Association of Body Mass Index With the Safety Profile of Nivolumab With or Without Ipilimumab

Jennifer L McQuade; Hans Hammers; Helena Furberg; Andreas Engert; Thierry André; George Blumenschein, Jr; Nizar Tannir; Ari Baron; James Larkin; Anthony El-Khoueiry; David P Carbone; John-Michael Thomas; Delphine Hennicken; Mary Coffey; Robert J Motzer

doi:10.1001/jamaoncol.2022.5409

. 2022 Dec 8:e225409. Online ahead of print. doi: 10.1001/jamaoncol.2022.5409

Association of Body Mass Index With the Safety Profile of Nivolumab With or Without Ipilimumab

Jennifer L McQuade ^1,^✉, Hans Hammers ², Helena Furberg ³, Andreas Engert ⁴, Thierry André ⁵, George Blumenschein Jr ⁶, Nizar Tannir ⁷, Ari Baron ⁸, James Larkin ⁹, Anthony El-Khoueiry ¹⁰, David P Carbone ¹¹, John-Michael Thomas ¹², Delphine Hennicken ¹², Mary Coffey ¹², Robert J Motzer ^13,^✉

¹Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston

²Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas

³Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York

⁴German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany

⁵Department of Medical Oncology, Sorbonne University and Saint-Antoine Hospital, Paris, France

⁶Department of Thoracic Medical Oncology, University of Texas MD Anderson Cancer Center, Houston

⁷Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston

⁸Division of Hematology Oncology, California Pacific Medical Center, San Francisco

⁹Department of Medical Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom

¹⁰Department of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, California

¹¹Department of Internal Medicine, Division of Medical Oncology, Ohio State University, Columbus

¹²Bristol Myers Squibb, Princeton, New Jersey

¹³Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York

Accepted for Publication: August 12, 2022.

Published Online: December 8, 2022. doi:10.1001/jamaoncol.2022.5409

^✉

Corresponding Authors: Jennifer L. McQuade, MD, University of Texas MD Anderson Cancer Center, 3400 Holcombe Blvd, Unit 463, Houston, TX 77030 (jmcquade@mdanderson.org); Robert J. Motzer, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (motzerr@mskcc.org).

Author Contributions: Drs Thomas and Coffey had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Tannir, El-Khoueiry, Carbone, Thomas, Coffey, Motzer.

Acquisition, analysis, or interpretation of data: McQuade, Hammers, Furberg, Engert, André, Blumenschein, Baron, Larkin, Carbone, Thomas, Hennicken, Coffey, Motzer.

Drafting of the manuscript: Blumenschein, Larkin, Carbone, Thomas, Motzer.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Furberg, Thomas, Hennicken.

Obtained funding: Thomas, Coffey.

Administrative, technical, or material support: McQuade, André, Blumenschein, Tannir, Thomas, Coffey, Motzer.

Supervision: McQuade, Baron, Larkin, Carbone, Thomas, Coffey, Motzer.

