This study enrolled patients with confirmed diagnosis of measurable stage IV cancer, who consecutively underwent treatment with single agent anti-PD-1/PD-L1 as 1^st or subsequent line, at the medical oncology departments of 17 Italian centers (Additional file 1), between September 2013 and May 2018.

Weight and height were obtained from the patient’s medical records at the time of immunotherapy initiation. BMI was calculated using the formula of weight/height² (kilograms per square meter) and classified according to the World Health Organization (WHO) categories: underweight, BMI < 18.5; normal, 18.5 ≤ BMI ≤ 24.9; overweight, 25 ≤ BMI ≤ 29.9; obesity, BMI ≥ 30. For the study purpose, the binomial cut-off for BMI </≥ 25 was used, and patients were categorized into non-overweight (< 25) and overweight/obese (≥ 25) for the final analysis. Underweight patients were included in the non-overweight group.

We conducted a “real-life”, multicenter, retrospective observational study aimed at comparing the clinical outcomes of cancer patients treated with ICIs according to baseline BMI levels.

Primary outcomes measures were: objective response rate (ORR), time to treatment failure (TTF), PFS and OS. ORR was defined as the proportion of patients experiencing an objective response (either complete response or partial response) as best response to immunotherapy. TTF was defined as the time from treatment’s start to discontinuation for any reason. Progression-free survival (PFS) was defined as the time from the start of immunotherapy to the date of disease progression or death, whichever occurred first. Patients who were alive without disease progression were censored on the date of their last disease assessment. Overall survival (OS) was defined as the time from the start of immunotherapy to death. Patients who were still alive were censored at the date of last contact. Patients were treated according to the tumor type indication with pembrolizumab, nivolumab or atezolizumab with standard doses and schedules.

In order to weighing the possible prognostic influence of obesity (30 BMI) and malnutrition (or cachexia), two subgroup analysis (according to each BMI categories) were performed. In the first one, overweight (25-30 BMI) and obese (≥ 30 BMI) patients were respectively compared to non-overweight (< 25) patients, in the second one overweight (25-30 BMI) and obese (≥ 30 BMI) patients were respectively compared to normal weight patients (18.5-25 BMI).

A subgroup analysis comparing clinical outcomes in males and females patients, using the binomial cut-off (BMI </≥ 25) was also conducted as secondary analysis.

The following covariates were considered for the multivariate analyses: primary tumor (NSCLC, melanoma, kidney and others), sex (male vs female), Eastern Cooperative Oncology Group Performance Status (ECOG-PS) (0-1 vs. ≥ 2), age (< 70 vs. ≥ 70 years old) [10–13], number of metastatic sites (≤ 2 vs. > 2) and treatment line (first vs non-first). As in some indications the anti-PD-1/PD-L1 agents dosages had been weight-based, weight was used as a continuous covariate in all the analyses, considering the possible dose-depending confounding effect on the clinical outcomes.

Immune-related AEs (irAEs) were graduated according to the Common Toxicity Criteria for Adverse Events (CTCAE; version 4.0) and cumulatively reported. Immune-related AEs were categorized on the basis of the organ/system involved as follows: endocrine irAEs (including thyroid disorders), gastro-intestinal (GI) irAEs (excluding pancreatitis), skin irAEs, pneumological irAEs, hepatic irAEs, rheumatologic irAEs and others irAEs (including neuro-muscolar, pancreatitis, fever, asthenia and anorexia). The safety analysis was performed for irAEs of any grade and for G3/G4 irAEs.

To determine ORR and PFS, scans were reviewed by a dedicated thoracic oncologist at each Institution using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. [14]. χ2 was used to compare ORR and incidence of irAEs among subgroups [15]. In the multivariate analysis, logistic regression was used to evaluate the role of parameters proven to be significant at the univariate analysis of ORR [16]. Median TTF, median PFS, and median OS were evaluated using the Kaplan-Meier method [17]. Median follow-up was calculated according to the reverse Kaplan-Meier method [18]. Cox proportional hazards model [19] was used to evaluate predictor variables in univariate and multivariate analysis for TTF, PFS and OS. The data cut-off was October 29^th, 2018. All statistical analyses were performed using MedCalc Statistical Software version 18.6 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2018).

