Association between single-nucleotide polymorphisms and adverse events in nivolumab-treated non-small cell lung cancer patients

Abstract

Background: Treatment with PD-1 inhibitors can be hampered by severe auto-immune-related toxicities. Our objective was to identify single-nucleotide polymorphisms (SNPs) in genes previously associated with auto-immunity, which are associated with toxicities in nivolumab-treated NSCLC patients. This was in order to identify patients prone to develop severe toxicities and to gain more insight into the underlying pathobiology.

Methods: We analysed 322 nivolumab-treated patients and assessed the association with toxicities for seven SNPs in four genes, which are considered contributors to PD-1-directed T-cell responses, i.e., PDCD1, PTPN11, ZAP70 and IFNG. Every SNP was tested for its association with toxicity endpoints. Significant associations were tested in a validation cohort.

Results: A multivariable analysis in the exploration cohort showed that homozygous variant patients for PDCD1 804C>T (rs2227981) had decreased odds for any grade treatment-related toxicities (n = 96; OR 0.4; 95% CI 0.2-1.0; p = 0.039). However, this result could not be validated (n = 85; OR 0.9; 95% CI 0.4-1.9; p = NS).

Conclusions: Our results show that it is unlikely that the investigated SNPs have a clinical implication in predicting toxicity. A finding, even though negative, that is considered timely and instructive towards further research in biomarker development for checkpoint inhibitor treatments.

Fig. 1

a Interaction between a tumour cell and a T cell. Tumour cells can activate T cells by presenting an antigen through major histocompatibility complex (MHC) to the T cell receptor (TCR). Under influence of interferon-gamma (IFNγ) tumours can express Programmed-Death ligand-1 (PD-L1), which inhibits TCR signalling by binding and activating Programmed-Death-1 (PD-1) expressed by T cells. b Proximal PD-1 pathway signalling. Activated PD-1 recruits SHP2, which inhibits ZAP70 function. ZAP70 is an important protein in the signalling pathway of the TCR. Complementary to its effect on ZAP70, SHP2 may also inhibit PI3K upon PD-1 activation. Both effects lead to inhibition of T cell activation. Note: the PD-1 pathway comprises many more proteins and signal transduction pathways, but these are omitted from this figure since they are not included in our analysis