1090P - Identification of patients at risk for severe toxicity under PD1 inhibitors: role of sarcopenic overweight

Date 09 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Immunotherapy
Therapy
Presenter Pascaline Boudou Rouquette
Citation Annals of Oncology (2016) 27 (6): 359-378. 10.1093/annonc/mdw378
Authors P. Boudou Rouquette1, A. Jouinot1, O. Huillard1, J. Arrondeau1, C. Tlemsani1, V. Heidelberg1, J. Chapron2, N. Kramkimel3, D. Damotte4, F. Batteux5, L. Dehghani6, B. Terrier7, L. Groussin8, N. Dupin3, B. Blanchet9, M. Alifano10, K. Leroy11, M. Revel12, J. Alexandre1, F. Goldwasser1
  • 1Medical Oncology, Certim, Hôpital Cochin, 75014 - Paris/FR
  • 2Pneumo-oncology, Hôpital Cochin, 75014 - Paris/FR
  • 3Onco-dermatology, Hôpital Cochin, 75014 - Paris/FR
  • 4Pathology, Hôpital Cochin, 75014 - Paris/FR
  • 5Immunology, Hôpital Cochin, 75014 - Paris/FR
  • 6Diabetology, Hôpital Cochin, 75014 - Paris/FR
  • 7Internal Medicine, Hôpital Cochin, 75014 - Paris/FR
  • 8Endocrinology, Hôpital Cochin, 75014 - Paris/FR
  • 9Functional Unit Of Pharmacokinetics And Pharmacochemistry, Hôpital Cochin, 75014 - Paris/FR
  • 10Thoracic Surgery, Hôpital Cochin, 75014 - Paris/FR
  • 11Biology, Hôpital Cochin, Paris/FR
  • 12Radiology, Hôpital Cochin, Paris/FR

Abstract

Background

PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events (irAEs). Body composition has been proven to influence the pharmacokinetics of many anti-neoplastic drugs. We evaluated the effect of decreased muscle mass (sarcopenia) on PD-1 inhibitors toxicity.

Methods

Pre-therapeutic biological and clinical assessments were prospectively performed for patients (pts) treated with anti-PD1. Muscle mass was estimated using Creatinine/Cystatine C (Cr/CysC) clearance ratio (Kim SW, 2016). Univariate and multivariate analysis tested the association between anti-PD1 induced severe toxicity and age, sex, Performans Status (PS), (Cr/CysC) clearance ratio, body mass index (BMI), lymphocytes, C-Reactive Protein (CRP) and albuminemia. The severity of AEs was graded according to the NCI CTC for AE V4.

Results

From July 2015 to April 2016, 74 pts, median age 65 years (41-84), 58.1% men, received at least one infusion of nivolumab (85%) or pembrolizumab (15%), for lung cancer (n = 44), melanoma (n = 13), renal carcinoma (n = 9) and others (n = 8). A total of 418 cycles (median per pt: 4, range 1-20) were analyzed. Median Cr/CysC clearance ratio was 1.17. Twenty pts (27%) had both Cr/CysC clearance ratio >1.17, reflecting low lean body mass and a BMI > 25 kg.m−2. Fifteen pts (20.2%) developed grade 3-5 AEs, some rare, such as insipid diabetes with hypophysitis (n = 1) after 1st cycle (C1), pulmonary arterial hypertension (n = 3, C1, C1, C5), polymyositis (n = 2, C2, C2) and thrombocytopenia (n = 1, C6). In univariate analysis, gr 3-5 AE was associated with Cr/CysC clearance ratio >1.17 (p = 0.006), high CRP (p = 0.036) and the combination of Cr/Cyst clearance ratio >1.17 with BMI > 25 kg/m2 (p= 0.024). In multivariate analysis, Cr/CysC clearance ratio >1.17 (p = 0.03) and the combination of Cr/CysC clearance ratio >1.17 with BMI >25 kg/m2 (p = 0.014) remained significant.

Conclusions

The Creatinine/Cystatine C clearance ratio associated with BMI helps to identify sarcopenic overweight pts who are at high risk of severe PD-1 inhibitors induced toxicity. To date, it is unknown if the development of irAEs is an inherent component of checkpoint blockade with anti–PD-1 or if modifying the dosage can decrease the rates of these events.

Clinical trial identification

Legal entity responsible for the study

Pascaline Boudou-Rouquette

Funding

AP-HP

Disclosure

D. Damotte: research contract (MSD) All other authors have declared no conflicts of interest.