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.
Introduction
Immune 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 methods
We 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.
Results
A 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).
Conclusion
We 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 novel coronavirus disease 2019 (COVID-19) shows a wide spectrum of clinical presentations, severity, and fatality rates. The reason older patients and males show increased risk of severe disease ...and death remains uncertain. Sex hormones, such as estradiol, progesterone, and testosterone, might be implicated in the age-dependent and sex-specific severity of COVID-19. High testosterone levels could upregulate transmembrane serine protease 2 (TMPRSS2), facilitating the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells via angiotensin-converting enzyme 2 (ACE2). Data from patients with prostate cancer treated with androgen-deprivation therapy seem to confirm this hypothesis. Clinical studies on TMPRSS2 inhibitors, such as camostat, nafamostat, and bromhexine, are ongoing. Antiandrogens, such as bicalutamide and enzalutamide, are also under investigation. Conversely, other studies suggest that the immune modulating properties of androgens could protect from the unfavorable cytokine storm, and that low testosterone levels might be associated with a worse prognosis in patients with COVID-19. Some evidence also supports the notion that estrogens and progesterone might exert a protective effect on females, through direct antiviral activity or immune-mediated mechanisms, thus explaining the higher COVID-19 severity in post-menopausal women. In this perspective, we discuss the available evidence on sex hormones and hormone therapy in patients infected with SARS-CoV-2, and we highlight the possible implications for cancer patients, who can receive hormonal therapies during their treatment plans.
Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell ...death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients.
We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI.
One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21–92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6–46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events irAEs (p < 0.0001), G3/G4 irAEs (p < 0.0001) and irAEs leading to discontinuation (LTD) (p < 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5–14.9 for overweight, and 16.6 (95%CI: 10.3–26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 95%CI: 6.4–22.3, p < 0.0001) and LTD irAEs (OR = 8.8 95%CI: 4.3–18.2, p < 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients.
Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.
•Several studies have found an association between higher BMI and improved outcomes in patients receiving PD-1/PD-L1 checkpoint inhibitors.•The upside of the downside of this obesity paradox, might be the association between BMI and immune-related adverse events (irAEs).•In this large case series, we found a significant association, between BMI and irAEs.
The predictive ability of metabolic conditions, such as hypercholesterolemia, on the outcome of cancer patients to immune-checkpoint inhibitors (ICIs) therapy, has been recently explored. The reasons ...for their value in this setting are to be searched in the individual himself more than in his tumor, as the target of the immune-checkpoint blockade is the immune system. The efficacy of ICIs on the tumor may be based on two simple premises: 1) the physiological immune function has been blocked, and 2) the tumor progression (mainly) depends on this block. The metabolic syndrome may represent the epiphenomenon of an "inflamed patient," no longer able of physiological functions required to prevent chronic inflammatory events. The metabolic dysfunction could represent merely "a biomarker" of the patient who satisfies both the two premises reported above. Suggestions from preclinical and translational researches should be transferred in the clinical setting, implementing randomized clinical trials with observational endpoints such as the effect of concomitant drug medications and the impact of blood cholesterol levels and other metabolic conditions on the outcome of ICI treatment.
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.
Beyond the overall relapse-free survival (RFS) advantage demonstrated in randomized trials (RCT) of adjuvant anti-PD-1 immunotherapy in radically resected stage III-IV melanoma, key issues about ...subgroups of interest have been raised in recent years, with non-conclusive results when considering single studies. In the present meta analysis, we pooled all RCT data in this setting, analyzing, overall, 3043 patients. The RFS benefit of adjuvant immunotherapy over the comparator (placebo or anti-CTLA-4) was strongly confirmed in the pooled analysis, and it was statistically significant in most subgroups, excluding patients with stage IIIA and stage IV M1c melanoma. Nevertheless, the relative benefit was not statistically significantly different when considering their IIIB-IIIC and M1a-M1b counterparts. Future trials in this setting should consider subgroups of interest for tailoring the adjuvant strategy in terms of duration and drug combination in light of literature data.
Immune-related adverse events (irAEs) developed during immunotherapy with anti-PD-1 agents, could be a predictive surrogate marker of clinical benefit in patients with advanced non–small-cell lung ...cancer (NSCLC).
Patients with NSCLC, treated with anti-PD-1 agents, were retrospectively evaluated. Univariate and multivariate analyses were performed to evaluate the relationships between types of irAEs (differentiated according to system/organ involved and to single-site/multiple-site), overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). We further performed a 6-week landmark analysis.
A total of 559 patients were enrolled; 231 patients (41.3%) developed irAEs of any grade and 50 patients (8.9%) G3/G4 events; 191 of them (82.6%) developed “single-site” irAEs and 40 (17.4%) “multiple-site” irAEs. At multivariate analysis, higher ORR was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), endocrine (P = .0043) and skin irAEs (P = .0005). Longer PFS was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), “multiple-site” irAEs (P = .0374), endocrine irAEs (P = .0084) and skin irAEs (P = .0001). Longer OS was related to irAEs of any grade (P < .0001), “single-site” irAEs (P < .0001), endocrine irAEs (P = .0044), gastrointestinal irAEs (P = .0437), skin irAEs (P = .0006), and others irAEs (P = .0378). At the 6-week landmark analysis, irAEs of any grade was confirmed an independent predictor of higher ORR, longer PFS, and longer OS.
Our study confirmed that irAEs are concordantly related to higher ORR, longer PFS, and longer OS with anti-PD-1 immunotherapy in patients with NSCLC.
The aim of this study was to investigate with a large sample size, the predictive and prognostic positive roles of occurrence of immune-related adverse events in patients with non–small-cell lung cancer treated with PD-1 inhibitors. The study confirmed that immune-related adverse events are independent predictors of higher overall response rate, longer progression-free survival and longer overall survival.
For years, prospective randomized clinical trials excluded patients with non-conventional histologies of renal cell carcinoma (RCC). The paucity of data has led to adopting the same treatment ...strategies used for clear-cell RCC (ccRCC). In the present narrative review, we explored state of the art about use of immune checkpoint inhibitors (ICIs) in variant histologies of RCC. According to the results collected, ICIs as monotherapy showed promising antitumor activity in advanced non-clear cell (ncc)RCC. The objective response rate (ORR) was similar to that observed with single-agent anti-PD-1 in the ccRCC population, either in the first-line or the second-line setting, and responder patients experienced an early and durable benefit. Combined ICI-based strategies have shown increasing evidence in nccRCC and robust results in the sarcomatoid variants of RCC. A definitive recommendation about treating non-conventional histologies, either in adjuvant or metastatic settings, should be supported by more extensive dedicated trials.
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