Joan Forns, MPH, PhD1; James A. Kaye, MD, DrPH2; Fabio A. Lievano, MD3; Jerzy E. Tyczynski, PhD, MSc3; The Safety of Antibody Drug Andrea V. Margulis, MD, ScD1 1RTI Health Solutions, Barcelona, Spain Conjugates: A Literature Review 2RTI Health Solutions, Waltham, Massachusetts, United States 3AbbVie Inc., North Chicago, Illinois, United States DISCLOSURES Joan Forns, James Kaye, and Andrea Margulis are full-time employees of RTI Health Solutions, a unit of RTI International, which is a nonprofit organization that conducts work for government, public, and private organizations, including pharmaceutical companies. Fabio A. Lievano and Jerzy E. Tyczynski are employees of AbbVie Inc. BACKGROUND Figure 1. Diagram Describing the Different Components of an ADC OBJECTIVE Antigen Antibody • Antibody-drug conjugates (ADCs) • To identify the most common adverse events (AEs) reported from phase 2-4 clinical • High homogeneous expression on tumor • High a nity and avidity for tumor antigen are a class of targeted therapies • Low or no expression on healthy tissues • Chimeric or humanized to decrease immunogenicity trials or observational studies for the 5 study ADCs. for cancer that combine the • High a nity and avidity for antibody recognition • Long half-life and high molecular weight relative selectivity of a monoclonal antibody with a cytotoxic agent joined covalently by a cleavable or METHODS noncleavable chemical linker • A targeted review of literature published from 2015 through July 2019 was (Figure 1). conducted in PubMed and Embase to identify peer-reviewed, English-language • A large number of ADCs are under articles reporting AEs associated with the use of ADCs with at least 20 patients in Fab Fab evaluation in clinical trials each arm. worldwide, but only 5 had been • Level 1 (titles and abstracts) and level 2 (full-text review) screening were conducted approved by both the United by 1 epidemiologist, and final decisions regarding inclusion of publications were States Food and Drug Linker Cytoxic payload • Stable in circulation • Highly potent agents — made based on consensus with a senior epidemiologist when necessary. Administration and the European • E cient release of payload at target site IC50 in subnanomolar range: • We first extracted AEs of any grade reported in at least 10% of patients in each study. Medicines Agency at the time of • Prevents premature release of payload Fc - Calicheamicin at non-target tissue - Maytansine derivative In a second step, we summarized the reported incidence for each AE and ADC by this literature review (July 2019): (DM1 or DM4) • E cient linker technology - Auristatin (monomethyl calculating the median incidence proportion across all studies reporting a particular brentuximab vedotin (BV), ado- - Cleavable vs. noncleavable auristatin E or monomethyl trastuzumab emtansine (T-DM1), • Site of conjugation auristatin F) AE with at least 10% incidence. The median was calculated to reduce the effect of - DAR aects drug distribution • Optimal DAR extreme values (outliers) for any particular AE. gemtuzumab ozogamicin (GO), and pharmacokinetics inotuzumab ozogamicin (IO), and • We also calculated the median reported incidence of AEs of any grade stratified by polatuzumab vedotin (PV). DAR = drug-antibody ratio; Fab = antigen-binding fragment; Fc = constant fragment; IC50 = half maximal inhibitory concentration. combinations of payload (cytotoxic agent) and linker. RESULTS Figure 2. Flowchart of Included Articles • The literature search identified 357 unique publications. After • For GO, safety information was scarce; the median incidence Articles identified through reviewing titles and abstracts, we selected 58 articles for full- was 45% for thrombocytopenia, 45% for increased aspartate database searching text review: 48 of these qualified for data extraction. Among the aminotransferase (AST), and 50% for fatigue. Finally, PV had N = 357 48 selected studies, 18 (38%) reported AEs for BV, 15 (31%) for the highest incidence of fatigue (60%) and diarrhea (47%) Articles excluded at level 1 n = 299 IDENTIFICATION • Study type n = 105 T-DM1, 7 (15%) for GO, 7 (15%) for IO, and 1 for PV (2%) (Figure 2). based on a single study. LEVEL 1 SCREEN • Population n = 10 • Outcomes n = 51 (Title/abstract screened) • • • Exposures n = 59 Most included articles reported on both efficacy and safety; GO and IO have a calicheamicin derivative payload and an N = 357 40 reported on clinical trials (22 phase 2, 17 phase 3, and acid-labile (cleavable) hydrazine-based linker. For most of the • Small sample size (< 20 patients) n = 4 SCREENING • Year of publication (< 2015) n = 29 1 phase 4), and 8 reported on observational studies. AEs, these ADCs showed higher median AE incidence than • Others n = 41 other types of