Clinical Outcomes and Toxic Effects of Single-Agent Immune Checkpoint Inhibitors Among Patients Aged 80 Years or Older With Cancer: A Multicenter International Cohort Study

Caroline A Nebhan; Alessio Cortellini; Weijie Ma; Teja Ganta; Haocan Song; Fei Ye; Rebecca Irlmeier; Neha Debnath; Anwaar Saeed; Maluki Radford; Asrar Alahmadi; Akiva Diamond; Christopher Hoimes; Nikhil Ramaiya; Carolyn J Presley; Dwight H Owen; Sarah Abou Alaiwi; Amin Nassar; Biagio Ricciuti; Giuseppe Lamberti; Melissa Bersanelli; Chiara Casartelli; Sebastiano Buti; Paolo Marchetti; Raffaele Giusti; Marco Filetti; Vito Vanella; Domenico Mallardo; Shravanti Macherla; Tamara A Sussman; Andrea Botticelli; Domenico Galetta; Annamaria Catino; Pamela Pizzutilo; Carlo Genova; Maria Giovanna Dal Bello; Foteini Kalofonou; Ella Daniels; Paolo A Ascierto; David J Pinato; Toni K Choueiri; Douglas B Johnson; Thomas U Marron; Yinghong Wang; Abdul Rafeh Naqash

doi:10.1001/jamaoncol.2021.4960

. 2021 Nov 4;7(12):1–6. doi: 10.1001/jamaoncol.2021.4960

Clinical Outcomes and Toxic Effects of Single-Agent Immune Checkpoint Inhibitors Among Patients Aged 80 Years or Older With Cancer

A Multicenter International Cohort Study

Caroline A Nebhan ¹, Alessio Cortellini ^2,³, Weijie Ma ^4,⁵, Teja Ganta ⁶, Haocan Song ⁷, Fei Ye ⁷, Rebecca Irlmeier ⁷, Neha Debnath ⁶, Anwaar Saeed ⁸, Maluki Radford ⁸, Asrar Alahmadi ^9,¹⁰, Akiva Diamond ^9,¹¹, Christopher Hoimes ^9,¹², Nikhil Ramaiya ⁹, Carolyn J Presley ¹³, Dwight H Owen ¹³, Sarah Abou Alaiwi ¹⁴, Amin Nassar ¹⁴, Biagio Ricciuti ¹⁵, Giuseppe Lamberti ¹⁶, Melissa Bersanelli ¹⁷, Chiara Casartelli ¹⁷, Sebastiano Buti ¹⁷, Paolo Marchetti ¹⁸, Raffaele Giusti ¹⁸, Marco Filetti ¹⁸, Vito Vanella ¹⁹, Domenico Mallardo ¹⁹, Shravanti Macherla ²⁰, Tamara A Sussman ²¹, Andrea Botticelli ²², Domenico Galetta ²³, Annamaria Catino ²³, Pamela Pizzutilo ²³, Carlo Genova ^24,²⁵, Maria Giovanna Dal Bello ²⁴, Foteini Kalofonou ²⁶, Ella Daniels ²⁶, Paolo A Ascierto ¹⁹, David J Pinato ^26,²⁷, Toni K Choueiri ¹⁴, Douglas B Johnson ^1,^✉, Thomas U Marron ⁶, Yinghong Wang ⁴, Abdul Rafeh Naqash ^20,^28,^29,^✉

¹Vanderbilt University Medical Center, Nashville, Tennessee

²Department of Biotechnology and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

³Department of Surgery and Cancer, Imperial College London, London, United Kingdom

⁴The University of Texas MD Anderson Cancer Center, Houston

⁵Zhongnan Hospital of Wuhan University, Wuhan, China

⁶Icahn School of Medicine at Mount Sinai, New York, New York

⁷Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee

⁸University of Kansas Cancer Center, Kansas City

⁹Case Western Reserve University, Division of Hematology & Oncology, Cleveland, Ohio

