1045P Safety and preliminary clinical activity of JNJ-78306358 (JNJ-358), an HLA-G and CD3 bispecific antibody, for the treatment of advanced stage solid tumor

HLA-G has limited normal tissue expression but is expressed in a variety of human cancers where it may have an immune evasion function. JNJ-6358 is a bispecific antibody that redirects T cells to kill HLA-G-expressing tumor cells. This phase 1 dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-6358 administered subcutaneously to adult participants (pts) with metastatic or unresectable solid tumors with a high prevalence of HLA-G expression: renal cell carcinoma (RCC), ovarian cancer (OC), and colorectal cancer (CRC). Dose escalation followed a modified continual reassessment method. As of 09 February 2023, 39 pts (23 with CRC, 10 with OC, and 6 with RCC) were dosed once weekly in 7 cohorts. Premedication included high dose corticosteroids. The majority of pts (54%) had 4 or more prior lines of systemic therapy for metastatic disease. The most common treatment-emergent adverse events were cytokine release syndrome (CRS) (49%), ALT/AST increase (39%), injection site erythema (39%), fatigue (36%), and abdominal pain (26%). CRS was G1 or G2 and responded to tocilizumab. Dose limiting toxicities (DLTs) were reported in 4 pts, 2 with G3 increased transaminases, 1 with G3 pneumonitis, and 1 with recurrent G1 CRS requiring dose reduction. G3 DLTs coincided with CRS. No treatment related deaths were reported. There were no objective responses per RECIST. Target lesion reduction >10% from baseline was observed in 5 pts. Two pts had stable disease >40 weeks. HLA-G was detected (IHC H-score > 0) in archival tissue from 12 of 25 pts. No relationship between tumor reduction and baseline HLA-G expression was observed. JNJ-6358 exposure levels increased with dose. Anti-drug antibodies (ADA) were observed in 45% of evaluable pts and were associated with loss of detectable exposure. JNJ-6358 dose escalation was limited by CRS-associated toxicities, which were only partially mitigated by step-up-dosing and premedication. Considering the CRS-related toxicities and the ADA formation, the Sponsor decided to halt dose escalation. No recommended phase 2 dose was determined.