1O - Association between single nucleotide polymorphisms and side effects in nivolumab treated NSCLC patients

Date 04 November 2016
Event ESMO Symposium on Immuno-Oncology 2016
Session Proffered paper session
Presenter Sander Bins
Citation Annals of Oncology (2016) 27 (suppl_8): viii1-viii2. 10.1093/annonc/mdw525
Authors S. Bins1, E.A. Basak2, S. El Bouazzaoui3, S.L.W. Koolen2, C. van der Leest4, S. Sleijfer2, R. Debets2, R.H.N. van Schaik3, J.G.J.V. Aerts5, R. Mathijssen2
  • 1Medical Oncology, Erasmus MC Cancer Institute, 3015 CN - Rotterdam/NL
  • 2Medical Oncology, Erasmus MC Cancer Institute, Rotterdam/NL
  • 3Clinical Chemistry, Erasmus University Medical Center, Rotterdam/NL
  • 4Pulmonology, Amphia Hospital, Breda/NL
  • 5Pulmonology, Erasmus University Medical Center, Rotterdam/NL

Abstract

Aim/Background

Treatment with PD-1 inhibitors is sometimes hampered by severe auto-immune related adverse events (AEs) compromising treatment outcomes. The objective of the current analysis was to identify single nucleotide polymorphisms (SNPs) in genes previously associated with auto-immunity or inflammatory over-response, which are associated with clinically relevant toxicities in NSCLC patients treated with nivolumab. This in order to identify patients prone to develop severe toxicities and to get more insight into the underlying pathobiology.

Methods

We analyzed 161 patients treated with nivolumab and assessed association with toxicity for 7 SNPs in 4 genes that are considered active contributors to PD-1-directed T cell responses, i.e. PDCD1, PTPN11, ZAP70 and IFNG, which respectively encode for the proteins PD-1, SHP-2, ZAP70 and IFN-γ. Toxicity was graded using CTCAE version 4.03. Next to nivolumab specific AEs such as liver enzyme elevation, more general endpoints were assessed, being any grade ≥ 3 toxicity, corticosteroid use, toxicity related treatment interruption and grade ≥ 3 immune related AEs. For every SNP, the best fitting model was selected from the dominant, recessive, additive and multiplicative model. If a SNP had a p 

Results

Thirty-one patients (19%) presented with any drug-related grade ≥3 toxicity. Patients with a polymorphism at PTPN11 333-223A>G (rs2301756) had higher odds for any grade ≥3 toxicity per mutant allele (OR 2.4; 95% CI 1.0 – 5.7; p = 0.045). The odds for elevated liver enzymes (n = 54) were higher in patients with at least one mutated allele at the same locus (OR 2.9; 95% CI 1.2-7.1; p = 0.018).

Conclusions

This study shows that SNPs in the SHP-2 gene (PTPN11) are associated with AEs in patients treated with nivolumab, which implicates that other enzymes in the PD-1 axis contribute to anti-PD-1 treatment outcome and that, if confirmed, its germline genetic variants should be taken into account in clinical decision making and management of NSCLC patients who are candidates for nivolumab.

Clinical trial identification

Legal entity responsible for the study

Erasmus MC

Funding

Erasmus MC

Disclosure

All authors have declared no conflicts of interest.