¹⁰Ohio State University, The James Comprehensive Cancer Center, Columbus

¹¹Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas

¹²Duke Cancer Institute, Duke University, Durham, North Carolina

¹³The Ohio State University Comprehensive Cancer Center, Columbus

¹⁴Dana-Farber Cancer Center, Boston, Massachusetts

¹⁵Department of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy

¹⁶Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

¹⁷Medical Oncology Unit, University Hospital of Parma and Medicine and Surgery Department, University of Parma, Parma, Italy

¹⁸Medical Oncology Unit, Azienda Ospedaliero Universitaria Sant’Andrea, Rome, Italy

¹⁹Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy

²⁰East Carolina University Brody School of Medicine, Division of Hematology & Oncology, Greenville, North Carolina

²¹Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio

²²Policlinico Umberto I, Clinical and Molecular Department, Sapienza University of Rome, Rome, Italy

²³IRCCS Istituto Tumori Giovanni Paolo II, Medical Thoracic Oncology Unit, Bari, Italy

²⁴UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

²⁵Dipartimento di Medicina Interna e Specialità Mediche, Università degli Studi di Genova, Genova, Italy

²⁶Department of Surgery and Cancer, Imperial College London, London, United Kingdom

²⁷Department of Translational Medicine, University of Piemonte Orientale “A. Avogadro”, Novara, Italy

²⁸Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland

²⁹Medical Oncology/TSET Phase 1 Program, Stephenson Cancer Center, University of Oklahoma, Oklahoma City

Accepted for Publication: July 22, 2021.

Published Online: November 4, 2021. doi:10.1001/jamaoncol.2021.4960

^✉

Corresponding Authors: Abdul Rafeh Naqash, MD, Medical Oncology/TSET Phase 1 program, Stephenson Cancer Center, University of Oklahoma, 800 NE 10th St, Oklahoma City, OK 73104 (abdulrafeh-naqash@ouhsc.edu); Douglas B. Johnson, MD, Vanderbilt University Medical Center, 777 PRB, 2220 Pierce Ave, Nashville, TN 37232 (douglas.b.johnson@vumc.org).

Author Contributions: Drs Nebhan and Naqash 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: Nebhan, Ganta, Debnath, Alahmadi, Vanella, Mallardo, Choueiri, Johnson, Marron, Naqash.

Acquisition, analysis, or interpretation of data: Nebhan, Cortellini, Ma, Ganta, Song, Ye, Irlmeier, Saeed, Brake, Alahmadi, Diamond, Hoimes, Ramaiya, Presley, Owen, Abou Alaiwi, Nassar, Ricciuti, Lamberti, Bersanelli, Casartelli, Buti, Marchetti, Giusti, Filetti, Macherla, Sussman, Botticelli, Galetta, Catino, Pizzutilo, Genova, Dal Bello, Kalofonou, Daniels, Ascierto, Pinato, Choueiri, Johnson, Marron, Wang, Naqash.

Drafting of the manuscript: Nebhan, Ye, Debnath, Vanella, Kalofonou, Ascierto, Pinato, Johnson, Marron, Naqash.

Critical revision of the manuscript for important intellectual content: Nebhan, Cortellini, Ma, Ganta, Song, Irlmeier, Saeed, Brake, Alahmadi, Diamond, Hoimes, Ramaiya, Presley, Owen, Abou Alaiwi, Nassar, Ricciuti, Lamberti, Bersanelli, Casartelli, Buti, Marchetti, Giusti, Filetti, Mallardo, Macherla, Sussman, Botticelli, Galetta, Catino, Pizzutilo, Genova, Dal Bello, Daniels, Ascierto, Pinato, Choueiri, Johnson, Marron, Wang, Naqash.

Statistical analysis: Nebhan, Ma, Song, Ye, Irlmeier, Johnson, Wang, Naqash.

Obtained funding: Nebhan, Johnson.

Administrative, technical, or material support: Nebhan, Ganta, Saeed, Alahmadi, Hoimes, Ramaiya, Owen, Ricciuti, Filetti, Mallardo, Sussman, Dal Bello, Kalofonou, Pinato, Johnson, Marron, Wang, Naqash.

Supervision: Cortellini, Ye, Saeed, Alahmadi, Diamond, Marchetti, Giusti, Filetti, Vanella, Botticelli, Galetta, Pizzutilo, Ascierto, Pinato, Choueiri, Johnson, Marron, Naqash.

