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.

Abstract

1038 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 .[Table: see text]

Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)–related interstitial lung disease/pneumonitis—Focus on proactive monitoring, diagnosis, and management

“…Trastuzumab [46] and the anti-HER2 ADCs T-DM1, [47] trastuzumab duocarmazine (SYD985), [48] ARX788, [49] and T-DXd [5] have been associated with ILD/pneumonitis. In a pooled analysis of eight trastuzumab trials, 162 (9.9%) of 1642 patients experienced ILD/ pneumonitis; three (0.2%) had grade 5 events [26].…”

“…In the phase 3 TULIP trial, 291 patients were randomized to receive SYD985; 7.6% experienced ILD/pneumonitis, including two who experienced a grade 5 event [50]. In two separate phase 1 trials of ARX788, grade > 3 pneumonitis was reported in 4.3% of 69 patients and 2.9% of 34 patients [49]. The association between ILD/pneumonitis and dose may vary by agent, as dose-dependent associations have not been found with other agents [23,51,52].…”

Discovery and Development of Dolastatin 10-Derived Antibody Drug Conjugate Anticancer Drugs

“…Based on these encouraging preclinical data several phase I studies were initiated. Partial results from four phase I studies at doses of 0.33 to 1.7 mg/kg were reported in meetings (2020–2021). − Positive responses were reported in patients with HER2+ tumors at doses of >1.0 mg/kg. The doses reported had not reached MTD.…”

HER2-Directed Therapy in Advanced Breast Cancer: Benefits and Risks

“…ARX788 is a novel ADC that combines a fully humanized monoclonal antibody directed to HER2, which is conjugated with a tubulin inhibitor (AS269) towards a synthetic amino acid: para-acetylphenylalanine. 85 This specific drug design prevents early payload detachment. In 19 heavily pretreated ABC patients, with HER2 overexpressing tumors, the reported overall response was 74%.…”