payload/linker combinations. Articles excluded at level 2 n = 9 • For the 2 ADCs with the largest numbers of included studies, • Study type n = 0 BV and T-DM1, the median incidences of AEs of any grade • BV and PV have a monomethyl auristatin E (payload) and a LEVEL 2 SCREEN • Population n = 4 • Outcomes n = 0 (Full text screened) were higher for BV than for T-DM1 for anemia (31% vs. 24%), protease-cleavable linker. T-DM1 has DM1 (derivative of • Exposures n = 1 N = 58 neutropenia (32% vs. 13%), thrombocytopenia (57% vs. 29%), maytansine) as payload and a noncleavable thioether linker. ELIGIBILITY • Small sample size (< 20 patients) n = 0 • Year of publication (< 2015) n = 0 peripheral sensory neuropathy (23% vs. 13%), fatigue (40% vs. For these 3 ADCs, the median incidences of most AEs of any • Others n = 4 30%), nausea (40% vs. 36%), vomiting (26% vs. 18%), and grade were similar, including anemia, thrombocytopenia, diarrhea (29% vs. 18%) (Figure 2). However, median constipation, nausea, vomiting, diarrhea, anorexia, pyrexia, Articles included 1 article excluded due to reporting of AEs N = 49 of an ADC after exposure to nivolumab incidences were lower for BV than for T-DM1 for anorexia myalgia, and cough. ADCs with monomethyl auristatin E (18% vs. 21%), pyrexia (19% vs. 25%), myalgia (12% vs. 16%), (payload) as the payload and a protease-cleavable linker had a Articles included and headache (14% vs. 27%). higher incidence of neutropenia, peripheral sensory N = 48 neuropathy, and fatigue relative to the ADC with a DM1 & EXTRACTED INCLUDED • IO was associated with higher median AE incidences than BV payload and noncleavable thioether linker. Brentuximab Ado-trastuzumab- Gemtuzumab Inotuzumab Polatuzumab and T-DM1 for neutropenia (42%), thrombocytopenia (72%), vedotin emtansine ozogamicin ozogamicin vedotin fatigue (45%), nausea (49%), and pyrexia (32%). N = 18 (38%) N = 15 (31%) N = 7 (15%) N = 7 (15%) N = 1 (2%) Figure 3. Median Incidence of Adverse Events of Any Grade by Antibody-Drug Conjugate 80 Brentuximab vedotin 72.0 70 Polatuzumab vedotin Gemtuzumab ozogamicin 60 59.5 Inotuzumab ozogamicin 56.5 Ado-trastuzumab emtansine 49.5 50 48.5 46.5 45.0 44.5 44.5 45.5 42.0 40 39.5 40.0 35.5 33.0 32.0 31.5 32.0 31.0 30.0 29.0 29.0 29.0 30 28.0 26.5 % of patients 25.5 25.5 25.0 25.0 24.0 24.0 24.0 23.0 23.0 23.0 21.0 20.5 21.5 21.0 21.0 19.5 19.0 19.0 19.0 20 17.5 18.0 17.5 18.0 16.5 13.0 14.0 14.0 12.5 13.0 13.0 12.5 10 0 Anemia Neutropenia Thrombocytopenia PN sensory Increased AST Constipation Fatigue Nausea Vomiting Diarrhea Anorexia Pyrexia Abdominal pain Cough Headache ALT = alanine aminotransferase; DM1 = derivative of maytansine; MMAE = monomethyl auristatin E (payload); PN = peripheral neuropathy. Figure 4. Median Incidence of Adverse Events of Any Grade by Payload and Linker 80 Payload: MMAE - Linker: Protease cleavable linker 72.0 70 Payload: Calicheamicin derivative - Linker: Acid-labile hydrazone-based linker Payload: DM1 - Linker: Noncleavable thioether linker 60 56.5 48.5 50 47.0 45.5 42.0 40 40.0 36.0 35.5 32.0 29.0 30.0 29.0 30 27.5 26.5 % of patients 26.0 24.0 25.0 25.0 25.0 24.0 22.0 23.0 21.0 21.5 20.5 21.5 21.0 19.5 19.0 20.0 19.0 20 18.0 17.5 18.0 15.0 16.0 14.0 14.0 12.5 13.0 13.0 12.0 13.0 10 0 Anemia Neutropenia Thrombocytopenia PN sensory Increased AST Increased ALT Constipation Fatigue Nausea Vomiting Diarrhea Anorexia Pyrexia Myalgia Abdominal pain Cough Headache DISCUSSION • For BV, the AEs reported in the largest number of studies were • Only 1 article reported safety data for patients treated with PV. CONCLUSIONS peripheral sensory neuropathy, diarrhea, and neutropenia. The The AE of any grade with the highest incidence was fatigue. AEs of any grade with the highest median incidence were • The 5 approved ADCs were found to have • Strengths: The present review comprehensively considered peripheral sensory neuropathy, nausea, and fatigue. AEs of approved ADCs for both clinical trials and observational somewhat distinct safety profiles. Most studies, • For T-DM1, the AEs reported in the largest number of studies studies; AEs were stratified by payload/linker combination. especially most observational studies, reported were epistaxis, thrombocytopenia, nausea, and headache. • Limitations: The extraction of AEs with an incidence of at least on BV and T-DM1, which have been in the Anemia, fatigue, and thrombocytopenia had the highest median 10% likely overestimated the true median incidence of a market longer than the other ADCs. incidence among all AEs of any grade. particular AE across all studies (because any studies with • For IO, increased AST and thrombocytopenia were the most lower than 10% incidence for a particular AE are omitted from commonly reported AEs of any grade. Of the 5 ADCs in this the calculation).