Toxicity and efficacy of antibody drug conjugates (ADC) in advanced solid tumors: A pooled analysis of Sarah Cannon UK

BackgroundADCs are a rapidly emerging modality of systemic anti-cancer treatment with 11 agents FDA approved and more under investigation.MethodsPatients that received at least 1 dose of ADC in phase 1-3 trials at SCRI UK between 2012-2023 were included. Patient and tumor characteristics, toxicity and outcomes overall and for subgroups of interest were assessed using descriptive statistics and cox regression.Results102 patients from 16 trials (8 phase 1, 8 phase 2-3) of 13 different ADCs were included (median age 62 (32-81), male 32.4%). Main tumor types were breast (n=40, 38.5%) and gynecological (n=19, 18.3%). Median number of prior treatment lines was 3 (1-18). Payloads comprised alkylating agents (AA, n=3), microtubule inhibitors (MTI, n=8) or a topoisomerase inhibitor (Topo-I, n=2). 3 ADCs targeted an oncogene (HER2) vs tumor associated antigens (TAA). TRAEs of any grade occurred in 88% of patients (grade 3-4 25%). Colitis occurred in 3.8% (2.9%), ILD 3.8% (1.0%), neuropathy 26.0% (0%), eye toxicity 22.1% (0%) and hepatotoxicity 27.8% (4.8%). Most toxicities occurred early (<7 weeks), excepting colitis (median 18.2 weeks [1.5-138.3]), ILD (15.6 [12.6-30.0]), peripheral neuropathy (11.6 [0-91.8]) and thrombocytopenia (26.6 [1.0-61.6]). There was no significant difference in rates of grade 3 AEs between payload class (p=0.59) or HER2 targeting (p=0.16). Significant responses were observed overall (29%), notably with Topo-I, in breast cancer, when targeting an oncogene (HER2) versus tumor-associated antigens and at the RP2D dose (Table). Table: 655P N ORR DCR mPFS* 95% CI P Overall 102 29 75 8.1 5.0-15.7 Payload 0.02 AA 18 6 72 5.4 1.7-20.3 MTI 66 24 76 6.7 3.3-11.4 Topo-I 19 47 84 26.3 8.9-NR Tumor Breast 41 50 88 21.5 13.2-31.3 <0.01 GU 12 17 50 8.9 1.4-NA Gyn 19 5 79 5.0 2.5-5.7 Lung 10 10 60 2.3 0.5-NA Melanoma 5 0 100 8.1 2.3-NA Upper GI 17 12 82 2.3 1.3-3.5 Dose at RP2D Yes 71 32 77 15.7 7.9-22.7 <0.01 No 33 9 70 2.6 2.2-3.5 Oncogene 37 51.3 97.4 22.7 14.7-35.3 <0.01 TAA 64 9.4 69.8 3.7 2.6-5.7 *Months. ConclusionsADC activity is seen across different tumors with higher efficacy when oncogene targeted. Identification of timelines of expected toxicities is critical for clinical management and mitigation strategies.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureR. Woodford, A. Cammarota, K. Joshi, R.M. Grochot: Financial Interests, Institutional, Full or part-time Employment: HCA International. A. Williams: Financial Interests, Institutional, Full or part-time Employment: HCA International; Financial Interests, Personal, Advisory Role: Ellipses Pharma UK. E. Fontana: Financial Interests, Personal, Invited Speaker: Caris Life Science, Repair Therapeutics; Financial Interests, Personal, Other, Conference attendance: Sapience Pharma; Financial Interests, Personal, Invited Speaker, Conference Attendance: Bicycles Therapeutics; Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International; Financial Interests, Personal, Officer: EORTC; Financial Interests, Institutional, Coordinating PI: Repair Therapeutics, Amgen, Taiho Pharmaceutical; Financial Interests, Institutional, Local PI: Bicycle Therapeutics, Artios Pharma, Seagen, Nurix Therapeutics, BioNTech SE, Relay Therapeutics, Pfizer, Roche, Daiichi Sankyo, Gilead Science, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, Hutchmed, Merus, Crescendo Biologics, GSK plc, BeiGene, Turning Point Therapeutics, Sapience Pharma, Arcus Bioscience, Exelixis, Nerviano Medica, Elipsees, Deciphera, Ribon Therapeutics. All other authors have declared no conflicts of interest.