457PFirst-in-human study of ABBV-621 in patients (pts) with previously treated sold tumours: Dose-optimization cohorts

Background ABBV-621, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist, induces cell death in tumor cells by activation of death receptor 4 and 5. Maximum tolerated dose was not reached in dose escalation (Ratain et al. ASCO 2019; NCT03082209). Herein is reported the analysis of safety and antitumor activity in additional pts enrolled in the dose-optimization cohorts with the goal of identifying the recommended phase 2 dose. Methods Eligible pts (≥18 years, relapsed/refractory [R/R] KRAS-mutant colorectal [CRC] or pancreatic cancer, ECOG 0–2, measurable disease, willingness to undergo mandatory biopsies) received ABBV-621 intravenously (1.25–7.5mg/kg) on day (D) 1, D8, and D15 of a 21-D cycle. Analyzed tumor types were evenly distributed across dose levels (DL). Results As of 16 Apr 2019, 48 pts received ≥1 dose of ABBV-621 (CRC, n=24/pancreatic, n=24; 1.25mg/kg, n=8/8; 3.75mg/kg, n=8/8; 7.5mg/kg, n=8/8). Median age: 63 years (range, 43–76); 65% male, 73% ≥3 prior treatment (Tx) regimens. Median duration of ABBV-621 exposure was 36 days (range, 1–251) with a median 2 Tx cycles (range, 1–12). Tx-emergent and Tx-related AEs are summarized in the table. Ten pts (20.8%) experienced AEs leading to discontinuation; 4 (9.3%) pts had dose-limiting toxicities possibly associated with ABBV-621 administration: respiratory failure (7.5mg/kg; Grade 5, the only Tx-related death), increased ALT and AST (1.25, 3.75mg/kg), toxic hepatitis (1.25mg/kg), non-cardiac chest pain (1.25mg/kg), and pleuritic pain (1.25mg/kg). ALT, alanine aminotransferase; AST, aspartate aminotransferase A partial response was observed in 1pt with CRC (1.25mg/kg) and 1pt with pancreatic cancer (3.75mg/kg). Stable disease at 12 weeks was the best response in 20 pts (41.7%; CRC, n=9/pancreatic, n=11).Table457PTableAEs, n (%)Related to ABBV-621, n (%)All grade (≥5 patients)Grade 3/4Serious1.25mg/kg (n=16)3.75mg/kg (n=16)7.5mg/kg (n=16)Total (N=48)1.25mg/kg (n=16)3.75mg/kg (n=16)7.5mg/kg (n=16)Total (N=48)1.25mg/kg (n=16)3.75mg/kg (n=16)7.5mg/kg (n=16)Total (N=48)Fatigue4 (25.0)3 (18.8)4 (25.5)11 (22.9)00000000Increased ALT1 (6.3)4 (25.0)5 (31.3)10 (20.8)1 (6.3)1 (6.3)1 (6.3)3 (6.3)01 (6.3)01 (2.1)Stomatitis1 (6.3)3 (18.8)5 (31.3)9 (18.8)00000000Increased AST1 (6.3)3 (18.8)4 (25.0)8 (16.7)1 (6.3)1 (6.3)2 (12.5)4 (8.3)01 (6.3)01 (2.1)Decreased appetite2 (12.5)1 (6.3)4 (25.0)7 (14.6)00000000Diarrhea1 (6.3)3 (18.8)3 (18.8)7 (14.6)00000000Nausea2 (12.5)1 (6.3)4 (25.0)7 (14.6)0000001 (6.3)1 (2.1)Vomiting3 (18.8)1 (6.3)3 (18.8)7 (14.6)0000001 (6.3)1 (2.1)Dysgeusia2 (12.5)2 (12.5)1 (6.3)5 (10.4)00000000Pyrexia01 (6.3)4 (25.0)5 (10.4)00000000 Conclusions Administration of ABBV-621 in pts with R/R CRC and pancreatic cancer shows an acceptable safety profile at all DL and evidence of antitumor activity. Clinical trial identification NCT03082209. Editorial acknowledgement Medical writing support was provided by Yanci M. Baker, PhD, from Aptitude Health, Atlanta, GA, and funded by AbbVie. Legal entity responsible for the study AbbVie Inc. Funding AbbVie Inc. Disclosure E. Calvo: Honoraria (self): HM Hospitales Group; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Janssen-Cilag; Advisory / Consultancy: PsiOxus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: EUSA Pharma, Inc.; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Guidepoint Global; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy: Gerson Lehrman Group; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Servier; Advisory / Consultancy: amcure; Leadership role: Foundation INTHEOS; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution), Shareholder / Stockholder / Stock options: START; Shareholder / Stockholder / Stock options: Oncoart Associated; Shareholder / Stockholder / Stock options: International Cancer Consultants. M.J.A. de Jonge: Advisory / Consultancy: Faron Pharmaceutical Ltd. D.W. Rasco: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Lily; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Rexahn; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution), Travel / Accommodation / Expenses: Asana BioSciences; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Aeglea; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Ascentage; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Apexian; Research grant / Funding (institution): Birdie; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Constellation; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Astex; Research grant / Funding (institution): Compugen; Research grant / Funding (institution): Coordination; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Incyte. V. Moreno: Advisory / Consultancy: Puma Biotechnology; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Regeneron. Y. Chang: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. M. Chiney: Full / Part-time employment, Former employee: AbbVie; Full / Part-time employment, Current employee: Bristol-Myers Squibb. M. Motwani: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. S. Penugonda: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. A.M. Petrich: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. M.J. Ratain: Advisory / Consultancy: Acentage Pharma; Advisory / Consultancy: Cyclacel; Advisory / Consultancy: Aptevo Therapeutics; Advisory / Consultancy: Shionogi; Research grant / Funding (institution): Dicerna; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Genentech/Roche; Licensing / Royalties: UGT1A1 genotyping for irinotecan; Licensing / Royalties: Genomic prescribing system; Officer / Board of Directors: Value in Cancer Care Consortium. P. LoRusso: Advisory / Consultancy: Agios; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Genmab; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: CytomX; Advisory / Consultancy: Five Prime; Advisory / Consultancy: Takeda; Advisory / Consultancy: Sotio; Advisory / Consultancy: Cybrexa; Advisory / Consultancy: Agenus.