Germline determinants of pneumonitis in patients with cancer treated with antibody drug conjugates.

12125 Background: Antibody-drug conjugates (ADCs) are now essential in the treatment of solid and hematologic cancers. While effective, ADCs can cause adverse events (AEs) requiring careful management. Pneumonitis, a potentially severe AE, may result in treatment discontinuation or mortality. However, its risk factors and underlying mechanisms remain poorly understood. Methods: Patients (pts) with solid or hematologic malignancies treated with ADCs at Dana-Farber Cancer Institute up to August 1, 2024, were screened. Only those with available genomic data were included. Pneumonitis was evaluated based on the Common Terminology Criteria for AEs v4.03. A total of 18 candidate single nucleotide polymorphisms (SNPs) linked to drug-related AEs and implicated in ADC metabolism pathways were identified using PharmGKB. SNPs were inferred from targeted panel sequencing using the STITCH pipeline, with 3 SNPs that could not be successfully imputed. The association between the SNPs, as probabilistic dosages, and occurrence of pneumonitis was tested using a multivariable Cox regression model, adjusting for age, sex, race, cancer type, and sequencing panel version. Pts were censored at the end of treatment or death. P-values were adjusted using the Bonferroni correction. Results: The study included 1,184 pts with cancer treated with ADCs, encompassing a total of 1,465 ADC treatments, as some pts received multiple lines of ADCs. The median age at treatment initiation was 60 years (interquartile range: 20). Most pts were female (80.7%). Breast cancer was the most common cancer (54.6%), followed by urothelial (13.3%), and ovarian (11.6%) cancers. The most frequently administered ADCs included trastuzumab deruxtecan (33.1%), sacituzumab govitecan (25.1%), and enfortumab vedotin (11.3%). A total of 92 pneumonitis events were observed in 89 pts (Table), among which 54 (58.6%) were grade 2 or higher. The prevalence of pts carrying the minor alleles (intermediate or poor metabolizers) of rs4646437 (CYP3A4) and rs776746 (CYP3A5) was 16.8% and 15.6%, respectively. Multivariable analysis revealed that carriers of the minor allele of rs4646437 (Hazard Ratio [HR]: 3.03, 95% Confidence Interval [CI]: 1.73–5.29, P= 0.001) or rs776746 (HR: 2.43, 95% CI: 1.56–3.81, P= 0.001) had a significantly higher risk of developing pneumonitis, after adjusting for age, sex, race, cancer type, and sequencing panel version. Conclusions: Our findings highlight the potential role of inherited genetic factors in modulating treatment-related toxicities of ADCs. Understanding these associations can provide valuable insights into personalized treatment strategies and inform risk assessment to optimize the safety and efficacy of ADCs. Rates of pneumonitis. % per Group N Trastuzumab Deruxtecan 13.1 64 Mirvetuximab Soravtansine 8.4 10 Tisotumab Vedotin 5.0 1 Enfortumab Vedotin 3.6 6 Trastuzumab Emtansine 3.3 6 Sacituzumab Govitecan 1.3 5