ipsen. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Papillary renal cell carcinoma (PRCC) represents 15% of RCCs but has no indicated therapies, with limited biomarker-based data to inform targeted treatment. MET alterations may be key; > 80% of PRCC tumours show MET upregulation. The objective of this study was to assess MET status in PRCC and its impact on clinical outcomes., Methods: This retrospective, observational study included patients with locally advanced/metastatic PRCC from three international registries. MET status was determined retrospectively by next generation sequencing (NGS) of archival tissue. MET-driven was defined as MET and/or hepatocyte growth factor amplification, chromosome 7 gain, and/or MET kinase domain mutations. Objectives included progression-free survival (PFS) and overall survival (OS) by MET status using a Cox proportional hazards model., Results: Of 308 patients, 305 received first-line treatment; most commonly sunitinib (n = 208; 68%), then everolimus (n = 40; 13%). Of 179 patients with valid NGS results, 38% had MET-driven and 49% MET-independent tumours (13% unevaluable). In the MET-driven versus MET-independent subgroups, respectively, of sunitinib-treated patients, median PFS was numerically longer, though not statistically significantly; PFS: 9.2 months (95% confidence interval [CI]: 5.4-13.2) versus 5.7 months (95% CI: 4.3-7.4), hazard ratio (HR) = 0.67; 95% CI: 0.41-1.08. There was no difference between the OS of each subgroup., Conclusions: MET-driven PRCC may respond to targeted agents. However, the presence of MET alterations did not appear to be predictive for outcomes in response to current therapies, which are not biomarker-driven, compared with MET-independent tumours., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

Background: In the phase III JAVELIN Renal 101 trial, first-line avelumab plus axitinib demonstrated a progression-free survival (PFS) and objective response rate (ORR) benefit versus sunitinib in patients with advanced renal cell carcinoma (aRCC). However, efficacy in elderly patients remains unclear. We report efficacy and safety by age group from the second interim analysis of overall survival (OS)., Patients and Methods: PFS and ORR as per blinded independent central review (RECIST 1.1), OS, and safety were assessed in patient groups aged <65, ≥65 to <75, and ≥75 years., Results: In the avelumab plus axitinib and sunitinib arms, 271/138/33 and 275/128/41 patients aged <65, ≥65 to <75, and ≥75 years, respectively, were randomized. At data cut-off (January 2019), median PFS [95% confidence interval (CI)] with avelumab plus axitinib versus sunitinib in these respective age groups was 11.6 (8.4-19.4) versus 6.9 (5.6-8.4) months [hazard ratio (HR), 0.63; 95% CI 0.501-0.786], 13.8 (11.1-18.0) versus 11.0 (7.8-16.6) months (HR, 0.88; 95% CI 0.627-1.231), and 13.8 [7.0-not estimable (NE)] versus 9.8 (4.3-NE) months (HR, 0.76; 95% CI 0.378-1.511). Median OS (95% CI) in the respective age groups was not reached (NR) (NE-NE) versus 28.6 (25.5-NE) months (HR, 0.74; 95% CI 0.541-1.022), 30.0 (30.0-NE) versus NR (NE-NE) months (HR, 0.89; 95% CI 0.546-1.467), and 25.3 (19.9-NE) versus NR (19.4-NE) months (HR, 0.87; 95% CI 0.359-2.106). ORR (95% CI) in the respective age groups was 49.4% (43.3% to 55.6%) versus 27.3% (22.1% to 32.9%), 60.9% (52.2% to 69.1%) versus 28.9% (21.2% to 37.6%), and 42.4% (25.5% to 60.8%) versus 22.0% (10.6% to 37.6%). In the avelumab plus axitinib arm, grade ≥3 adverse events (AEs) and immune-related AEs occurred in 76.9%/81.2%/72.7% and 45.5%/48.1%/36.4% in the respective age groups., Conclusions: First-line avelumab plus axitinib demonstrated favorable efficacy across age groups, including patients aged ≥75 years. OS data were still immature; follow-up is ongoing. The safety profile was generally consistent across age groups., Competing Interests: Disclosure YT has received honoraria from Pfizer, Astellas Pharma, Novartis, Ono Pharmaceutical, Bristol Myers Squibb, and Chugai Pharma; has served in a consulting or advisory role for Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical; and has received research funding paid to his institution from Pfizer, Ono Pharmaceutical, Takeda, Astellas Pharma, AstraZeneca, Novartis, Chugai Pharma, MSD, and Eisai. RJM has served in a