Nine hundred and seventy-six, consecutive advanced cancer patients were evaluated. Patient characteristics are summarized in Table 1. The median age was 68 years (range: 24 – 92), male/female ratio was 663/313. Primary tumors were: NSCLC (635 patients), melanoma (183 patients), renal cell carcinoma (135 patients) and others (23 patients). ECOG-PS was 0/1 in 831 patients (85.1%), and ≥ 2 in 145 patients (14.9%); 467 patients (47.9%) had ≤ 2 metastatic sites while 509 (52.1%) had more than 2 metastatic sites. PD-1/PD-L1 inhibitors were administered as first-line treatment in 260 patients (26.6%). Median weight was 71 Kg, median BMI was 24.9; according to WHO classification 40 patients (4.1%) were defined as underweight, 452 patients (46.3%) as having a normal weight, 377 patients (38.6%) as overweight and 107 patients (11%) as obese. For the study purpose, 492 patients were considered as non-overweight (50.4%) and 484 patients were categorized as overweight/obese (49.6%) according to a BMI cut-off of 25 (<25 vs. ≥25).Tab1

Patients’ characteristics

Among male patients median age was 69 years, median weight was 72 Kg (range: 35 – 139) and median BMI was 24.8 (range: 14 – 46.6). Among female patients median age was 67, median weight was 70 Kg (range: 40 – 130) and median BMI was 25.4 (range: 13.6 – 46.1).

In the entire cohort, 393 patients (40.3%) experienced irAEs of any grade. Sixty-three patients (6.5%) experienced G3/G4 irAEs. Overweight/obese patients were significantly more likely to experience any grade irAEs compared to non-overweight patients (55.6% vs. 25.2%, p < 0.0001). However, no difference in the rate of G3/G4 irAEs was observed between Overweight/obese patients and non-overweight patients (7.6 vs. 5.3%, p = 0.1338). The safety profile of ICIs according to BMI is summarized in Additional file 2.

Univariate and multivariate analyses for ORR are detailed in Additional file 3. Among 910 patients evaluable for activity, 283 patients had a response to ICIs (ORR: 31.1%). Overweight/obese patients had a significantly higher ORR compared non-overweight patients (41.3% vs. 20.9%, p < 0.0001). Similarly, we found a significantly higher ORR among patients who experienced at least 1 irAE compared to those without irAEs (45.1% vs. 21.1%, p < 0.0001). Both BMI (overweight/obese vs. non-overweight) and the development of irAEs of any grade, were independently associate with higher ORR in the multivariate analysis (p = 0.0239 and p < 0.0001, respectively).

At median follow-up of 17.2 months, median TTF was 5.9 months (95% CI: 5.3 – 6.7; 681 events), median PFS was 6.5 months (95% CI: 6.1 – 7.1; 644 events) and median OS was 13.4 months (95% CI: 11.0 – 16.5; 488 censored patients) in the entire cohort.

When these outcomes where analyzed according to BMI, we found that median TTF was significantly longer in overweight/obese patients compared to non-overweight patients (9.3 [95% CI: 8.1 – 11.6; 318 events] vs. 3.6 months [95% CI: 3.2 – 4.1; 363 events]; HR= 0.51 [95% CI: 0.44 – 0.60], p < 0.0001) (Fig. 1a). Similarly, median PFS was significantly improved in the overweight/obese group compared to the non-overweight group (11.7 months [95% CI: 9.4 – 15; 286 events] vs. 3.7 months [95% CI: 3.2 – 4.1; 358 events]; HR= 0.46 [95%CI: 0.39 – 0.54], p < 0.0001) (Fig. 1b). Consistently we also found a significantly prolonged median OS among overweight/obese patients compared to non-overweight patients (26.6 months [95% CI: 21.4 – 36.8; 286 censored patients] vs. 6.6 months [95% CI: 5.8 – 8.5; 182 censored patients]; HR= 0.33 [95%CI: 0.28 – 0.41], p < 0.0001) (Fig. 1c).Fig1Fig. 1