Conflict of Interest Disclosures: Dr McQuade reported receiving honoraria from Bristol Myers Squibb and Roche and consulting for Merck during the conduct of the study. Dr Hammers reported receiving grants from Bristol Myers Squibb outside the submitted work. Dr Furberg reported receiving grants from the National Cancer Institute (P30-CA008748 and R01CA233885) during the conduct of the study. Dr Engert reported receiving grants from Bristol Myers Squibb during the conduct of the study and personal fees from Takeda, AstraZeneca, Merck Sharpe & Dohme, Janssen Cilag, Innovent Biologics, TS Oncology, and Hexal AG outside the submitted work. Dr André reported receiving personal fees from Bristol Myers Squibb, Amgen, Astellas Pharma, AstraZeneca, Chugai, Clovis, Gritstone Oncology, GlaxoSmithKline, HalioDx, Kaleido Biosciences, Merck, MSD, Pierre Fabre, Roche/Genentech, Roche/Ventana, Sanofi, Seagen, Servier, Tesaro, and Transgene outside the submitted work. Dr Blumenschein reported receiving grants from Bristol Myers Squibb during the conduct of the study; grants from Amgen, Bayer, Adaptimmune, Exelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, MacroGenics, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Sanofi, Torque, Xcovery, Tmunity Therapeutics, Regeneron, BeiGene, Repertoire Immune Medicines, Verastem, and CytomX Therapeutics outside the submitted work; consulting fees from AbbVie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, InterVenn Biosciences, CytomX Therapeutics, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Genzyme, Gilead, Eli Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Sanofi Tyme Oncology, Xcovery, Virogin Biotech, Maverick Therapeutics, BeiGene, and Regeneron; being a member of Therapeutics SAB and Virogin SAB, with stock ownership; owning stock and stock options in Verastem; having a family member employed by Johnson & Johnson/Janssen; and participating on a scientific advisory board for Maverick Therapeutics and Virogin Biotech. Dr Tannir reported receiving grants and honoraria from Calithera Bioscience during the conduct of the study; grants from Bristol Myers Squibb, Nektar Therapeutics, Arrowhead Pharmaceuticals, Eisai, and Novartis; and honoraria from Bristol Myers Squibb, Pfizer, Nektar Therapeutics, Exelixis Inc, Eisai Medical Research, Eli Lilly, Oncorena, Surface Oncology, Novartis, Ipsen, and Merck Sharp & Dohme outside the submitted work. Dr Baron reported receiving fees from Bristol Myers Squibb for serving on a speakers bureau during the conduct of the study and personal fees from Eli Lilly, Janzen, and Bayer outside the submitted work. Dr Larkin reported receiving personal fees from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare, RCGP, VJOncology, Agence Unik, Bristol Myers Squibb, Pierre Fabre, Ipsen, Roche, EUSA Pharma, Aptitude, AstraZeneca, GlaxoSmithKline, Calithera Bioscience, Ultimovacs, Seagen, eCancer, Insel Gruppe, Goldman Sachs, MSD, iOnctura, Apple Tree, Debiopharm, Achilles Therapeutics, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, and Aveo Research outside the submitted work. Dr El-Khoueiry reported receiving nonfinancial support from Bristol Myers Squibb during the conduct of the study; personal fees from Bristol Myers Squibb, Bayer, Roche Genentech, Eisai, Merck, Agenus, Gilead, Senti Biosciences, Qurient, Tallac, ABL Bio, Servier, Exelixis, QED, Gilead, and AstraZeneca; and grants from Fulgent, AstraZeneca, and Astex outside the submitted work. Dr Carbone reported receiving personal fees from Bristol Myers Squibb, Roche, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Iovance, Novartis, Pfizer, Lilly, Amgen, Janssen, and Sanofi outside the submitted work. Dr Thomas reported receiving personal fees from Bristol Myers Squibb as an employee during the conduct of the study. Dr Coffey reported receiving personal fees from Bristol Myers Squibb and nonfinancial support from Bristol Myers Squibb and Spark Medica during the conduct of the study and receiving personal fees and nonfinancial support from Bristol Myers Squibb outside the submitted work. Dr Motzer reported receiving grants from Bristol Myers Squibb during the conduct of the study; personal fees from Genentech/Roche, Pfizer, Eisai, Exelixis, EMD Serono, Merck, and CalitheraBioscience outside the submitted work; and grants from Genentech/Roche, Pfizer, Eisai, Exelixis, Merck, and Aveo outside the submitted work. No other disclosures were reported.

Funding/Support: All studies included in this pooled analysis were sponsored by Bristol Myers Squibb. Patients treated at Memorial Sloan Kettering Cancer Center were supported in part by a Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748).

Role of the Funder/Sponsor: Bristol Myers Squibb was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Additional Contributions: Medical writing support and editorial assistance were provided by Bernard Kerr, PGDipSci, and Matthew Weddig, BA, of Spark Medica Inc and funded by Bristol Myers Squibb according to Good Publication Practice guidelines.

Additional Information: Bristol Myers Squibb company policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. Ms Hennicken was employed by Bristol Myers Squibb when the analysis was performed but was no longer employed there at manuscript acceptance.

^✉

Corresponding author.

PMCID: PMC9857666 PMID: 36480191

Key Points

Question

Is there an association between pretreatment obesity and the safety of immune checkpoint inhibitors?

Findings

In this pooled analysis of 3772 patients with advanced cancer, obesity was associated with an increased incidence of any-grade, but not grade 3 or 4, immune-related adverse events compared with normal weight or underweight body mass index among patients receiving nivolumab monotherapy (n = 2746). This differential likelihood was consistent across all subgroups evaluated except for a higher likelihood of grade 3 or 4 immune-related adverse events among female patients with obesity vs normal weight or underweight body mass index.

Meaning

Obesity may be associated with an increased incidence of mild or moderate immune-related adverse events among patients receiving immune checkpoint inhibitors.

Abstract

Importance

Increased survival with immune checkpoint inhibitors has been reported for patients with obesity vs a normal body mass index (BMI). However, the association of obesity with the safety of immune checkpoint inhibitors warrants study.

Objective

To investigate associations between BMI and immune-related adverse events (irAEs) among patients with advanced cancers treated with nivolumab monotherapy and nivolumab plus ipilimumab combination therapy.

Design, Setting, and Participants

This study was a retrospective pooled analysis of 3772 patients from 14 multicenter CheckMate clinical trials across 8 tumor types. Patients with advanced cancers received nivolumab, 3 mg/kg (n = 2746); nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg (n = 713); or nivolumab, 1 mg/kg, plus ipilimumab, 3 mg/kg (n = 313). Baseline BMI was categorized as normal weight or underweight (<25), overweight (25 to <30), or obese (≥30) according to World Health Organization criteria. The studies began patient enrollment between February 9, 2012, and May 21, 2015, and patients were followed up to database lock on May 1, 2019. Data analysis was conducted from May 1 to September 1, 2019.