consulting or advisory role for AstraZeneca, Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Exelixis, Genentech/Roche, Incyte, Lilly, MSD, Novartis, and Pfizer; has received research funding paid to his institution, from Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, MSD, Novartis, and Pfizer; and has received travel, accommodations, and expenses from Bristol Myers Squibb. TKC owns stock and additional ownership interests in Pionyr and Tempest Therapeutics; has received honoraria from Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, MSD, Michael J. Hennessy Associates, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, New England Journal of Medicine, and UpToDate; has served in a consulting or advisory role for Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, MSD, Michael J. Hennessy Associates, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, New England Journal of Medicine, and UpToDate; has received research funding paid to his institution, from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Congressionally Directed Medical Research Programs (DOD), Corvus Pharmaceuticals, Eisai, Exelixis, Foundation Medicine, Gateway for Cancer Research, GlaxoSmithKline, Ipsen, MSD, NCI, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and TRACON Pharmaceuticals; owns patents, royalties, or other intellectual property for international patent application no. PCT/US2018/058430, entitled ‘Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy’ and international patent application no. PCT/US2018/12209, entitled ‘PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response’; and has received travel, accommodations, and expenses from Alexion Pharmaceuticals, Alligent, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, MSD, Michael J. Hennessy Associates, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, New England Journal of Medicine, and UpToDate. BIR owns stock and other ownership interests in PTC Therapeutics; has served in a consulting or advisory role for Bristol Myers Squibb, Pfizer, Genentech/Roche, Aveo, Synthorx, Compugen, MSD, Corvus, Surface Oncology, 3D Medicines, Aravive, Alkermes, Arrowhead, GSK, and Shionogi; has received research funding paid to his institution, from Pfizer, MSD, Genentech/Roche, Aveo, AstraZeneca, Bristol Myers Squibb, and Exelixis; and has received travel, accommodations, and expenses from MSD, Pfizer, and Bristol Myers Squibb. HM has received honoraria; served in a consulting or advisory role for; and has received research funding paid to his institution from Pfizer. HU has received speakers’ bureau fees from Pfizer, Bayer, MSD, Bristol Myers Squibb, and Janssen; and has received research funding paid to his institution from Takeda, Daiichi Sankyo, Astellas Pharma, Ono Pharmaceutical, AstraZeneca, Sanofi, and Kissei Pharmaceutical. LA has served in a consulting or advisory role for Amgen, Bristol Myers Squibb, Ipsen, Roche, Novartis, Pfizer, Astellas Pharma, Merck, MSD, AstraZeneca, Exelixis, Corvus, Peloton Therapeutics, Exelixis, and Janssen; has received research funding paid to her institution, from Bristol Myers Squibb; and has received travel, accommodations, and expenses from Bristol Myers Squibb and MSD. YF is an employee of Pfizer R&D Japan. YU is an employee of Pfizer R&D Japan and owns stock in Pfizer. JW is an employee of Pfizer and owns stock in Pfizer. MM is an employee of Pfizer. MS has received honoraria from Pfizer, Merck, Bristol Myers Squibb, MSD, Ipsen, Exelixis, Eisai, EUSA, and Alkermes; has served in a consulting or advisory role for Pfizer, Merck, Bristol Myers Squibb, MSD, Ipsen, Exelixis, Eisai, EUSA, and Alkermes; and has received travel, accommodations, and expenses from Pfizer, Roche, and Ipsen. Data sharing Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Vaccination is an important preventive health measure to protect against symptomatic and severe COVID-19. Impaired immunity secondary to an underlying malignancy or recent receipt of antineoplastic systemic therapies can result in less robust antibody titers following vaccination and possible risk of breakthrough infection. As clinical trials evaluating COVID-19 vaccines largely excluded patients with a history of cancer and those on active immunosuppression (including chemotherapy), limited evidence is available to inform the