Results Of A Phase 1 Dose Escalation Study Of Ery974, An Anti-Glypican 3 (Gpc3)/Cd3 Bispecific Antibody, In Patients With Advanced Solid Tumors.

Abstract Background: ERY974, a bispecific T cell-redirecting antibody, redirects T cells to tumor cells by engaging the CD3 antigen on T cells and the glypican 3 (GPC3) antigen selectively expressed on tumors. ERY974 demonstrates T cell-dependent cellular cytotoxicity in vitro and transient cytokine elevations in preclinical toxicology studies (Ishiguro et al. 2017). The primary objective of this dose escalation (DE) study was to determine ERY974's maximum tolerated dose in patients with locally advanced or metastatic solid tumors expressing GPC3. Methods: The study included adult patients with advanced or metastatic solid tumors not amenable to standard therapy, histologically confirmed, with measurable disease and a life expectancy ≥ 3 months, including patients with ≤ 1cm and ≤ 1 brain metastasis. Patients with interstitial lung disease, or acute/active chronic infection were excluded. ERY974 was administered IV and dosed weekly. DE was initiated with an accelerated titration design of single patient cohorts followed by three patient cohorts. To mitigate for the toxicity of cytokine release syndrome (CRS), steroid prophylaxis and a flexible study design was implemented which included a two-step intra-patient escalation (regimen A), and a three-step intra-patient escalation (regimen B). Results: 29 patients were enrolled in dose levels ranging from 0.003 μg/kg to 0.81 μg/kg. Treatment-related adverse events that occurred in greater than 20% of patients included CRS and pyrexia. Dose level 0.81 μg/kg (regimen A) was confirmed not tolerable due to DLTs of Grade 3 CRS and Grade 2 CRS in two out of three patients (assessed according to Lee, et al. 2014). The Grade 3 CRS was associated with Grade 3 transaminitis and a Grade 3 elevation of bilirubin. Both CRS events led to dose delay and dose reduction. Increases in IL-6, IL-8 and IL-10 were observed in patients with the CRS. The severity and frequency of CRS in regimen B were similar to those observed in regimen A at the same dose level. One partial response (per modified RECIST criteria) was observed in a patient with esophageal cancer treated with 0.54 μg/kg (regimen B) and having 40% of the tumor tissue staining positive for GPC3 via immunohistochemistry. Stable disease lasting 3 months or longer was observed in four patients. Conclusions: The observed responses and CRS side effects are markers of ERY974 biologic activity. At doses below 0.81 μg/kg (regimen A), ERY974 was generally well tolerated with a manageable toxicity profile, including ERY-induced CRS which was manageable with steroid administration and anti-IL6R therapy. Further research is required to determine if combined prophylactic anti-IL6R and steroid therapy is a more effective strategy for managing CRS. References: 1. Ishiguro, Takahiro, et al. Science translational medicine, 2017, 9.410: eaal4291. 2. Lee, Daniel W., et al. Blood, 2014, 124.2: 188-195. Citation Format: Howard Safran, Mihaela Druta, Michael Morse, Filipa Lynce, Sofya Pintova, Khaldoun Almhanna, Daniel Weiss, Athos Gianella-Borradori, Yoshitaka Ogita, Roland Morley, Mikiko Nakamura, Junnosuke Matsushima, Takahiro Ishiguro. Results of a phase 1 dose escalation study of ERY974, an anti-glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT111.