PO.CL01.16 · 临床研究
Investigation of inherited genetic variation for predictors of immune mediated colitis following immune checkpoint inhibitor (ICI) therapy of patients (pts) with melanoma
作者与单位
摘要 Abstract
Background: Immune mediated colitis is a common toxicity following ICI therapy of melanoma and can be life threatening. Therefore, predicting the risk of developing colitis may inform the treatment plan and clinical follow up. We hypothesize that inherited genetic variation is an important factor in predisposing pts to this immune related adverse event (irAE).
Methods: We conducted genome-wide genotyping on samples from 744 consenting pts enrolled in ECOG-ACRIN E1609 trial (NCT01274338) that tested ipilimumab. We used Illumina Infinium Global Screening Array v.3.0 + Multi-Disease BeadChip with 730059 designed loci. Genotypes were quality controlled, harmonized with the 1000 Genomes Phase 3 (1KGP3) genotypes, and imputed against the hrc-r1.1 reference panel using the Michigan Imputation Server 2, pipeline v2.0.6. We used logistic regression implemented in plink (v2.00a4LM glm with firth fallback) to estimate associations between inherited genetic markers and the occurrence of colitis, adjusting for genetic ancestry. We also calculated the value for 5 published polygenic risk scores (PRS) for inflammatory bowel disease (IBD) listed in PGS-Catalog v20240318 and tested the association with colitis in E1609 pts treating irAE grades as categorical (Kruskal-Wallis test) and as dichotomous (Wilcoxon rank-sum test) variables. IrAEs were graded using CTCAE v.4.
Results: There was no significant difference in distribution of the PRS across grade of colitis (Kruskal-Wallis) with any of the 5 PRS. However, all demonstrated stronger differences when irAE grades were dichotomized at >3 vs. other. PRS PGS004253 was most significant in association with grades 4-5 colitis (P = 0.01; AUC 0.73). This PRS ( Medha. Nature Commun 2024 ) was trained in a non-melanoma European population that has a genetic ancestry similar to our melanoma study cohort ( Tarhini. AACR 2025 ) and for which all markers in the PRS were available in our dataset. From our genome-wide association analysis, we identified 10 independent SNPs that were significantly associated with colitis irAE. When combined using log(OR) as weights, these SNPs were significantly associated with the severity of irAE grades, both across irAE grades (Kruskal-Wallis P = 2.5e-26) and when dichotomized as any colitis irAE vs. none (Wilcoxon P = 8.9e-30). In multivariable survival analysis adjusting for primary status (known, unknown) and sex (male, female), our 10-SNP PGS trended towards an association with survival outcomes.
Conclusion: Our results support an association between inherited genetic variation and the risk of colitis following ICI, including PRS for IBD selected based on inherited genetic similarity with the population used to train the PRS as well as a novel PRS score computed using 10 SNPs identified from our GWAS analysis.
利益披露 Disclosure
A. A. Tarhini,
Bristol Myers Squibb Other, Consulting or advisory role.
Merck Other, Consulting or advisory role.
Genentech Other, Consulting or advisory role.
Novartis Other, Consulting or advisory role.
Sanofi Other, Consulting or advisory role.
Regeneron Other, Consulting or advisory role.
Partner Therapeutics Other, Consulting or advisory role.
Clinigen Group Other, Consulting or advisory role.
Eisai Other, Consulting or advisory role.
Bayer Other, Consulting or advisory role.
Instil Bio Other, Consulting or advisory role.
ConcertAI Other, Consulting or advisory role.
OncoSec ).
InflaRx ).
Acrotech Biopharma ).
Pfizer ).
Agenus ).
Scholar Rock ).
Z. Chen, None..
M. Khaksar, None..
S. J. Lee, None.
F. Hodi,
Bristol Myers Squibb ).
Merck ).
Novartis ).
compass Therapeutics ).
Apricity ).
Puretech ).
Curis ).
Bicara ).
Checkpoint Therapeutics ).
Astra Zeneca ).
Bioentre ).
Gossamer ).
Iovance ).
Catalym ).
Immunocore ).
Kairos ).
Rheos ).
Bayer ).
Zumutor ).
Corner Therapeutics ).
T. Li, None..
H. Streicher, None.
V. K. Sondak,
Neogene Therapeutics ).
SkylineDx ).
Turnstone Biologics ).
Bristol Myers Squibb Other, Consultant.
Merck Other, Consultant.
Mural Oncology Other, Consultant.
Regeneron Other, Consultant.
J. M. Kirkwood,
Ankyra Therapeutics Other, Consulting/advisory boards under 10,000 per year.
Axio Research, LLC Other, Consulting/advisory boards under 10,000 per year.
Bristol Myers Squibb Other, Consulting/advisory boards under 10,000 per year.
Boxer Capital Other, Consulting/advisory boards under 10,000 per year.
Cytom X Therapeutics Other, Consulting/advisory boards under 10,000 per year.
Daiichi Sankyo Inc Other, Consulting/advisory boards under 10,000 per year.
Derm Tech Other, Consulting/advisory boards under 10,000 per year.
Engage Health Media Other, Consulting/advisory boards under 10,000 per year.
GE Healthcare Inc Other, Consulting/advisory boards under 10,000 per year.
iOnctura Other, Consulting/advisory boards under 10,000 per year.
Iovance Biotherapeutics Other, Consulting/advisory boards under 10,000 per year.
IQVIA Other, Consulting/advisory boards under 10,000 per year.
Takeda Other, Consulting/advisory boards under 10,000 per year.
Pfizer Other, Consulting/advisory boards under 10,000 per year.
Magnolia Innovations, LLC Other, Consulting/advisory boards under 10,000 per year.
Mural Oncology Other, Consulting/advisory boards under 10,000 per year.
Merck Other, Consulting/advisory boards under 10,000 per year.
Istari Oncology Other, Consulting/advisory boards under 10,000 per year.
Jazz Pharmaceuticals, Inc Other, Consulting/advisory boards under 10,000 per year.
Lytix Biopharma AS Other, Consulting/advisory boards under 10,000 per year.
X. Wang, None..
P. A. Kanetsky, None.