Conflict of Interest Disclosures: Dr Cortellini receives grant consultancies/speaking fees from MSD, BMS, AstraZeneca, Novartis, Astellas, SunPharma and Roche. Dr Saeed receives research funding (to institution) from Merck, Bristol Myers Squibb (BMS), AstraZeneca, Exelixis, Clovis, and Daiichi Sankyo, and also serves on advisory boards for Merck, BMS, AstraZeneca, Pfizer, Exelixis, and Daiichi Sankyo. Dr Owen receives research funding (to institution) from BMS, Merck, PaloBiofarma, and Genentech. Dr Owen reports clinical consulting for theMednet.org. Dr Giusti has/had a consultant/advisory role for Roche-Genentech, AstraZeneca, Takeda, Boehringer Ingelheim. Travel support from Boehringer Ingelheim. Dr Bersanelli received honoraria as a speaker at scientific events by BMS, Novartis, AstraZeneca, and Pfizer and as a consultant for advisory role by Novartis, BMS, and Pfizer; she also received fees for copyright transfer by Sciclone Pharmaceuticals and research funding by Seqirus UK, Pfizer, Novartis, BMS, AstraZeneca, Roche S.p.A., and Sanofi Genzyme. Dr Buti received honoraria as a speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, and Novartis; he also received research funding from Novartis. Dr Genova receives honoraria from AstraZeneca, BMS, Merck Sharp & Dohme, Boehringer Ingelheim, and Roche. Dr Ascierto has/had a consultant/advisory role for BMS, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pierre-Fabre, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Takis, Lunaphore. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Array, Sanofi and travel support from MSD. Dr Pinato received lecture fees from ViiV Healthcare, Roche, Eisai, Bayer Healthcare, Falk Foundation; travel expenses from BMS, MSD, Roche, and Bayer Healthcare; consulting fees for Mina Therapeutics, Eisai, Roche, AstraZeneca, H3B, DaVolterra; received research funding (to institution) from MSD, BMS. Dr Choueiri has served on advisory boards, consultant and/or received honorarium from AstraZeneca, Aravive, Aveo, Bayer, BMS, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Ipsen, Kanaph, Lilly, Merck, Nikang, Novartis, Pfizer, Roche, Sanofi Aventis, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, and others). Dr Johnson serves on advisory boards for Array Biopharma, BMS, Catalyst, Iovance, Janssen, Merck, Novartis, and Oncosec, and receives research funding from BMS and Incyte. Dr Marron has served on advisory boards for Regeneron, Boehringer Ingelheim, AstraZeneca, Genentech, and Atara. He has research grants from Regeneron, Boehringer Ingelheim, Merck, and BMS. Dr Wang serves as consultant for Tillotts Pharma. No other disclosures were reported.

Funding/Support: Dr Nebhan is supported by the National Cancer Institute (1F32CA254070-01). Dr Presley is supported by the National Institute on Aging (R03AG064374) and the Ohio State University Comprehensive Cancer Center. Dr Owen is a Paul Calebrasi Scholar supported by the OSU K12 Training Grant for Clinical Faculty Investigators (K12 CA133250). Research support provided by the REDCap project and The Ohio State University Center for Clinical and Translational Science grant support (National Center for Advancing Translational Sciences, Grant UL1TR002733). Drs Genova and Dal Bello wish to thank the Italian Ministry of Health (5x1000 funds Co-2016-02361470; Ricerca Corrente 2018-2020) and Compagnia di San Paolo (2017.0529), that financially support their current research focused on the identification of prognostic and predictive markers for immunotherapy. Dr Pinato acknowledges grant support from the Wellcome Trust Strategic Fund (IPPRF Scheme 2019), infrastructural support provided by Imperial Experimental Cancer Medicine Centre, Cancer Research UK Imperial Centre, the Imperial College Healthcare NHS Trust Tissue Bank and the Imperial College BRC. Dr Choueiri acknowledges support from the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI. Dr Naqash acknowledges research funding support from the Conquer Cancer Foundation, National Cancer Institute and the Lung Cancer Initiative of North Carolina.

