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Meta-Analysis
. 2022 Dec:177:175-185.
doi: 10.1016/j.ejca.2022.09.031. Epub 2022 Oct 5.

Comparative assessment of early mortality risk upon immune checkpoint inhibitors alone or in combination with other agents across solid malignancies: a systematic review and meta-analysis

Giuseppe Viscardi  1 , Antonino C Tralongo  2 , Francesco Massari  3 , Matteo Lambertini  4 , Veronica Mollica  3 , Alessandro Rizzo  5 , Francesca Comito  3 , Raimondo Di Liello  6 , Salvatore Alfieri  7 , Martina Imbimbo  8 , Carminia M Della Corte  9 , Floriana Morgillo  9 , Vittorio Simeon  10 , Giuseppe Lo Russo  11 , Claudia Proto  11 , Arsela Prelaj  11 , Alessandro De Toma  11 , Giulia Galli  12 , Diego Signorelli  13 , Fortunato Ciardiello  9 , Jordi Remon  14 , Nathalie Chaput  15 , Benjamin Besse  16 , Filippo de Braud  11 , Marina C Garassino  17 , Valter Torri  18 , Michela Cinquini  18 , Roberto Ferrara  19
Affiliations
Meta-Analysis

Comparative assessment of early mortality risk upon immune checkpoint inhibitors alone or in combination with other agents across solid malignancies: a systematic review and meta-analysis

Giuseppe Viscardi et al. Eur J Cancer. 2022 Dec.

Abstract

Background: The early crossing of survival curves in randomised clinical trials (RCTs) with immune checkpoint blockers suggests an excess of mortality in the first months of treatment. However, the exact estimation of the early death (ED) rate, the comparison between ED upon immune checkpoint inhibitors (ICI) alone or in combination with other agents and the impact of tumour type, and PD-L1 expression on ED are unknown.

Methods: RCTs comparing ICI alone (ICI-only group) or in combination with other non-ICI therapies (ICI-OT group) (experimental arms) versus non-ICI treatments (control arm) were included. ED was defined as death within the first 3 months of treatment. The primary outcome was the comparison of ED between experimental and control arms, and the secondary outcome was the comparison of ED risk between ICI-only and ICI-OT. ED rates estimated by risk ratio (RR) were pooled by random effect model.

Results: A total of 56 RCTs (40,215 participants, 14 cancer types) were included. ED occurred in 14.2% and 6.7% of patients in ICI-only and ICI-OT groups, respectively. ED risk significantly increased with ICI-only (RR: 1.29, 95% CI 1.05-1.57) versus non-ICI therapies, while it was lower with ICI-OT versus non-ICI treatments (RR: 0.81, 95% CI 0.73-0.90). ED risk was significantly higher upon ICI-only compared to ICI-OT (RR: 1.57, 95% CI 1.26-1.95). Gastric and urothelial carcinoma were at higher risk of ED. PD-L1 expression and ICI drug classes were not associated with ED.

Conclusions: ED upon first-line ICI is a clinically relevant phenomenon across solid malignancies, not predictable by PD-L1 expression but preventable through the addition of other treatments to ICI.

Keywords: Breast cancer; Chemotherapy; Early mortality; Gastrointestinal cancer; Genitourinary cancer; Immune checkpoint blockers; Immunotherapy; Lung cancer; Melanoma; Meta-analysis.

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Conflict of interest statement

Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Matteo Lambertini: advisory role for Roche, Lilly, Novartis, Pfizer, Astrazeneca, MSD, Seagen, Gilead and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Ipsen, Libbs, Knight. Dr Raimondo Di Liello: consultant Janssen, educational Astellas. Dr Martina Imbimbo: independent safety board member for Immatics. Dr Carminia Maria Della Corte: advisory board for MSD and Astrazeneca. Prof Floriana Morgillo: BMS, MSD, Astrazeneca, Incyte (Consultory/Advisory relationship). Dr Giuseppe Lo Russo: personal fees from AstraZeneca, Italfarmaco, Lilly, Novartis, Pfizer, and Roche; support for attending meetings/travel from Bristol-Myers Squibb, Italfarmaco, Merck Sharp & Dohme, and Roche; and participation as a DSMB or advisory board member for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Sanofi. Dr Claudia Proto: personal fees from BMS and MSD. Dr Arsela Prelaj: personal fees from Roche, AstraZeneca and BMS. Dr Diego Signorelli: personal fees from Astrazeneca, BMS, MSD, Sanofi, Boehringer Ingelheim, Roche. Prof Fortunato Ciardiello: Merck, Roche, Amgen, Bayer, Servier, Symphogen, Pfizer (Consultant/Avisory relationship), Roche, Merck, Amgen, Bayer, Ipsen (Research funding). Dr Nathalie Chaput: sponsored research from AstraZeneca, GSK, Roche, Sanofi, Cytune Pharma, Gilead, Servier. Lectures and educational activities: Gilead and Servier. Dr Jordi Remon: advisory board: MSD, Boehringer Ingelheim, BMS, Astrazeneca, Roche; Bayer, Janssen. Speaker: Pfizer, Janssen; travel reimbursement: Ose immunotherapeutics, BMS, Astrazeneca, Roche. Prof Benjamin Besse: grants from AstraZeneca, Pfizer, Eli Lilly, Onxeo, Bristol Myers Squibb, Inivata, AbbVie, Amgen, Blueprint Medicines, Celgene, GlaxoSmithKline, Ignyta, Ipsen, Merck KGaA, MSD Oncology, Nektar, PharmaMar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Therapeutics, Cristal Therapeutics, Daiichi Sankyo, Janssen Oncology, OSE Immunotherapeutics, BeiGene, Boehringer Ingelheim, Genentech, Servier, Tolero Pharmaceuticals. Prof Filippo De Braud: Consultant Advisory Board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini. Speaker: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, ACCMED, Nadirex, MSD, Pfizer, Servier, Sanofi, Roche, AMGEN, Incyte, Dephaforum. Principal Investigator for Novartis, F. Hoffmann-LaRoche Ltd, BMS, Ignyta Operating INC, Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., LOXO Oncology Incorporated, DAICHI SANKIO Dev. Limited, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, Merck KGAA. Prof Marina Chiara Garassino: personal financial interests with the following organisations: AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S. p.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda; institutional financial interests with the following organisations: Eli Lilly, MSD, Pfizer (MISP), AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S. p.A, Celgene, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine; funding from the following organisations: AIRC, AIFA, Italian Moh, TRANSCAN. All the other authors have no conflicts to declare. Dr Roberto Ferrara: advisory board for Beigene and MSD. All the other authors (Dr Giuseppe Viscardi, Dr Antonino Carmelo Tralongo, Dr Francesco Massari, Dr Veronica Mollica, Dr Alessandro Rizzo, Dr Francesca Comito, Dr Salvatore Alfieri, Dr Vittorio Simeon, Dr Alessandro De Toma, Dr Giulia Galli, Dr Valter Torri, Dr Michela Cinquini) have no conflicts to declare.

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