Abstract
Abstract
Background: Hyperprogressive disease (HPD) has been described in advanced solid tumors patients treated with anti PD1 anti PDL1 monotherapy (Champiat, Clin Can Res 2016; Saada-Bouzid, Ann Oncol, 2017). Our aim was to explore whether host constitutional variations in the nucleotide sequence of genes involved in immune response might be associated with the occurrence of HPD in patients treated with anti PD-(L)1.
Methods : From April to August 2017, 98 patients were treated in the Centre Antoine Lacassagne (Nice, France) with anti PD-(L)1. Potential SNPs for four candidate genes with a minor allele frequency≥ 5% in caucasians were selected according to genome browser data-base: PD1 (rs10204525, rs11568821, rs2227981), PD-L1 (rs2282055, rs2297136, rs2297137, rs4143815, rs10815225), IDO1 (rs3739319, rs3808606, rs373931, rs9657182) and VEGR2 (rs2305948, rs1870377, rs2071559). High through-output genotyping was done by MassARRAY (AGENA). HPD was defined as a TGKR (ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) ≥ 2.
Results: Patients were treated for head and neck squamous cell carcinoma (16/98), non-small cell lung cancer (48/98), melanoma (13/98), renal cell carcinoma (14/98) and 7 others. Median age was 66 years old, 33 were male. All tested SNPs were in Hardy-Weinberg equilibrium. Responses were associated with G3-G4 toxicities (10% vs 42%, p=0.001). TGKR was assessable in 80 patients. HPD was observed in 11/80 (14 %) patients. HPD was significantly associated with age≥70y (6% vs 25%, p=0.02) and genotype for PD1 rs 2227981 (8/32=35% G/G vs 2/43=5% A/G or A/A, p=0.02), PDL1 rs 2282055 (1/37=3% T/T vs 10/43=23% T/G or G/G,p=0.02) and VEGFR2 rs1870377 (2/48=5% T/T vs 9/32=28% T/A or A/A, p=0.005). Multivariate analysis confirmed the association between HPD and VEGFR2 rs1870377 T/A or A/A (OR=15.3, p=0.007), PDL1 rs 2282055 T/G or G/G (OR=18.7, p=0.01) and age≥70y (OR=14.4, p=0.006).). Combining the three alleles at risk for HPD gave an OR =12.4 (p=0.001).
Conclusion: In patients treated with anti PD-(L)1, HPD was independently associated with older age and host related gene variations. Host related immunogenetics could become an integrative part of predictive factor for immunotherapy outcome.
Citation Format: Sadal Refae, Nathalie Ebran, Jocelyn Gal, Josiane Otto, Damien Giacchero, Delphine Borchiellini, Joel Guigay, Frederique Peyrade, Gerard Milano, Esma Saada. Host immunogenetics and hyperprogression under PD1/PD-L1 checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4548.