Role of the Funder/Sponsor: The funding agencies listed had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

^✉

Corresponding author.

PMCID: PMC8569601 PMID: 34734989

Key Points

Question

What are the clinical outcomes and spectrum of immune-related adverse events (irAEs) following treatment with single-agent immune checkpoint inhibitors (ICIs) in geriatric patients with cancer (aged ≥80 years)?

Findings

In this cohort study of 928 patients 80 years or older, single-agent ICIs demonstrated promising antitumor outcomes in non–small cell lung cancer, melanoma, and genitourinary tumors; although there was no significant difference in rate of irAEs, irAE-related ICI discontinuation was higher in patients aged 90 years or older, even for lower-grade irAEs.

Meaning

Geriatric patients with cancer can derive benefit from ICIs, but have a lower threshold for and higher rate of irAE-related ICI discontinuation with increasing age.

This cohort study examines clinical outcomes and safety of immune checkpoint inhibitors among geriatric patients with cancer.

Abstract

Importance

Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population.

Objective

To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer.

Design, Setting, and Participants

A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021.

Main Outcomes and Measures

Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs.

Results

Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti–programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non–small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged <85 vs ≥85 years). Among all 928 patients, 383 (41.3%) experienced ≥1 irAE(s), including 113 (12.2%) that were reported to be grade (G) 3 to 4 based on Common Terminology Criteria for Adverse Events (version 5.0). The median time to irAE onset was 9.8 weeks; 219 (57%) occurred within the first 3 months after ICI initiation. Discontinuation of treatment with ICIs owing to irAEs occurred in 137 (16.1%) patients. There was no significant difference in the rate of irAEs among patients aged younger than 85, 85 to 89, and 90 years or older. Despite the similar rate of G3 or higher irAEs, ICIs were discontinued due to irAEs more than twice as often among patients aged 90 years or older compared with patients younger than 90 years (30.9% vs 15.1%, P = .008).

Conclusions and Relevance

The findings of this international cohort study suggest that treatment with ICIs may be effective and generally well tolerated among older patients with cancer, though ICI discontinuation owing to irAEs was more frequent with increasing age.

Introduction

Historically, geriatric patients have been underrepresented in clinical trials. Between 2005 and 2015, patients aged 80 years or older comprised only 4% of cancer clinical trial participants, largely owing to restrictive eligibility criteria, exclusionary comorbidities, prior cancers, and worse performance status.^1,2,3 Because of this poor representation, geriatric patients and their oncologists must extrapolate from clinical trial data of younger patients to make treatment decisions.

Although immune checkpoint inhibitors (ICIs) generally have a more tolerable toxic effects profile compared to other cancer treatments (eg, cytotoxic chemotherapy), immune-related adverse events (irAEs) may cause hospitalization, significant chronic toxic effects, and death.^4,5,6 Both irAEs and their treatments impose substantial physiologic stress that particularly affects geriatric patients with compromised functional reserve. Our study aims to evaluate the real-world clinical outcomes and toxic effects of ICIs among geriatric patients aged 80 years or older from multiple medical centers.

Methods

Study Design and Data Sources

After institutional review board approval at each participating institution with waiver of written informed consent, retrospective deidentified data were collected from 18 medical centers in the US and Europe for patients with cancer treated between 2010 and 2019. Data were retrospectively obtained from 18 medical centers in the US and Europe for patients treated between 2010 and 2019 (eTable 1 in the Supplement). Patients who were treated with ICIs until they were 80 years or older (n = 19) or were 80 years or older (n = 909) at ICI initiation were included. Single-agent ICIs included anti–programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) or anticytotoxic T-lymphocyte–associated protein-4 (CTLA-4) therapies; combination regimens, including chemotherapy/ICI and ICI/ICI, were not included. χ² tests were used to compare categorical variables. Kaplan-Meier curves assessed progression free survival (PFS) and overall survival (OS) for all patients and by stratifying patients based on age (ie, <85 and ≥85 years); groups were compared using log rank testing. Clinical outcomes were analyzed using multivariable Cox proportional hazards and logistic regression models. Analyses were conducted using R (version 4.0.3; R Foundation). Mixed-effect models were fitted to account for potential clustering within institutions. Missing covariate data were imputed with multiple imputation using R statistical software (package mi, R Foundation). Analyses were conducted from January 2021 to April 2021. For additional methodology see eMethods in the Supplement.

