Safety and unique pharmacokinetic profile of ARX788, a site-specific ADC, in heavily pretreated patients with HER2-overexpresing solid tumors: Results from two phase 1 clinical trials.

person Sara A. Hurvitz David Geffen School of Medicine, University of California, Los Angeles/ Jonsson Comprehensive Cancer Center, Los Angeles, CA info_outline Sara A. Hurvitz, Haeseong Park, Sophia Frentzas, Catherine M. Shannon, Katharine Cuff, Richard Wilhelm Eek, George Thomas Budd, Amelia McCartney, Joyce O'Shaughnessy, Janice M. Lu, Jian Zhang, Dongmei Ji, Weina Shen, Matt Li, Jinchun Yan, Gang Xia, Yanping Ji, Sulan Yao, Gaozhun Xiong, Xichun Hu

Authors person Sara A. Hurvitz David Geffen School of Medicine, University of California, Los Angeles/ Jonsson Comprehensive Cancer Center, Los Angeles, CA info_outline Sara A. Hurvitz, Haeseong Park, Sophia Frentzas, Catherine M. Shannon, Katharine Cuff, Richard Wilhelm Eek, George Thomas Budd, Amelia McCartney, Joyce O'Shaughnessy, Janice M. Lu, Jian Zhang, Dongmei Ji, Weina Shen, Matt Li, Jinchun Yan, Gang Xia, Yanping Ji, Sulan Yao, Gaozhun Xiong, Xichun Hu Organizations David Geffen School of Medicine, University of California, Los Angeles/ Jonsson Comprehensive Cancer Center, Los Angeles, CA, Washington University School of Medicine in St. Louis, St. Louis, MO, Monash Hospital, Victoria, Australia, Mater Cancer Care Centre, South Brisbane, QLD, Australia, Princess Alexandra Hospital, Queensland, Australia, Border Medical Oncology, Wodonga, VIC, Australia, Department of Hematology/Oncology, Cleveland Clinic, Cleveland, OH, Monash Medical Centre, Clayton, VIC, Australia, Texas Oncology-Baylor Sammons Cancer Center, US Oncology, Dallas, TX, USC Norris Comprehensive Cancer Center, Los Angeles, CA, Fudan University Shanghai Cancer Center, Shanghai, China, Ambrx, Inc, Princeton Junction, NJ, NovoCodex Biopharmaceuticals, Shaoxing, China, Ambrx, Inc., La Jolla, CA, Department of Medical Oncology, Fudan University Cancer Hospital, Shanghai, China Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Ambrx, Inc Background: ARX788 is a site-specific, homogeneous, and highly stable ADC. The payload AS269 is conjugated to the synthetic amino acids para-acetylphenylalanine (pAF) in a humanized anti-HER2 mAb. ARX788 demonstrated promising activity in HER2-positive, HER2-low, and T-DM1 resistant tumors in preclinical studies. Here we present the phase 1 clinical data evaluating the safety, antitumor activity, and PK of ARX788 in advanced solid tumors. Methods: The standard 3+3 design (0.33 - 1.5 mg/kg; Q3W or Q4W) is used to determine the MTD and/or RP2D in two phase 1 studies in HER2-positive solid tumors in U.S. and Australia (ACE-Pan tumor-01) and in HER2-positive breast cancers in China (ACE-Breast-01). The efficacy endpoints include ORR and DCR. Intensive PK sampling in first 3 cycles is performed to characterize serum PK profiles of ARX788, total Ab, and pAF-AS269. Results: 69 and 34 heavily pretreated patients received ARX788 monotherapy in the ACE-Breast-01 (median 6 prior lines of therapy) and ACE-Pan tumor-01 trial (including breast, gastric/GEJ, NSCLC, ovarian, urothelial, biliary track, endometrial, and salivary gland cancer) respectively. Dose escalation for both studies have been completed with no DLT reported. MTD has not been reached. ARX788 was generally well tolerated with most AEs being grade 1 or 2. The most common grade >3 AEs include ocular AEs (5.7 %) and pneumonitis (4.3%) in the ACE-Breast-01 trial; pneumonitis (2.9%) and fatigue (2.9%) in the ACE-Pan tumor-01 trial. Low systemic toxicities in terms of the incidence rate and grade (as shown in table). No treatment-related death. In the 1.5 mg/kg cohort, ORR was 74% (14/19) and 67% (2/3) for ACE-Breast-01 and ACE-Pan tumor-01, respectively. DCR was 100%. Median DOR or median PFS has not been reached. PK profiles for total antibody and ARX788 were generally comparable across all dose levels. Mean T1/2 for ARX788 and total antibody had approximately 100 hours at the dose of 1.5 mg/kg. Serum pAF-AS269 concentrations peaked with a median time of 168 h. Serum exposure of pAF-AS269 was low with the Cmax and AUC at cycle 1 being approximately 0.1% and 0.18% of those for ARX788 on a molar basis, respectively. Conclusions: High stability of ARX788 and low serum exposure of pAF-AS269 may underlie the low systemic toxicity, which differentiates it from other ADCs. Clinical trial information: NCT032550070. Low Systemic toxicity of ARX788. n,% ACE-Breast-01 (N=69) ACE-Pan tumor-01 (N=34) All Grades Grade 3 or 4 All Grades Grade 3 or 4 Nausea/ Vomiting 3 (4.3)/4 (5.8) 0/0 5 (14.7)/2 (5.9) 0/0 Constipation/ Diarrhea 6 (8.7)/3 (4.3) 0/0 5 (14.7)/6 (17.6) 0/0 Neutropenia 14 (20.3) 0 1 (2.9) 0 Decreased WBC 12 (17.4) 0 1 (2.9) 0 Thrombocytopenia 9 (14.3) 1 (1.4) 3 (8.8) 0 Anemia 6 (8.7) 0 4 (11.8) 0 Fatigue 20 (29.0) 0 12 (35.3) 1 (2.9) Neuropathy 0 0 2 (5.9) 0