REAL-WORLD PHARMACOVIGILANCE OF ANTIBODY-DRUG CONJUGATES: PAYLOAD-SPECIFIC SAFETY SIGNALS FROM DISPROPORTIONALITY ANALYSIS
Author(s)
Abhijna Vithal Yergolkar, MPH, PharmD1, Shalaka Somayaji, PharmD2, Priyank Tripathi, PharmD3;
1Loyola University Chicago, Student, Chicago, IL, USA, 2Ramaiah Medical College and Teaching Hospital, Oncology, Bangalore, India, 3HCG Cancer Care Centre, Bengaluru, India
1Loyola University Chicago, Student, Chicago, IL, USA, 2Ramaiah Medical College and Teaching Hospital, Oncology, Bangalore, India, 3HCG Cancer Care Centre, Bengaluru, India
OBJECTIVES: This study utilized disproportionality analysis to identify and characterize ADR signals associated with antibody - drug conjugates (ADCs), stratified by calicheamicin and monomethyl auristatin E (MMAE) payloads in hematologic malignancies.
METHODS: Retrospective disproportionality analysis of spontaneous adverse event reports (2015 and 2024) was conducted using MedDRA Preferred Terms. Potential signals were identified using the proportional reporting ratio (PRR ≥ 2), reporting odds ratio lower limit (ROR > 1), information component (IC > 0) and empirical Bayes geometric mean using the multi-item gamma Poisson Shrinker model (EBGM05 ≥ 2).
RESULTS: A total of 11,618 reports involving four ADCs (gemtuzumab ozogamicin, inotuzumab ozogamicin, brentuximab vedotin, and polatuzumab vedotin) were analyzed, meeting all predefined criteria. Of the 127 detected signals, 77 were associated with calicheamicin-based ADCs (gemtuzumab ozogamicin and inotuzumab ozogamicin) and 85 with Monomethyl Auristatin E (MMAE)-based ADCs (brentuximab vedotin and polatuzumab vedotin) with some signals overlapping between drug classes. Common signals across all agents included pancytopenia and hepatotoxicity. Calicheamicin-containing ADCs were mainly associated with hepatotoxicity (ROR 10.001, 95% CI 6.78 - 14.75; ROR 8.54 95% CI 4.93 - 14.77). Gemtuzumab ozogamicin exhibited unique signals for cerebral hemorrhage, mental status changes and bradycardia. In contrast, MMAE-containing ADCs were associated with higher disproportionality for peripheral neuropathy (ROR 16.65, 95% CI: 14.71 - 18.85; ROR 7.49, 95% CI: 5.84 - 9.61) and interstitial lung disease (ROR 3.61, 95% CI: 2.52 - 5.17; ROR 6.64, 95% CI: 4.57 - 9.64). Brentuximab vedotin exhibited strong signals for Colitis and Polyneuropathy. Polatuzumab vedotin was associated with hypomagnesemia, disseminated intravascular coagulation, cardiac failure and intestinal perforation.
CONCLUSIONS: This payload-stratified disproportionality analysis identified distinct and biologically plausible ADR profiles for calicheamicin and MMAE-based ADCs. The study provides a comparative, payload-stratified evaluation of real-world pharmacovigilance signals, allowing differentiation between class-wide, payload-driven, and drug-specific toxicities.
METHODS: Retrospective disproportionality analysis of spontaneous adverse event reports (2015 and 2024) was conducted using MedDRA Preferred Terms. Potential signals were identified using the proportional reporting ratio (PRR ≥ 2), reporting odds ratio lower limit (ROR > 1), information component (IC > 0) and empirical Bayes geometric mean using the multi-item gamma Poisson Shrinker model (EBGM05 ≥ 2).
RESULTS: A total of 11,618 reports involving four ADCs (gemtuzumab ozogamicin, inotuzumab ozogamicin, brentuximab vedotin, and polatuzumab vedotin) were analyzed, meeting all predefined criteria. Of the 127 detected signals, 77 were associated with calicheamicin-based ADCs (gemtuzumab ozogamicin and inotuzumab ozogamicin) and 85 with Monomethyl Auristatin E (MMAE)-based ADCs (brentuximab vedotin and polatuzumab vedotin) with some signals overlapping between drug classes. Common signals across all agents included pancytopenia and hepatotoxicity. Calicheamicin-containing ADCs were mainly associated with hepatotoxicity (ROR 10.001, 95% CI 6.78 - 14.75; ROR 8.54 95% CI 4.93 - 14.77). Gemtuzumab ozogamicin exhibited unique signals for cerebral hemorrhage, mental status changes and bradycardia. In contrast, MMAE-containing ADCs were associated with higher disproportionality for peripheral neuropathy (ROR 16.65, 95% CI: 14.71 - 18.85; ROR 7.49, 95% CI: 5.84 - 9.61) and interstitial lung disease (ROR 3.61, 95% CI: 2.52 - 5.17; ROR 6.64, 95% CI: 4.57 - 9.64). Brentuximab vedotin exhibited strong signals for Colitis and Polyneuropathy. Polatuzumab vedotin was associated with hypomagnesemia, disseminated intravascular coagulation, cardiac failure and intestinal perforation.
CONCLUSIONS: This payload-stratified disproportionality analysis identified distinct and biologically plausible ADR profiles for calicheamicin and MMAE-based ADCs. The study provides a comparative, payload-stratified evaluation of real-world pharmacovigilance signals, allowing differentiation between class-wide, payload-driven, and drug-specific toxicities.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
RWD153
Topic
Real World Data & Information Systems
Disease
No Additional Disease & Conditions/Specialized Treatment Areas, SDC: Oncology