Results

Patient Characteristics

A total of 928 patients were included (eTable 2 in the Supplement) and were treated with anti–PD-1 (806 [86.9%]), anti–PD-L1 (79 [8.5%]), and anti–CTLA-4 (43 [4.6%]). Median (range) age at ICI initiation was 83.0 (75.8-97.0) years, with 626 (67.5%) patients younger than 85, 242 (26.1%) aged 85 to 89 years, and 60 (6.5%) aged 90 years or older. The 3 most common tumor types represented were NSCLC (345 [37.2%]), melanoma (329 [35.5%]), and genitourinary malignant disease (GU, 153 [16.5%]), which included urothelial cell carcinoma, renal cell carcinoma, and prostate cancer; remaining patients (101 [10.9%]) had 18 additional tumor histologic findings (eFigure 1 in the Supplement).

Clinical Outcomes

We assessed the 3 most common histologic subgroups for clinical outcomes. Among patients with NSCLC with documented response data (276), ORR was 32.2% (3.6% CR, 28.6% PR). The ORR in patients with NSCLC younger than 85 and 85 years or older was 34.5% vs 25.7% respectively (P = .18). In the overall NSCLC cohort (345), median PFS was 6.7 months (95% CI, 5.2-8.6 months) and median OS was 10.9 months (95% CI, 8.6-13.1 months) (Figure 1A and Figure 2A). In patients with NSCLC younger than 85 years and aged 85 years or older, the median PFS was 8.0 (95% CI, 5.6-9.5) and 5.0 (95% CI, 4.0-8.4) months, respectively (P = .40). The median OS was 11.8 (95% CI, 9.3-15.3) months vs 7.5 (95% CI, 5.0-11.5), months, respectively (P = .047) (eFigure 2A and 2B in the Supplement).

Among response-evaluable patients with melanoma (280), ORR was 39.3% (18.2% CR, 21.1% PR). The ORR in patients with melanoma younger than 85 years and aged 85 years or older was 35.8% and 45.5%, respectively (P = .11). In the overall melanoma cohort (329), the median PFS was 11.1 (95% CI, 8.9-16.0) months and median OS was 30.0 (95% CI, 23.6-46.4) months (Figure 1B and Figure 2B). In patients with melanoma younger than 85 and aged 85 years and older, median PFS was 13.6 (95% CI, 9.6-22.8) vs 7.4 (95% CI, 5.0-15.0) months, respectively (P = .23). The median OS was 34.2 (95% CI, 27.8-47.6) vs 24.5 (95% CI, 13.8-NA) months, respectively (P = .30) (eFigure 2C and 2D in the Supplement).

Among response-evaluable patients with GU tumors (126), the ORR was 26.2% (4.0% CR, 22.2% PR). The ORR in patients with GU tumors younger than 85 and those aged 85 years or older was 29.8% vs 19.0%, respectively (P = .20). In the overall GU tumor cohort (153), the median PFS was 6.0 (95% CI, 5.0-10.7) months and median OS 15.0 (95% CI 9.1-25.4) months (Figure 1C and Figure 2C). Among patients with GU tumors younger than 85 years and those aged 85 years or older, the median PFS was 6.5 (95% CI, 5.0-16.6) vs 6.0 (95% CI, 3.6-11.2) months, respectively (P = .25). The median OS was 15.7 (95% CI, 11.4-34.9) vs 7.2 (95% CI, 6.6-NA) months, respectively (P = .13) (eFigure 2E and 2F in the Supplement).

We performed multivariable analysis to determine which variables were independently associated with survival in the 3 histologic subgroups. After adjusting for appropriate covariates (sex, stage, prior therapy, ECOG performance status) in our geriatric cohort, increasing age did not show a statistically significant association with either PFS or OS in NSCLC, melanoma, or GU tumors (eTable 3 in the Supplement).