Interventions

Nivolumab, 3 mg/kg; nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg; and nivolumab, 1 mg/kg, plus ipilimumab, 3 mg/kg.

Main Outcomes and Measures

Odds ratios (ORs) and 95% CIs for incidence of any-grade and grade 3 or 4 irAEs were calculated for patients with obesity vs normal weight or underweight BMI in the overall cohort and in subgroups based on patient and tumor characteristics. Analyses for nivolumab plus ipilimumab cohorts were exploratory.

Results

A total of 3772 patients were included, 2600 were male (69%), and median age was 61 years (range, 18-90 years). For patients receiving monotherapy with nivolumab, 3 mg/kg (n = 2746), the incidence of any-grade irAEs was higher in patients with obesity (n = 543) vs those with normal weight or underweight BMI (n = 1266; OR, 1.71; 95% CI, 1.38-2.11). Incidence of grade 3 or 4 irAEs did not differ between patients with obesity and those with normal weight or underweight BMI (OR, 1.21; 95% CI, 0.92-1.61). Risk of any-grade and grade 3 or 4 irAEs appeared consistent with that in the overall population across all subgroups evaluated except for a higher likelihood of grade 3 or 4 irAEs among female patients with obesity vs normal weight or underweight BMI (OR, 1.73; 95% CI, 1.07-2.79). For patients receiving nivolumab plus ipilimumab, the incidence of irAEs appeared consistent across BMI categories.

Conclusions and Relevance

Obesity appeared to be associated with an increased incidence of any-grade irAEs among patients treated with nivolumab monotherapy and with grade 3 or 4 irAEs among female patients only. These findings may inform the monitoring of patients at high risk of developing irAEs.

This pooled analysis investigates the association between pretreatment obesity and the safety of immune checkpoint inhibitors in adult patients with advanced cancer.

Introduction

Obesity, defined by a high body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), is an established risk factor for multiple malignancies. Obesity has been associated with poor patient outcomes across multiple tumor types; however, retrospective analyses among patients with metastatic melanoma, non–small cell lung cancer, or renal cell carcinoma treated with immune checkpoint inhibitors (ICIs) suggest that obesity is paradoxically associated with improved survival in this setting. Investigation of the mechanisms behind improved survival with obesity is ongoing, with hypothesized reasons including immunomodulatory effects of adiposity and increased programmed cell death 1–mediated T-cell dysfunction, resulting in greater tumor susceptibility to ICI treatment.

The programmed cell death 1 inhibitor nivolumab and the cytotoxic T-lymphocyte–associated antigen 4 inhibitor ipilimumab have been approved by the US Food and Drug Administration for the treatment of a range of tumor types, both alone and in combination. Nivolumab monotherapy and nivolumab plus ipilimumab were first approved with weight-based dosing, reflecting the regimens used in registrational trials. However, flat dosing of nivolumab monotherapy was approved by the US Food and Drug Administration in September 2016 based on population pharmacokinetic modeling and exposure-response analyses and has replaced weight-based dosing in all adult monotherapy indications in the United States and Europe. Body weight (BW)–based dosing is still used for the nivolumab plus ipilimumab combination and for pediatric patients with microsatellite instability–high or mismatch repair deficient metastatic colorectal cancer and a BW of less than 40 kg. Population pharmacokinetic studies have shown interindividual variability in nivolumab clearance associated with patient characteristics, including BW and sex; thus, there is a strong rationale to investigate the association between these factors and safety. Nivolumab dose is calculated with actual BW, whereas some oncologists calculate cytotoxic chemotherapy dosing with adjusted BW or body surface area.

Retrospective analyses investigating the association between BMI and risk of immune-related adverse events (irAEs) have been heterogeneous, with some showing higher incidence among patients with overweight or obesity vs normal BMI, whereas others have found no significant association between BMI and incidence of irAEs. This analysis builds on previous studies to further investigate the potential association between BMI and safety among patients receiving ICIs by using existing randomized clinical trial data with rigorous, prospectively collected AE grading and reporting.

For a pooled cohort of patients treated with nivolumab monotherapy in 12 CheckMate trials across 8 tumor types, we reported associations between BMI and irAEs and investigated whether they differed by patient and tumor characteristics. We also performed exploratory analyses to examine these associations among patients treated with nivolumab plus ipilimumab.

