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Patients with cancer were observed to have a higher risk of severe events compared with patients without cancer (39 vs 8%; p=0.0003). [...]cancer patients who underwent recent chemotherapy or surgery had a higher risk of clinically severe events than did those not receiving treatment. [...]an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells has been reported, and CD8 T cells were found to harbor high concentrations of cytotoxic granules, suggesting that overactivation of T cells tends to contribute to the severe immune injury of the disease (17). [...]the pathological findings associated with acute respiratory distress syndrome in COVID-19 showed abundant interstitial mononuclear inflammatory infiltrate in the lungs, dominated by lymphocytes, once again implying that the immune hyperactivation mechanisms are at least partially accountable for COVID-19 severity (17). Tocilizumab is currently used for rheumatoid arthritis, but its efficacy has been demonstrated also against ICI-induced irAEs, starting from the rationale of an ICI-induced systemic inflammatory response syndrome similar to CRS (21). [...]along with the improvement in symptoms related to systemic inflammatory response syndrome, some authors reported a clinical improvement in other irAEs with tocilizumab used in cancer patients with immune-related toxicity from anti-PD-1 agents (21,22). [...]one can argue that the alleged tocilizumab efficacy both for treating COVID-19 and irAEs might suggest a potentially increased danger from SARS-CoV-2 infection for ICI-treated patients, maybe hypothesizing a synergy in the promotion of the viral morbidity.

IntroductionImmune checkpoint inhibitors (ICIs) represent a cornerstone for the treatment of many advanced tumors. When 65 is considered as a cut-off age, ICIs are equally effective in younger and older patients. However, the efficacy of ICIs among patients aged ≥ 75 remains uncertain, since those patients were generally under-represented in clinical trials. We performed a pooled analysis of major randomized trials including data of outcome in very older population.Material and methodsWe searched PubMed, Embase, and the Cochrane Library for randomized controlled trials published from the inception of each database to November 22th, 2019. We only included (1) randomized studies comparing ICIs alone or in combinations with no ICIs, (2) studies reporting data of patients older than 75 years, (3) studies for solid tumors, and (4) studies with HR and 95% confidence interval (CI) available for OS based on 75 years as cut-off age. All data were expressed as the combination of HR and 95% CI, and P < 0.05 was considered to be statistically significant.ResultsA total of n = 8 publications for a total of n = 12 randomized studies were aggregated in the quantitative analysis. Overall, the pooled analysis showed a borderline significant OS benefit for ICIs compared to no ICIs arms (HR = 0.84, 95% CI 0.7–1; P = 0.05) in particular in first-line trials with HR = 0.77 (95%CI 0.61–0.96; P = 0.02).ConclusionWe conclude that ICIs may be offered in patients older than 75 years, providing a complete geriatric and clinical evaluation is performed in all subjects before starting therapy.

The purpose of the present study was to validate the new GRade, Age, Nodes and Tumor (GRANT) score for renal cell carcinoma (RCC) prognostication within a large population of patients. Within the Surveillance, Epidemiology, and End Results database, we identified patients with either clear-cell or papillary RCC, who underwent nephrectomy between 2001 and 2015. Harrell’s C-Index, calibration plot and decision curve analysis were used to validate the GRANT model using a five-risk group stratification (0 vs. 1 vs. 2 vs. 3 vs. 4 risk factors). The primary endpoint was overall survival (OS) at 60 months. The analyses were repeated according to the histologic subgroup. The overall population included 73217 cases; 60900 with clear-cell RCC and 12317 with papillary histology, respectively. According to a five-risk group stratification, 23985 patients (32.8%) had no risk factor (0), 35019 (47.8%) had only one risk factor (1), 13275 (18.1%) had risk score 2, 854 (1.2%) had 3 risk factors and 84 (0.1%) of cases had a GRANT score of 4, respectively. At 60 months, OS rates as determined by the GRANT score were respectively 94% (score 0) vs. 86% (score 1) vs. 76% (score 2) vs. 46% (score 3) vs. 16% (score 4). In both histologic subtypes, the GRANT score yielded good calibration and high net benefit. OS C-Index values were 0.677 and 0.650 for clear-cell and papillary RCC at 60 months after surgery, respectively. In conclusion, the GRANT score was validated with a five-risk group stratification in a huge population from the SEER database, offering a further demonstration of its reliability for prognostication in RCC.