Toxic Effects

Among all 928 patients, 338 (41.3%) experienced 1 or more irAE(s), based on Common Terminology Criteria for Adverse Events version (version 5.0), including 113 (12.2%) G3 to G4 irAEs. No irAE-related deaths occurred; 85 (22.2%) patients who experienced an irAE required hospitalization for irAE, largely for G3 to G4 irAEs (49 [57.6%] hospitalizations). The median time to irAE onset was 9.8 weeks. The most common irAEs (any grade) were dermatitis (132 [14.2%]), colitis/diarrhea (85 [9.2%]) and thyroid toxic effects (75 [8.1%]). Patients in each age subgroup developed any-grade irAEs at similar rates: 270 (43.1%) vs 90 (37.2%) vs 23 (38.3%) for patients younger than 85, aged 85 to 89, and those aged 90 years or older, respectively (P = .15) (Table; eTable 4 in the Supplement). Similarly, there was no difference in the rate of G3 to G4 irAEs by age; 81 (12.9%) patients younger than 85 years vs 25 (10.3%) patients aged 85 to 89 years vs 7 (11.7%) patients aged 90 years or older (P = .57). Among patients treated with CTLA-4 inhibitors, 21 (48.8%) experienced irAEs; the most common irAE seen was diarrhea/colitis (11 [25.6%]) (eTable 5 in the Supplement).

Among all 852 patients with ICI discontinuation data available, irAE-related ICI discontinuation was reported in 137 (16.1%) patients; 64 (46.7%) of these irAEs leading to ICI discontinuation were G3 to G4 (Table). Notably, patients aged 90 years or older were more likely to discontinue treatment with ICIs owing to irAEs than patients younger than 90 years (17 [30.9%] vs 120 [15.1%], P = .008). All 7 patients aged 90 years or older with G3 or G4 irAEs discontinued treatment with ICIs.

Table. Toxic Effects of ICI Treatment in Geriatric Patients by Age.

Variable	No. (%)
	All (n = 928)		Age, y
	All (n = 928)		<85 (n = 626)		85-89 (n = 242)		≥90 (n = 60)
	Any	G3+	Any	G3+	Any	G3+	Any	G3+
irAE	383 (41.3)	113 (12.2)	270 (43.1)	81 (12.9)	90 (37.2)	25 (10.3)	23 (38.3)	7 (11.7)
irAE leading to discontinuation^a	137 (16.1)		87 (15.1)		33 (15.0)		17 (30.9)
Specific irAE^b
Colitis/diarrhea	85 (9.2)	33 (3.6)	60 (9.6)	22 (3.5)	21 (8.7)	8 (3.3)	4 (6.7)	3 (5.0)
Dermatitis	132 (14.2)	26 (2.8)	95 (15.2)	20 (3.2)	27 (11.2)	4 (1.7)	10 (15.0)	2 (3.3)
Hepatitis	47 (5.1)	24 (2.6)	28 (4.5)	17 (2.7)	14 (5.8)	6 (2.5)	5 (8.3)	3 (5.0)
Pneumonitis	48 (5.2)	20 (2.2)	38 (6.1)	18 (2.9)	7 (2.9)	2 (0.8)	3 (5.0)	0
Thyroid	75 (8.1)	10 (1.1)	58 (9.3)	8 (1.3)	13 (5.4)	1 (0.4)	4 (6.7)	1 (1.7)
Mucositis	9 (1.0)	3 (0.3)	7 (1.1)	3 (0.5)	2 (0.8)	0	0	0
Other	143 (15.4)	46 (5.0)	104 (16.6)	35 (5.6)	32 (13.2)	10 (4.1)	7 (11.7)	1 (1.7)

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Abbreviations: ICI, immune checkpoint inhibitors; irAE, immune-related adverse events.

^{^a}

Continuation data missing for 76 patients (49 patients aged <85 years, 22 patients aged 85-90 years, 5 patients aged ≥90 years).

^{^b}

Based on Common Terminology Criteria for Adverse Events version (version 5.0).