Kaplan-Meier survival curves according to binomial BMI levels (cut-off 25). (a) Time to Treatment Failure. BMI < 25: 3.6 months (95% CI: 3.2–4.1); BMI ≥ 25: 9.3 months (95%CI: 8.1–11.6). (b) Progression Free Survival. BMI < 25: 3.7 months (95% CI: 3.2–4.1); BMI ≥ 25: 11.7 months (95% CI: 9.4–15). (C) Overall Survival. BMI < 25: 6.6 months (95% CI: 5.8–8.5); BMI ≥ 25: 26.6 months (95% CI: 21.4–36.8)

Table 5 reports the univariate and multivariate gender analyses for TTF, PFS and OS of male patients (Table 5A) and female patients (Table 5B). As shown overweight/obese male patients had significantly longer TTF (p = 0.0330) and OS (p = 0.0013), but not PFS (p = 0.0668), when compared with non-overweight patients, while overweight/obese female patients had significantly longer TTF (p = 0.0037), PFS (p = 0.0132) and OS (p < 0.0001), when compared to non-overweight patients.Tab5

Cox proportional-hazards regression: univariate and multivariate analyses

Median TTF was not significantly different between overweight and obese patients (10.3 months [95%CI: 8.2 – 4.1; 238 events] vs. 7.3 [95%CI: 5.5 – 11.7; 80 events], HR=1.23 [95%CI: 0.95 – 1.58], p = 0.1087). Similarly, we found no significant differences in median PFS (11.2 months [95%CI: 9.1 – 15.6; 223 events patients] vs. 12.9 months [95%CI: 7.1 – 18; 63 events], HR=0.99 [95%CI: 0.75 – 1.31], p = 0.9798) and median OS (26.6 months [95%CI: 21.4 – 36.8; 223 censored patients] vs. not reached [63 censored patients], HR=1.04 [95%CI: 0.75 – 1.46], p = 0.7767) between overweight and obese patients. Table 6 reports the univariate and multivariate analyses of TTF, PFS and OS, comparing overweight (non-obese) patients and obese patient with non-overweight patients. Figure 2 reports the Kaplan-Meier survival curves of obese, overweight and non-overweight patients.Tab6

Cox proportional-hazards regression: univariate and multivariate analyses according to non-overweight (< 25), overweight (25-30) and obese (≥ 30) BMI levels

When we analyzed the clinical outcomes of normal weight vs. underweight patients, we found a significantly longer median TTF (3.9 months [95%CI: 3.4 – 5.0; 327 events] vs. 1.8 [95%CI: 1.7 – 2.9; 36 events], HR= 0.51 [95%CI: 0.35 – 0.71], p = 0.0001 and median PFS (4.4 months [95%CI: 3.6 – 5.3; 322 events] vs. 1.9 months [95%CI: 1.7 – 2.9; 36 events] HR= 0.45; 95%CI: 0.32 – 0.64], p < 0.0001) in normal weight patients compared with underweight patients. We also found a significant prolonged median OS among normal weight compared to underweight patients (7.9 months [95%CI: 6.4 – 9.8; 178 censored patients] vs. 2.8 months [95%CI: 1.8 – 3.6; 4 censored patients], HR= 0.33 [95%CI: 0.23 – 0.48], p < 0.0001). Table 7 reports the univariate and multivariate analyses of TTF, PFS and OS, comparing overweight (non-obese) patients and obese patients with normal weight patients. Figure 3 reports the Kaplan-Meier survival curves of obese, overweight and normal weight patients.Tab7

Cox proportional-hazards regression: univariate and multivariate analyses according to normal weight (18.5-25), overweight (25-30) and obese (≥ 30) BMI levels