On June 16, 2020, the US Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab for the treatment of patients with unresectable or metastatic tumour mutational burden-high (TMB-high) solid tumours (as determined by the FDA-approved test, the FoundationOneCDx assay; Foundation Medicine, Cambridge, MA, USA) whose cancer has progressed after previous treatment and who have no satisfactory alternative treatment options.1 The decision was based on the results of the prespecified analysis of ten cohorts of patients with previously treated unresectable or metastatic TMB-high solid tumours enrolled in the multicentre, non-randomised, open-label, KEYNOTE-158 trial. Aurélien Marabelle and colleagues report the results of this prespecified biomarker analysis in their Article in The Lancet Oncology.2 In their Article, Marabelle and colleagues defined high tissue TMB (tTMB-high) as at least 10 non-synonymous somatic mutations per megabase of tumour genome.1,2 The higher the TMB, the greater the number of neoantigens expressed by the tumour, enhancing the probability of cancer cells being recognised by the immune system.3 This simple but captivating rationale likely underlies the clear advantage from pembrolizumab treatment found for patients with tTMB-high tumours, in terms of objective response rate and duration of response.2 However, the benefit of the tTMB-high status with pembrolizumab treatment in terms of progression-free survival and overall survival was not significant in the overall population (nor, apparently, clinically meaningful, in terms of median survival times). [...]TMB was not associated with PD-L1 expression, and, in this study, the predictive value of tTMB was stronger than that of PD-L1 and independent of PD-L1 expression.2 These elements suggest the potential of combining these factors, possibly together with the tumour microsatellite status, into a biomarker score to improve the predictive ability of each individual biomarker.

Purpose of ReviewTherapeutic alternatives to treat metastatic renal cell carcinoma (mRCC) are increasing, and combination therapies, including antiangiogenic agents and tyrosine kinase/mTOR/immune checkpoint inhibitors, are identified as the gold standard driven by the results of recent clinical studies. Nevertheless, the real-world RCC population is very heterogeneous, with categories of patients not represented in the enrolled trial population who may not benefit more from these treatments. The purpose of this expert review is to assess the rationale on which tyrosine kinase alone may still be a viable first-line treatment option for some subgroups of patients with mRCC.Recent FindingsThe first-line treatment with tyrosine kinase inhibitor monotherapy can still be considered an effective tool for addressing selected mRCCs, as highlighted by the successful outcome in a range of subjects such as favorable-risk patients, the ones suffering from autoimmune diseases, those with pancreatic or lung metastases, or previously undergoing organ transplantation and elderly subjects.SummarySome selected categories of patients may still benefit from monotherapy with TKI, and smart sequential therapies can also be considered instead of a combination strategy. Tyrosine kinase inhibitors can also act as immune modulator agents, boosting the immune response to facilitate and potentiate the therapeutic effectiveness of subsequent immunotherapy.

Background: Effective systemic treatment of non-clear cell renal carcinoma (nccRCC) is still an unmet clinical need, with few studies to support an evidence-based approach. To date, the only recommended standard first-line treatment is sunitinib. Pazopanib may also be used in nccRCC but its place in therapy is not clearly established. It has comparable efficacy and better tolerability than sunitinib in clear cell renal carcinoma. Our objective was to review the use of pazopanib in metastatic nccRCC. Methods: We conducted a systematic review according to PRISMA guidelines. Any type of study reporting the use of pazopanib in metastatic renal cell carcinoma including cases with non-clear cell histology was eligible. Results: In all, 15 studies were included in our analysis, including a total of 318 nccRCC patients treated with pazopanib. Most studies were retrospective (n = 12); three were prospective trials. The specific outcomes of nccRCC patients were reported by four studies. Pazopanib alone as first-line treatment gave overall response rates ranging from 27% to 33%, disease control rates of 81–89%, median progression free survival of 8.1–16.5 months and median overall survival of 17.3–31.0 months. Grade 3–4 adverse events rates were 21–55%. Conclusion: The present review provides for the first time a systematic summary of evidence about the possible use of pazopanib as first-line treatment for nccRCC, with a favorable outcome despite the low strength of evidence. Pazopanib could be considered as a possible therapeutic option in this setting.