Methods

Safety data for this pooled analysis were from a total of 3772 patients with advanced cancers treated with weight-based nivolumab monotherapy (n = 2746) or nivolumab plus ipilimumab combination therapy (nivolumab, 3 mg/kg, plus ipilimumab, 1 mg/kg [NIVO3 + IPI1] [n = 713] or nivolumab, 1 mg/kg, plus ipilimumab, 3 mg/kg [NIVO1 + IPI3] [n = 313]) in 14 CheckMate trials across 8 tumor types (ClinicalTrials.gov Identifiers: NCT01472081, NCT01592370, NCT01642004, NCT01658878, NCT01668784, NCT01673867, NCT01721772, NCT01844505, NCT02041533, NCT02060188, NCT02105636, NCT02181738, NCT02231749, and NCT02387996) (eTable 1 in the Supplement). Included studies were the most extensive data sets available with published primary data at the time of analysis. Data from patients receiving NIVO3 were included from 12 trials across 8 tumor types (CheckMate 017, 025, 026, 039, and 040 [all expansion cohorts]; 057, 066, 067, 141, and 142 [all microsatellite instability–high/mismatch repair deficient colorectal cancer per local laboratory; 205 [cohorts A, B, and C]; and 275), data from patients receiving NIVO3 + IPI1 were included from 3 trials across 2 tumor types (CheckMate 016, 142 [all microsatellite instability–high/mismatch repair deficient colorectal cancer], and 214), and data from patients receiving NIVO1 + IPI3 were from 1 trial in 1 tumor type (CheckMate 067) (eTable 1 in the Supplement). Patient enrollment began between February 9, 2012, and May 21, 2015, and patients were followed up to database lock on May 1, 2019. Data analysis was conducted from May 1 to September 1, 2019. Follow-up was defined as the time between randomization date (or first dose date for nonrandomized studies) and last known alive date (for participants who were alive) or death. Instiutional review board approval was not required because the study was a retrospective analysis of data from published clinical trials.

Safety was defined as the incidence of any-grade and grade 3 or 4 irAEs according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0 and the Medical Dictionary for Regulatory Activities, version 21.0 (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) (CheckMate 016, 017, 026, 057, 025, 275, 141, and 205) or version 21.1 (CheckMate 039, 040, 066, 067, 142, and 214) for patients receiving at least 1 dose of nivolumab or nivolumab plus ipilimumab. Immune-related adverse events were defined as specific AEs, including pneumonitis, diarrhea or colitis, hepatitis, nephritis or kidney dysfunction, rash, endocrine AEs, and hypersensitivity, that occurred during the treatment period or within 100 days of the last dose of the study therapy; were considered to be potential irAEs by the investigator; were treated with immune-modulating medication regardless of causality; and had no clear alternative etiology according to investigator assessment. Endocrine AEs, including adrenal insufficiency, hypothyroidism or thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis, were considered irAEs regardless of immune-modulating medication because they are often managed without such medications.

Baseline BMI was categorized according to World Health Organization criteria as normal weight or underweight (<25), overweight (25 to <30), or obese (≥30). Because of the small number of patients in the underweight category (n = 160), data were grouped with the normal category; sensitivity analyses showed no differences in safety outcomes between underweight and normal categories. For the CheckMate 016, 025, and 214 trials, the Karnofsky performance status was recalculated to the Eastern Cooperative Oncology Group (ECOG) performance status scale. Cumulative doses of nivolumab and ipilimumab per kilogram of BW from the initiation of study treatment to study drug discontinuation or date of last follow-up were calculated for each BMI category.

Incidence of irAEs was reported by BMI category for each treatment cohort. We focused on the 2 extreme BMI categories and calculated odds ratios (ORs) and 95% CIs for the occurrence of any-grade and grade 3 or 4 irAEs for patients with obesity vs normal weight or underweight BMI. These analyses were descriptive. Breslow-Day testing was conducted to determine data homogeneity. Some variability was identified across the NIVO3 studies, but the data remained homogeneous overall; NIVO3 + IPI1 studies were homogeneous, and NIVO1 + IPI3 comprised a single study, so Breslow-Day testing was not conducted. Formal statistical tests and multivariable analyses were not performed. We further examined the association between BMI category and incidence of irAEs within predefined subgroups (age, ECOG performance status, geographic region, sex, smoking status, and tumor type). Odds ratios were not calculated for subgroups with fewer than 10 patients per treatment group.

Results

A total of 3772 patients were included in the study. There were 2600 men (69%) and 1172 women (31%). Median age was 61 years (range, 18-90 years).

Nivolumab Monotherapy Cohort

The safety analysis included data from 2746 patients treated with NIVO3 (Table). A total of 1881 were male (68%) and 865 were female (32%). Analysis of race was not planned for inclusion in the analysis when it was designed, and these data are not available for the pooled patient population. Patient distribution by BMI category and tumor type in the NIVO3 monotherapy cohort is shown in eFigure 1 in the Supplement. The proportion of patients with obesity was numerically higher in the renal cell carcinoma and melanoma subgroups. Patients received a median of 10 nivolumab doses (range, 1-149 doses), with a higher median number of doses and cumulative dose in patients with overweight and obesity compared with those with normal weight or underweight BMI (eTable 2 in the Supplement).

Table. Patient Demographic and Baseline Characteristics.