clinical efficacy of COVID-19 vaccination across the spectrum of patients with cancer., Patients and Methods: We describe the clinical features of patients with cancer who developed symptomatic COVID-19 following vaccination and compare weighted outcomes with those of contemporary unvaccinated patients, after adjustment for confounders, using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19)., Results: Patients with cancer who develop COVID-19 following vaccination have substantial comorbidities and can present with severe and even lethal infection. Patients harboring hematologic malignancies are over-represented among vaccinated patients with cancer who develop symptomatic COVID-19., Conclusions: Vaccination against COVID-19 remains an essential strategy in protecting vulnerable populations, including patients with cancer. Patients with cancer who develop breakthrough infection despite full vaccination, however, remain at risk of severe outcomes. A multilayered public health mitigation approach that includes vaccination of close contacts, boosters, social distancing, and mask-wearing should be continued for the foreseeable future., Competing Interests: Disclosure ALS reports non-financial support from Astellas, non-financial support from Pfizer, outside the submitted work. CL reports research support from Genentech/imCORE, outside the submitted work. ZB reports non-financial support from Bristol Myers Squibb, grants from Genentech/imCORE, personal fees from UpToDate, outside the submitted work. CYH reports personal fees from NashBio, outside the submitted work. SAB reports personal fees from Exelixis, personal fees from Seattle Genetics, personal fees from Pfizer, personal fees from Bristol Myers Squibb, outside the submitted work. CRF reports research grants from the Merck Foundation and National Comprehensive Cancer Network (NCCN)/Pfizer, outside the submitted work. EAG reports personal fees and other from Alexion Pharmaceuticals, personal fees and non-financial support from Novartis Pharmaceuticals, personal fees, non-financial support and other from Astex/Otsuka Pharmaceuticals, other from Apellis Pharmaceuticals, personal fees, non-financial support, and other from Celgene/Bristol Myers Squibb, grants and personal fees from AbbVie/Genentech, other from Celldex Therapeutics, personal fees from Boston Biomedical, outside the submitted work. JEH reports research funding paid to her institution from Dendreon Pharmaceuticals LLC, research funding paid to her institution from Regeneron Pharmaceuticals, personal fees from Genzyme, personal fees from Seagen, outside the submitted work. RRM reports grants and personal fees from Bayer, grants from Pfizer, grants from Tempus, personal fees from AVEO, personal fees from Caris, personal fees from Bristol Myers Squib, personal fees from Exelixis, personal fees from Janssen, personal fees from Novartis, personal fees from Pfizer, personal fees from Sanofi, personal fees from Tempus, personal fees from Dendreon, personal fees from Vividion, personal fees from AstraZeneca, personal fees from Calithera, personal fees from Merck, outside the submitted work. OAP reports personal fees from International Consulting Associates, Inc., outside the submitted work. EMW-B reports personal fees from Astellas, personal fees from AVEO Oncology, personal fees from Bristol Myers Squibb, other from Exelixis, grants from Pfizer Global Medical Grants, other from Nektar, other from Immunomedics, outside the submitted work. SM reports personal fees from National Geographic, outside the submitted work. DF reports a grant from Merck to study COVID-19 in immunocompromised patients, outside of the submitted work. YS reports personal fees from Novartis, personal fees from Roche, personal fees from Pfizer, personal fees from Janssen, personal fees from Eisai, personal fees from AstraZeneca, outside of the submitted work. JLW reports personal fees from Westat, personal fees from Roche, personal fees from Melax Tech, personal fees from Flatiron Health, other from HemOnc.org LLC (ownership), outside the submitted work. TKC reports institutional and personal, paid and unpaid support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda, Tempest, UpToDate, CME events (Peerview, OncLive and others), outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)