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Association Between Body Mass Index and Survival Outcomes In Patients Treated With Immune Checkpoint Inhibitors: Meta-analyses of Individual Patient Data.

ABSTRACT: Despite that immune checkpoint inhibitors (ICIs) had tremendous improved the survival of multiple solid tumors, only a limited proportion of patients are responsive to ICIs. Therefore, effective variables are urgently needed to predict the probability of response to ICIs. Systematic searches were conducted from inception up to May, 2020. Prospective or retrospective studies of ICIs that investigated the association between body mass index (BMI) and survival outcomes, including overall survival (OS) and/or progression-free survival (PFS), were selected. The association between each BMI category and survival outcomes was calculated using Cox proportional hazard regression models and quantified as hazard ratio (HR) with corresponding 95% confidence interval. Seven clinical studies involving data from 3768 individual patients were included. The median OS was 15.5 months (95% confidence interval: 14.7-16.2 mo) and the median PFS was 5.7 months (5.2-6.3 mo). The median OS was significantly longer in overweight/obese patients than in nonoverweight patients (20.7 vs. 11.3 mo; P<0.001). The difference in OS between overweight and obese patients was not statistically significant (HR: 1.14, P=0.098). Similar results were observed for PFS outcomes. Subgroup analysis demonstrated improved OS in overweight/obese patients with nonsmall-cell lung cancer (HR: 0.81, P=0.002), melanoma (HR: 0.66, P<0.001), renal cell carcinoma (HR: 0.53, P<0.001), and multiple cancer type (HR: 0.34, P<0.001), with parallel results noted regarding PFS outcomes. Results of the present study suggested that BMI may be a satisfactory prognostic factor for patients treated with ICIs.

SUBMITTER: Nie RC

PROVIDER: S-EPMC8500279 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundA male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.MethodsAdvanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models.ResultsOverweight/Class-I (25- < 35 kg/m2) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m2). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HRmales:0.11; 95%CI:0.03-0.4; adjusted-HRfemales: 0.56; 95%CI:0.16-1.89; p-valueinteraction:0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-valueinteraction:0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts.ConclusionsThe findings support the existence of an "obesity paradox" restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).

Project description:BackgroundOverweight and obese patients with solid tumors receiving anti-programmed cell death-1 (PD-1)/PD-ligand-1(PD-L1) immune checkpoint inhibitors exhibit improved survival and higher risk of immune-related adverse events (irAEs) than those with a normal body mass index (BMI). In classic Hodgkin lymphoma (cHL), the impact of BMI on survival and immune-related toxicity is unknown. We evaluated for the first time associations of BMI with survival and irAEs in patients with relapsed/refractory (RR)-cHL undergoing PD-1 blockade.MethodsData from a multicenter study on 133 patients treated with the anti-PD1 antibody nivolumab (July 2015-December 2016) were retrieved from a prospective database. Progression-free (PFS), overall survival (OS), incidence and severity of irAEs according to BMI categories were estimated by Kaplan-Meier method, landmark-analyses and Cox regressions.ResultsPatients, mostly males (63%, n = 84) with a median age of 35 years (range, 15-82), advanced stage (75%), B symptoms (63%), bulky disease (24%), a median of 4 previous treatments (range, 1-9), received a median of 18 nivolumab doses (range, 1-57). No statistically significant differences across BMI subgroups emerged as to PFS, with 1-year rates of 67.1% for both normal weight (n = 66; 49.6%) and overweight (n = 31; 23.3%) patients. Underweight (n = 12; 9%) and obese (n = 24; 18%) patients had a 1-year PFS of 54.5% and 49%, respectively. In survival analyses, BMI either as a continuous (P = 0.5) or categorical (P for trend = 0.63) variable failed to associate with PFS. Response rates and time-to-response did not cluster in any BMI subset. No BMI-related differences in OS emerged across normal, overweight and obese patients but underweight patients had the worst survival. Occurrence of irAEs of whatever severity did not statistically associate with BMI.ConclusionsIn patients with RR-cHL receiving nivolumab, no statistically significant differences emerged in response rates, PFS and OS across BMI categories of normal weight, overweight and obese. Overweight/obese patients did not display an increased risk of irAEs. The exquisite sensitivity to anti-PD-1 antibodies, the unique cytokine milieu and effector pathways triggered by nivolumab in cHL, may represent biologic 'equalizers' counteracting the immunoregulatory effects of adiposity. Differently from solid tumors, BMI is not associated with treatment efficacy and immune-related toxicity and does not represent a predictive tool for PD-1-targeted immunotherapies in cHL.

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Association Between Body Mass Index and Survival Outcomes In Patients Treated With Immune Checkpoint Inhibitors: Meta-analyses of Individual Patient Data.

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