Characteristic	NIVO3				NIVO3 + IPI1				NIVO1 + IPI3
	All patients (n = 2746)^a	BMI category			All patients (n = 713)	BMI category			All patients (n = 313)^a	BMI category
	All patients (n = 2746)^a	<25 (n = 1266)^b	25 to <30 (n = 881)	≥30 (n = 543)	All patients (n = 713)	<25 (n = 232)^b	25 to <30 (n = 277)	≥30 (n = 200)	All patients (n = 313)^a	<25 (n = 94)^b	25 to <30 (n = 108)	≥30 (n = 104)
BMI, median (range)	25.3 (14.7-67.5)	22.2 (14.7-24.9)	27.0 (25.0-29.9)	32.9 (30.0-67.5)	27.0 (15.1-54.9)	22.5 (15.1-24.9)	27.3 (25.0-29.9)	33.3 (30.0-54.9)	27.7 (12.6-53.4)	23.0 (12.6-24.9)	27.5 (25.0-29.8)	33.2 (30.0-53.4)
Sex, No. (%)
Male	1881 (68.5)	797 (63.0)	662 (75.1)	392 (72.2)	514 (72.1)	147 (63.4)	218 (78.7)	147 (73.5)	205 (65.5)	54 (57.4)	77 (71.3)	70 (67.3)
Female	865 (31.5)	469 (37.0)	219 (24.9)	151 (27.8)	199 (27.9)	85 (36.6)	59 (21.3)	53 (26.5)	108 (34.5)	40 (42.6)	31 (28.7)	34 (32.7)
Age, median (range), y	61 (18-90)	60 (18-90)	62 (19-90)	61 (19-87)	61 (21-88)	59 (21-88)	61 (35-85)	61 (30-85)	61 (18-87)	58 (18-78)	62 (22-85)	61 (31-87)
Follow-up, median (range), mo^c	17.8 (0.1-72.2)	14.2 (0.1-84.2)	19.6 (0.2-83.9)	22.7 (0.2-85.3)	35.2 (0.1-63.1)	49.4 (0.1-74.3)	49.1 (0.6-74.1)	47.3 (0.1-73.0)	55.5 (0.1-68.7)	37.9 (0.5-85.4)	66.6 (0.1-85.5)	66.2 (0.4-86.4)
Tumor type, No. (%)
Non–small cell lung cancer	685 (24.9)	351 (27.7)	224 (25.4)	96 (17.7)	NA	NA	NA	NA	NA	NA	NA	NA
Metastatic melanoma	519 (18.9)	169 (13.3)	199 (22.6)	140 (25.8)	NA	NA	NA	NA	313 (100)	94 (100)	108 (100)	104 (100)
Renal cell carcinoma	406 (14.8)	135 (10.7)	145 (16.5)	111 (20.4)	594 (83.3)	167 (72.0)	243 (87.7)	180 (90.0)	NA	NA	NA	NA
Hodgkin lymphoma	342 (12.5)	164 (13.0)	95 (10.8)	79 (14.5)	NA	NA	NA	NA	NA	NA	NA	NA
Metastatic urothelial carcinoma	270 (9.8)	123 (9.7)	85 (9.6)	58 (10.7)	NA	NA	NA	NA	NA	NA	NA	NA
Squamous cell carcinoma of the head and neck	236 (8.6)	168 (13.3)	52 (5.9)	13 (2.4)	NA	NA	NA	NA	NA	NA	NA	NA
Hepatocellular carcinoma	214 (7.8)	116 (9.2)	63 (7.2)	32 (5.9)	NA	NA	NA	NA	NA	NA	NA	NA
MSI-H/dMMR metastatic colorectal cancer	74 (2.7)	40 (3.2)	18 (2.0)	14 (2.6)	119 (16.7)	65 (28.0)	34 (12.3)	20 (10.0)	NA	NA	NA	NA

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Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); dMMR, mismatch repair deficient; IPI1, ipilimumab, 1 mg/kg; IPI3, ipilimumab, 3 mg/kg; MSI-H, microsatellite instability–high; NA, not applicable; NIVO1, nivolumab, 1 mg/kg; NIVO3, nivolumab, 3 mg/kg.

^{^a}

Includes 56 patients (2.0%) in the NIVO3 group, 4 (0.6%) in the NIVO3 + IPI1 group, and 7 (2.2%) in the NIVO1 + IPI3 group with no reported BMI.

^{^b}

Includes 146 patients (11.5%) in the NIVO3 group, 9 (1.3%) in the NIVO3 + IPI1 group, and 5 (1.6%) in the NIVO1 + IPI3 group with an underweight BMI (<18.5).

^{^c}

For randomized studies, follow-up was defined as the time between randomization date and last known alive date (for patients who were alive) or death. For nonrandomized studies, follow-up was defined as the time between first dose of the study drug and last known alive date (for patients who were alive) or death.

