The impact of body composition parameters on severe toxicity of nivolumab

Laure Hirsch; Audrey Bellesoeur; Pascaline Boudou-Rouquette; Jennifer Arrondeau; Audrey Thomas-Schoemann; Julien Kirchgesner; Claire Gervais; Anne Jouinot; Jeanne Chapron; Frédérique Giraud; Marie Wislez; Jérôme Alexandre; Benoit Blanchet; François Goldwasser

doi:10.1016/j.ejca.2019.11.003

The impact of body composition parameters on severe toxicity of nivolumab

Eur J Cancer. 2020 Jan:124:170-177. doi: 10.1016/j.ejca.2019.11.003. Epub 2019 Nov 30.

Authors

Affiliations

¹ Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France. Electronic address: laure.hirsch@wanadoo.fr.
² Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France.
³ Department of Clinical Pharmacy, Cochin Hospital, AP-HP 5, CERTIM, Paris, France; UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, Université Paris Descartes, PRES Sorbonne Paris Cité, 75006, Paris, France.
⁴ Department of Gastroenterology, Saint-Antoine Hospital, AP-HP 6, Paris, France; Sorbonne Université, INSERM, Institut Pierre Louis D'Épidémiologie et de Santé Publique, Paris, France.
⁵ Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France; Cochin Institute, Inserm U1016, Université Paris Descartes, Paris, France.
⁶ Department of Pneumology, Cochin Hospital, AP-HP 5, Paris, France.
⁷ Department of Pneumology, Cochin Hospital, AP-HP 5, Paris, France; Cordeliers Research Center, Université Paris Descartes, Université de Paris, UMRS1138 "Inflammation, Complement and Cancer" Team, F-75006, Paris, France.
⁸ UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, Université Paris Descartes, PRES Sorbonne Paris Cité, 75006, Paris, France; Department of Pharmacokinetics and Pharmacochemisty, Cochin Hospital, AP-HP 5, CARPEM, Paris, France.
⁹ Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France; Laboratory of Biological Nutrition EA, Pharmacy University, Université Paris Descartes, 4466, Paris, France.

PMID: 31794927
DOI: 10.1016/j.ejca.2019.11.003

Abstract

Background: The occurrence of severe, acute limiting toxicity in patients receiving anti-programmed cell death receptor-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found to be associated with anti-cytotoxic T-lymphocyte-associated protein 4 acute toxicity. We explore the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition.

Methods: From June 2015 to January 2017, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship between muscle mass assessed by computed tomography, nivolumab trough level (C_min) at day 14 assessed using the enzyme-linked immunosorbent assay method, and the occurrence of immune grade III or IV toxicity or any toxicity leading to treatment discontinuation (immune-related acute limiting toxicity [irALT]).

Results: In our population (n = 92) with a majority of lung cancer (72%), forty-five (51.7%) patients were sarcopenic. The median plasma nivolumab C_min at day 14 was 15.4 μg/mL (interquartile range = 11.8-21.0). In multivariate analysis, hypoalbuminaemia (<35 g/L) was independently associated with low nivolumab C_min on day 14 (odds ratio [OR] = 0.09; 95% confidence interval [CI] = 0.01-0.59, p = 0.01) and overweight/obesity with high nivolumab C_min on day 14 (OR = 5.94; 95% CI = 1.25-28.29, p = 0.03). We observed 22 irALTs in 19 patients (21%). The most frequent irALT was respiratory (6.5%) disorders and gastrointestinal (4.3%) disorders. Patients with sarcopenia were at significantly increased risk of experiencing an irALT (OR = 3.84; 95% CI = 1.02-14.46, p = 0.047). No association was found between toxicity and nivolumab plasma C_min at day 14.

Conclusions: Our results highlight the importance of assessing body composition and suggest that sarcopenia could predict severe immune-related toxicity of nivolumab in real life.

Keywords: Body composition; Lung cancer; Nivolumab; Pharmacology; Toxicity.

MeSH terms

Aged
Body Composition / drug effects*
Female
Humans
Male
Middle Aged
Nivolumab / toxicity*
Prospective Studies

Substances

Nivolumab