Preliminary monotherapy efficacy of novel immune checkpoint blockade GV20-0251 (anti-IGSF8) in advanced melanoma patients with primary resistance to anti-PD1.

Abstract

2531 Background: GV20-0251 is an AI-designed, first-in-class, cross-species reactive, Fc-attenuated IgG1 antibody that targets the novel cancer immune checkpoint IGSF8 which is broadly expressed across solid tumors. In syngeneic tumor models, anti-IGSF8 alone or with anti-PD1 inhibits tumor growth by increasing cytotoxicity and infiltration of natural killer cells (NK) and antigen cross-priming by dendritic cells which in turn activates T cells. Methods: The phase 1 portion of this first-in-human, phase I/IIa study (NCT05669430) was conducted across multiple U.S. centers. The study utilized a standard 3+3 design to evaluate the safety, pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary efficacy of GV20-0251, and to establish a preliminary recommended phase 2 dose (RP2D). Results: Forty-two patients with advanced solid tumors (median age 61 years, median 4 prior treatment lines) were enrolled across six dose levels (0.5, 1, 3, 6, 10, and 20 mg/kg) and two schedules (D1/D8 Q3W and D1 Q3W). GV20-0251 demonstrated favorable safety and tolerability across all doses and schedules with no dose-limiting toxicities, and 10 and 20 mg/kg D1 Q3W were selected as the preliminary RP2D. Treatment-related adverse events occurred in 55% of patients, predominately grade 1/2, with a single grade 3 event of pneumonitis. The most common treatment-related AEs were fatigue and rash (12% each), with no dose-dependent trends. Full target occupancy and half-life of 26 days with linear PK were observed at ≥10 mg/kg, without significant serum cytokine elevation or anti-drug antibody signals. Among 38 efficacy-evaluable patients, 17 had cutaneous melanoma, all of whom progressed on prior anti-PD1 therapy and 16 progressed on prior anti-CTLA4 therapy. Among the 9 melanoma patients with primary resistance to anti-PD1, confirmed partial response (PR) was achieved in 3 (33%) patients and tumor shrinkage was observed in an additional 3 patients. Notably, responses were observed in 2 patients with liver metastases, which are typically refractory to immunotherapy. Although no responses were seen in the melanoma patients with acquired resistance to anti-PD1 (n = 8) or in patients with other tumor types (n = 21), potentially due to the lower frequency of IGSF8 protein expression in these tumors, tumor shrinkage was observed in one non-small cell lung cancer (n = 4) and one cervical cancer (n = 1) patient. Preliminary immunohistochemistry analyses of trial patient biopsies suggest IGSF8 high tumors have low anti-PDL1 at baseline, and GV20-0251 treatment increases tumor-infiltrating NK and T cells. Conclusions: GV20-0251 demonstrated a favorable safety profile in heavily pretreated patients with advanced solid tumors and showed promising monotherapy efficacy in cutaneous melanoma patients with primary resistance to anti-PD1. Clinical trial information: NCT05669430 .