Discussion

To our knowledge, this is the largest multicenter, international cohort study of geriatric patients with cancer aged 80 years or older treated with ICIs. Although we did not directly compare younger vs older patients, we find that our results are largely consistent with smaller studies suggesting that older patients experience similar efficacy compared with younger patients.^7,8,9,10

There has been theoretical concern whether immunosenescence (age-related changes in immune function) could compromise ICI efficacy. Findings of this study suggest that this concern of immunosenescence and poor outcomes to ICIs may not translate to clinical practice. Importantly, preclinical and clinical data have suggested lower infiltration of regulatory T cells in tumors from older hosts relative to CD8-positive T-cell infiltrate, potentially resulting in improved ICI efficacy.¹¹ Although a more precise understanding of age-related biology is warranted, findings of this study suggest that advanced age in itself should not preclude ICI therapy.

Several studies have suggested that toxic effects profiles may differ slightly by age, with more skin toxic effects in older patients, and higher rates of colitis and hepatitis in younger patients.^12,13 This cohort study found comparable rates of any-grade and severe irAEs (G3-G4) across geriatric age subgroups (aged <85, 85-80, and ≥90 years) (Table). However, we observed a higher rate of irAE-related treatment discontinuation in patients aged 90 years or older. This could suggest lower tolerance for toxic effects among this unique geriatric patient population, potentially driven by patient preference, declining functional status, or physician risk aversion.

Limitations

Major limitations of this study include selection bias due to lack of a younger comparator cohort, missing data for tumor PD-L1 status, and the inclusion of mixed histologic findings (especially for GU tumors).

Conclusions

The findings of this international cohort study suggest that single-agent checkpoint inhibitors may be effective and generally well tolerated in patients older than 80 years, suggesting that age alone should not preclude patients from treatment with ICIs. Randomized clinical trials using ICIs for geriatric patients are needed to further elucidate the clinical effect of our findings and identify histology-specific outcomes using appropriate controls.

Supplement.

eFigure 1. Cohort Composition

eFigure 2. Progression-Free and Overall Survival of Geriatric Patients Treated with ICI, by age group

eTable 1. Contributing Centers

eTable 2. Patient Characteristics

eTable 3. Multivariable analysis of factors associated with survival

eTable 4. Toxicity of ICI Treatment in Geriatric Patients, by histology

eTable 5. Toxicity of Ipilimumab Treatment in Older Adult Patients with Melanoma

eMethods

Click here for additional data file.^{(547.1KB, pdf)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eFigure 1. Cohort Composition

eFigure 2. Progression-Free and Overall Survival of Geriatric Patients Treated with ICI, by age group

eTable 1. Contributing Centers

eTable 2. Patient Characteristics

eTable 3. Multivariable analysis of factors associated with survival

eTable 4. Toxicity of ICI Treatment in Geriatric Patients, by histology

eTable 5. Toxicity of Ipilimumab Treatment in Older Adult Patients with Melanoma

eMethods

Click here for additional data file.^{(547.1KB, pdf)}

[cbr210015r1] 1.Denson AC, Mahipal A. Participation of the elderly population in clinical trials: barriers and solutions. Cancer Control. 2014;21(3):209-214. doi: 10.1177/107327481402100305 [DOI] [PubMed] [Google Scholar]

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[cbr210015r3] 3.Sedrak MS, Mohile SG, Sun V, et al. Barriers to clinical trial enrollment of older adults with cancer: a qualitative study of the perceptions of community and academic oncologists. J Geriatr Oncol. 2020;11(2):327-334. doi: 10.1016/j.jgo.2019.07.017 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr210015r4] 4.Patrinely JR Jr, Young AC, Quach H, et al. Survivorship in immune therapy: assessing toxicities, body composition and health-related quality of life among long-term survivors treated with antibodies to programmed death-1 receptor and its ligand. Eur J Cancer. 2020;135:211-220. doi: 10.1016/j.ejca.2020.05.005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr210015r5] 5.Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721-1728. doi: 10.1001/jamaoncol.2018.3923 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr210015r6] 6.Wang LX, Quach HT, Moodabigil NV, et al. Health care utilization and steroid-refractory toxicities from immune checkpoint inhibitors. Cancer. 2020;126(2):322-328. doi: 10.1002/cncr.32542 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr210015r7] 7.Johns AC, Wei L, Grogan M, et al. Checkpoint inhibitor immunotherapy toxicity and overall survival among older adults with advanced cancer. J Geriatr Oncol. 2021;12(5):813-819. doi: 10.1016/j.jgo.2021.02.002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr210015r8] 8.Olsson-Brown AC, Baxter M, Dobeson C, et al. Real-world outcomes in older adults treated with immunotherapy: a United Kingdom multicenter series of 2049 patients. J Clin Oncol. 2021;39(15_suppl):12026-12026. [Google Scholar]