Patients with obesity (n = 543) and overweight (n = 881) who were treated with NIVO3 had a higher incidence of any-grade and grade 3 or 4 irAEs vs those with normal weight or underweight BMI (n = 1266). The incidences of irAEs for patients with obesity vs overweight vs normal weight or underweight BMI were 70.0% (95% CI, 65.9%-73.8%), 63.6% (95% CI, 60.3%-66.7%), and 57.7% (95% CI, 55.0%-60.5%), respectively, for any grade and were 15.8% (95% CI, 12.9%-19.2%), 14.9% (95% CI, 12.6%-17.4%), and 13.4% (95% CI, 11.6%-15.4%), respectively, for grade 3 or 4 (eFigure 2 in the Supplement).

Odds ratios for any-grade and grade 3 or 4 irAEs for patients with obesity vs normal weight or underweight BMI in the overall NIVO3 cohort and across various patient subgroups are shown in Figure 1. The likelihood of any-grade irAEs was higher among patients with obesity vs normal weight or underweight BMI (OR, 1.71; 95% CI, 1.38-2.11), which was consistent across subgroups of age, sex, smoking status, and ECOG performance status. The likelihood of grade 3 or 4 irAEs was not higher among patients with obesity vs normal weight or underweight BMI (OR, 1.21; 95% CI, 0.92-1.61); this finding was consistent across all subgroups except for a higher likelihood of grade 3 or 4 irAEs among female patients with obesity vs normal weight or underweight BMI (OR, 1.73; 95% CI, 1.07-2.79). Across geographic region subgroups, ORs for any-grade and grade 3 or 4 irAEs remained consistent with that of the overall population except for a higher likelihood of grade 3 or 4 irAEs among patients from Europe with obesity vs normal weight or underweight BMI (OR, 1.56; 95% CI, 1.01-2.40). Similarly, ORs for any-grade and grade 3 or 4 irAEs among patients with obesity vs normal weight or underweight BMI were consistent across tumor type subgroups.

Figure 1. — Symbols indicate the point estimates of the ORs, and horizontal lines indicate the 95% CIs. BMI indicates body mass index; CRC, colorectal cancer; dMMR, mismatch repair deficient; ECOG PS, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular carcinoma; HL, Hodgkin lymphoma; MEL, melanoma; MSI-H, microsatellite instability–high; mUC, metastatic urothelial carcinoma; NSCLC, non–small cell lung cancer; RCC, renal cell carcinoma; and SCCHN, squamous cell carcinoma of the head and neck.

^aForty-one patients had unknown smoking status.

^bBaseline ECOG PS was not available for 2 patients.

^cOdds ratios for occurrence of any-grade and grade 3 or 4 irAEs were not calculated for 176 patients in the Asia subgroup because fewer than 10 patients were categorized as having obesity. Asia was not included in the “rest of world” analysis.

^dAn OR could not be calculated for occurrence of any-grade irAEs in the CRC subgroup because all patients categorized as having obesity had at least 1 any-grade irAE.

Higher incidence of some individual any-grade irAEs among male and female patients appeared to be associated with increasing BMI, mirroring the trend for overall incidence of irAEs (eFigure 3 in the Supplement). Evaluation of the frequency of individual occurrences of any-grade irAEs by irAE and BMI categories showed that the increasing frequency of diarrhea or colitis, dermatitis or immune-related skin reactions, and nephritis or kidney disorders appeared to be associated with increasing BMI in the overall NIVO3 cohort (eFigure 4 in the Supplement).

Nivolumab and Ipilimumab Combination Therapy Cohorts

The safety analysis included 713 patients treated with NIVO3 + IPI1 and 313 patients treated with NIVO1 + IPI3. Most patients who received combination therapy were male (Table). Median age was 61 years (range, 21-88 years) for the NIVO3 + IPI1 cohort and 61 years (range, 18-87 years) for the NIVO1 + IPI3 cohort. Patients received a median of 16 nivolumab doses (range, 1-131 doses) in the NIVO3 + IPI1 group, 4 nivolumab doses (range, 1-137 doses) in the NIVO1 + IPI3 group, and a median of 4 ipilimumab doses (range, 1-4 doses) in both the NIVO3 + IPI1 and NIVO1 + IPI3 groups. The cumulative dose of both nivolumab and ipilimumab was similar for patients with obesity vs normal weight or underweight BMI (eTable 2 in the Supplement).

