Germline determinants of pneumonitis in patients with cancer treated with antibody drug conjugates.
Year: 2025
Type: conference-abstract
Abstract: 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
Source: Journal of Clinical Oncology
Authors: Emre Yekeduz, Eddy Saad, Marc Machaalani, Berkay Simsek, Clara Steiner, Karl Semaan, Aya Abdelnaser, Marc Eid, Mitra Shavakhi, Rashad Nawfal, Razane El Hajj Chehade, Renee Maria Saliby, Wassim Daoud Khatoun, Mustafa Saleh, Paolo Tarantino, Bradley Alexander McGregor, Joaquim Bellmunt, Sara M. Tolaney, Alexander Gusev, Toni K. Choueiri
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4410808238