Background: In recent years, new therapeutic combinations based on immunotherapy provided significant benefits as a first-line treatment for patients with advanced renal cell carcinoma (mRCC). Objective: This work aims to address the lack of head-to-head comparisons and the uncertainty of the benefit from immunotherapy-based combinations in all the International Metastatic RCC Database Consortium (IMDC) subgroups. Design, setting, and participants: A systematic review and a network meta-analysis were performed. Overall survival (OS) in the intention-to-treat (ITT) population was the primary endpoint. OS according to IMDC subgroups (favorable, intermediate, poor), PD-L1 expression, and grade ⩾3 adverse events (AEs) were secondary endpoints. A SUCRA analysis was performed. Results and limitations: Six randomized phase III trials with 5121 patients were included. There was a high likelihood (82%) that nivolumab-cabozantinib was the preferred treatment in OS. The benefit of ICI-based combinations over sunitinib was unclear in the favorable-risk subgroup. Nivolumab-ipilimumab had the best risk/benefit ratio among all the ICI-based combinations. The limitations were the lack of individual patient data; the heterogeneity of patients’ characteristics, trial designs, and follow-up times; and a limited number of studies for indirect comparisons. Conclusions: A customized approach for the first-line treatment of patients with mRCC should consider the risk/benefit profile of each treatment option, especially considering the likeliness of long-term survival finally reached in this setting.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: The treatment of heavily pretreated patients with metastatic renal cell carcinoma (mRCC) represents an unmet medical need and is still challenging. Objectives: The primary objective was to assess the effectiveness of the lenvatinib plus everolimus combination and the secondary objective was the toxicity profile of this combination. Design: We conducted a longitudinal retrospective study examining mRCC patients pre-treated with one or more lines of therapy among different cancer centers in Italy. Methods: The study included patients who received the combination of lenvatinib plus everolimus as either a second-line treatment or beyond. We assessed progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), response rate (RR), and toxicity profile. In addition, we explored the potential relationship between treatment effectiveness and clinical and laboratory parameters. Results: In all, 33 patients were assessed, the median age was 60 years, 57% had an Eastern Cooperative Oncology Group performance status of 1–2 and. 63% received ⩾ 3 prior lines of therapy. 62% were ‘intermediate risk’ according to the International Metastatic Renal Cell Carcinoma Database Consortium and 30% were ‘poor risk’. The RR was 42% (no complete response), 18% stable disease. Median OS was 11.2 months (95% CI 6.8–19.9), median PFS was 6.7 months (95% CI 0.6–30.8), and median TTF was 6.7 months (95% CI 4.8–16.6). A shorter OS was significantly associated with lymph node metastases (p = 0.043, 95% CI), neutrophils/ lymphocytes ratio (NLR) ⩾ 3 (p = 0.007), hemoglobin/red cell distribution width ratio cutoff value <0.7 was significant (p = 0.03) while a shorter PFS was associated with lung (p = 0.048) and brain metastases (p = 0.023). The most frequent G1 toxicity was diarrhea (24%), G2 was fatigue (30%), and hypertension and skin toxicity (6%) for G3. Conclusion: Our findings suggest a clinically relevant effectiveness of lenvatinib plus everolimus combination with an acceptable toxicity profile for heavily pretreated patients with mRCC.