[cbr210015r9] 9.Ridolfi L, De Rosa F, Petracci E, et al. ; Italian Melanoma Intergroup (IMI) . Anti-PD1 antibodies in patients aged ≥ 75 years with metastatic melanoma: a retrospective multicentre study. J Geriatr Oncol. 2020;11(3):515-522. doi: 10.1016/j.jgo.2019.12.012 [DOI] [PubMed] [Google Scholar]

[cbr210015r10] 10.Sattar J, Kartolo A, Hopman WM, Lakoff JM, Baetz T. The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population. J Geriatr Oncol. 2019;10(3):411-414. doi: 10.1016/j.jgo.2018.07.015 [DOI] [PubMed] [Google Scholar]

[cbr210015r11] 11.Kugel CH III, Douglass SM, Webster MR, et al. Age Correlates with response to Anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin Cancer Res. 2018;24(21):5347-5356. doi: 10.1158/1078-0432.CCR-18-1116 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr210015r12] 12.Betof AS, Nipp RD, Giobbie-Hurder A, et al. Impact of age on outcomes with immunotherapy for patients with melanoma. Oncologist. 2017;22(8):963-971. doi: 10.1634/theoncologist.2016-0450 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr210015r13] 13.Shah KP, Song H, Ye F, et al. Demographic factors associated with toxicity in patients treated with anti-programmed cell death-1 therapy. Cancer Immunol Res. 2020;8(7):851-855. doi: 10.1158/2326-6066.CIR-19-0986 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Clinical Outcomes and Toxic Effects of Single-Agent Immune Checkpoint Inhibitors Among Patients Aged 80 Years or Older With Cancer

Caroline A Nebhan, MD, PhD

Alessio Cortellini, MD

Weijie Ma, MD

Teja Ganta, MD

Haocan Song, MS

Fei Ye, PhD

Rebecca Irlmeier, MS

Neha Debnath, MD

Anwaar Saeed, MD

Maluki Radford

Asrar Alahmadi, MBBS

Akiva Diamond, MD

Christopher Hoimes, MD

Nikhil Ramaiya, MD

Carolyn J Presley, MD, MHS

Dwight H Owen, MD, MS

Sarah Abou Alaiwi, MD

Amin Nassar, MD

Biagio Ricciuti, MD

Giuseppe Lamberti, MD

Melissa Bersanelli, MD

Chiara Casartelli, MD

Sebastiano Buti, MD

Paolo Marchetti, MD

Raffaele Giusti, MD

Marco Filetti, MD

Vito Vanella, MD

Domenico Mallardo, MD

Shravanti Macherla, MD

Tamara A Sussman, MD

Andrea Botticelli, MD, PhD

Domenico Galetta, MD

Annamaria Catino, MD

Pamela Pizzutilo, MD

Carlo Genova, MD

Maria Giovanna Dal Bello, MD

Foteini Kalofonou, MD, PhD

Ella Daniels, MBBS

Paolo A Ascierto, MD

David J Pinato, MD, PhD

Toni K Choueiri, MD

Douglas B Johnson, MD, MSCI

Thomas U Marron, MD, PhD

Yinghong Wang, MD, PhD

Abdul Rafeh Naqash, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Study Design and Data Sources

Results

Patient Characteristics

Clinical Outcomes

Figure 1. Progression-Free Survival (PFS) in Geriatric Patients Treated With Immune Checkpoint Inhibitors.

Figure 2. Overall Survival (OS) of Geriatric Patients Treated With Immune Checkpoint Inhibitors.

Toxic Effects

Table. Toxic Effects of ICI Treatment in Geriatric Patients by Age.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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