For the NIVO3 + IPI1 cohort, exploratory analyses showed that an upward trend in any-grade irAE incidence was associated with increasing BMI, from 82.3% (95% CI, 76.8%-87.0%) for patients with normal weight or underweight BMI to 85.2% (95% CI, 80.5%-89.2%) for those with overweight and 88.0% (95% CI, 82.7%-92.2%) for those with obesity, with no trend observed for grade 3 or 4 irAEs (eFigure 5 in the Supplement; Figure 2), similar to the NIVO3 cohort. The likelihood of irAEs in the NIVO1 + IPI3 cohort did not increase with increasing BMI (eFigures 6 and 7 in the Supplement). Although the female subgroup sample size was small, there was a numerically higher incidence of grade 3 or 4 irAEs among female patients with overweight vs normal weight or obesity who received NIVO3 + IPI1 and an association of increased likelihood of grade 3 or 4 irAEs with increasing BMI among female patients who received NIVO1 + IPI3. No clear trends were observed in the incidence of individual any-grade irAEs and frequency of individual irAEs as presented in eFigures 8, 9, 10, and 11 in the Supplement.

Figure 2. — Symbols indicate the point estimates of the ORs, and horizontal lines indicate the 95% CIs. BMI indicates body mass index; CRC, colorectal cancer; dMMR, mismatch repair deficient; ECOG PS, Eastern Cooperative Oncology Group performance status; MSI-H, microsatellite instability–high; and RCC, renal cell carcinoma.

^aSmoking status was unknown for 8 patients.

^bOdds ratios for occurrence of any-grade and grade 3 or 4 immune-related adverse events were not calculated for 28 patients in the Asia subgroup because fewer than 10 patients were categorized as having obesity. Asia was not included in the “rest of world” analysis.

Discussion

Obesity, a risk factor for developing many tumor types, has paradoxically been associated with improved outcomes for patients receiving ICIs. Studies on the BMI-safety association using clinical trial data have shown heterogeneous results, with some studies indicating no association and others suggesting an increased risk. Similarly, meta-analyses have demonstrated heterogeneous results. Our study analyzed primary trial data in which irAEs were uniformly defined across the trials and included 2746 patients receiving nivolumab monotherapy and 1026 patients treated with combination therapy. We focused our analysis on the most extreme BMI categories of obese vs normal weight or underweight BMI because BMI is less likely to misclassify adiposity in these categories than in patients with overweight BMI. In our primary analysis of NIVO3 monotherapy, a higher incidence of any-grade irAEs, but not grade 3 or 4 irAEs, was observed among patients with obesity vs normal weight or underweight BMI. Although a formal comparison of irAE likelihood was not conducted for the groups with overweight vs normal weight or underweight BMI, we observed a trend for increasing incidence of any-grade irAEs with increasing BMI category, supporting a biological association between BMI and irAEs.

Results of subgroup analyses of the NIVO3 monotherapy group, including age, sex, ECOG performance status, smoking status, geographic region, and tumor type, were generally consistent with that of the overall population in that there was an association between increasing incidence of any-grade irAEs in patients with obesity vs normal weight or underweight BMI. There was no increase in the likelihood of grade 3 or 4 irAEs, consistent with the overall population, except for higher incidence observed among female patients with obesity. However, given the post hoc design of this analysis, these results should be interpreted with caution. Limitations when multiple subgroup analyses are performed are well known, and the probability of a false-positive finding can be substantial.

A systematic review found that higher BMI was associated with increased incidence of irAEs among patients receiving ipilimumab monotherapy or nivolumab plus ipilimumab. Our current analysis of patients treated with this combination indicated that the incidence of irAEs trended upward with BMI in the NIVO3 + IPI1 cohort but not in the NIVO1 + IPI3 cohort. Further evaluation of BMI and safety associations among patients receiving combination therapy is needed to draw more definitive conclusions. It is also possible that any increase in the overall incidence of irAEs attributable to BMI was masked by the high overall incidence of irAEs in the combination group.

In contrast to the steep dose-response relationship with chemotherapy, ICIs have a wide therapeutic window, with BW having a minimal association with clinical efficacy and pharmacokinetics. Although pharmacokinetic modeling identified BW as contributing to interindividual variability in nivolumab pharmacokinetics, steady-state exposure was comparable across evaluated BWs (34.1-168.2 kg), suggesting that the effect of BW was unlikely to be clinically relevant. Subsequent exposure-response modeling studies provided further evidence that nivolumab exposure is not a significant predictor for AEs, suggesting a relatively flat exposure-response relationship. In addition, many cytotoxic agents are associated with cumulative toxicities after repeated dosing, which has not been observed among patients receiving ICIs. These factors suggest that the association between BMI and irAEs in this study may not have been due to differences in ICI exposure.

The potential mechanisms through which obesity affects outcomes with ICI therapies are only partially understood. Studies to date have largely focused on improvements in ICI efficacy for patients with obesity vs normal BMI, whereas few studies have investigated the associations between obesity and safety. Obesity may be associated with response to ICI through increased chronic inflammation, increased programmed cell death 1 expression on CD8⁺ T cells, decreased T-cell function, and increased frequency of exhausted T cells. A study of patients with renal cell carcinoma also theorized that peritumoral fat may serve as a reservoir of activated immune cells that are mobilized after ICI administration. It is unclear whether some or all of the suggested mechanisms involved in the increased effectiveness of ICIs in patients with obesity may contribute to increased incidence of irAEs. Results from a number of studies indicate a possible association between irAEs and improved ICI efficacy, with suggested mechanisms including immune responses against antigens common to both tumor cells and healthy tissue or off-target immune responses resulting from preexisting inflammation in healthy tissue. Male-female differences in immune function have also been identified and are attributed to various factors, including diet, sex hormones, and other physiologic differences, which could explain our observation of increased incidence of grade 3 or 4 irAEs associated with obesity in female patients. Alterations to the gut microbiome have been associated with obesity, response to ICIs, and irAE occurrence. Because potential roles of the microbiome in these areas have been only newly discovered and are rapidly evolving, further studies to determine clinical relevance are warranted.

Limitations

This analysis is subject to several limitations because of its retrospective pooled-data design, the use of descriptive univariable analyses, and the heterogeneity of the included studies in terms of study designs, tumor types, treatment settings, and patient demographic and clinical characteristics. However, homogeneity testing showed that the overall populations were homogeneous, and associations between BMI and incidence of irAEs were similar across all subgroups except for increased incidence of grade 3 or 4 irAEs with obesity among female patients. The irAE incidence data used for this analysis were limited to prospectively collected data for specific irAEs included in the case report form used during the conduct of each study, as described in the Methods. Because knowledge of ICI-related irAEs has continued to evolve since these studies were designed, data were not available for some irAEs that were identified more recently. Furthermore, because increased median follow-up duration and cumulative nivolumab exposure were associated with increased BMI, our analysis is subject to immortal time bias. Investigation of associations between BMI-associated exposure and effectiveness outcomes using this pooled data set was not possible because of the heterogeneous tumor types, lines of therapy, and patient populations. The finding of an apparent association between obesity and an increased incidence of mild but not severe irAEs has potential clinical relevance. Additional studies are needed to confirm this result and further elucidate the associated mechanisms, especially because this finding could be related to statistical power given that grade 3 or 4 events account for only a small proportion of irAEs. The association between BMI and ICI efficacy remains an area of interest, with retrospective studies in specific tumor types identifying possible relationships. Finally, the value of BMI as a surrogate measure of body composition is subject to considerable interindividual differences in body composition and fat distribution.

Conclusions

In this pooled analysis of patients treated with weight-based nivolumab monotherapy or combination therapy across 14 CheckMate trials and 8 tumor types, an increased incidence of any-grade irAEs, but not grade 3 or 4 irAEs, was observed for patients with obesity vs normal weight or underweight BMI who were treated with NIVO3 monotherapy. The likelihood of any-grade irAEs among patients with obesity vs normal weight or underweight BMI who received NIVO3 appeared consistent with that of the overall population across subgroups according to patient demographic characteristics, baseline characteristics, and tumor type. Similarly, the likelihood of grade 3 or 4 irAEs across all evaluated subgroups appeared consistent with that of the overall population except for a higher likelihood of grade 3 or 4 irAEs among female patients with obesity vs normal weight or underweight BMI. The results of this analysis highlight the importance of BMI as a clinical covariate for patients receiving ICIs and support further evaluation in prospective studies of associations between body composition and patient outcomes during ICI treatment.

Supplement.

eTable 1. Included Clinical Trials

eTable 2. Cumulative Dose of Nivolumab by BMI

eFigure 1. Distribution of Patients Into BMI Categories by Tumor Type in the NIVO3 Cohort

eFigure 2. Incidence of irAEs by Sex and BMI in the NIVO3 Cohort

eFigure 3. Incidence of Any-Grade (Top) and Grade 3 or 4 (Bottom) irAEs in (A) Male and (B) Female Patients in the NIVO3 Cohort

eFigure 4. Frequency of Individual irAEs of Any Grade by BMI in the Overall NIVO3 Cohort

eFigure 5. Incidence of irAEs by Sex and BMI in the NIVO3 + IPI1 Cohort

eFigure 6. Incidence of Individual Any-Grade (Top) and Grade 3 or 4 irAEs (Bottom) by BMI in (A) Male and (B) Female Patients in the NIVO3 + IPI1 Cohort

eFigure 7. Frequency of Individual Any-Grade irAEs by BMI in the NIVO3 + IPI1 Cohort

eFigure 8. Incidence of irAEs by Sex and BMI in the NIVO1 + IPI3 Cohort

eFigure 9. ORs for irAE Occurrence in Obese vs Normal or Underweight Patients in Subgroups Based on Patient Characteristics in the NIVO1 + IPI3 Cohort

eFigure 10. Incidence of Individual Any-Grade (Top) and Grade 3 or 4 irAEs (Bottom) by BMI in (A) Male and (B) Female Patients in the NIVO1 + IPI3 Cohort

eFigure 11. Frequency of Individual Any-Grade irAEs by BMI in the NIVO1 + IPI3 Cohort

eReferences.

Click here for additional data file.^{(1.6MB, pdf)}

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