acasunlimab (GEN1046)

P1/2, N=429, Active, not recruiting, Genmab | Trial completion date: Oct 2025 --> Feb 2026 | Trial primary completion date: Jan 2025 --> Feb 2026

P3, N=702, Recruiting, Genmab

The study was conducted in accordance with the International Council for Harmonisation E6(R2) guidelines on good clinical practice and the principles of the Declaration of Helsinki. All patients provided written informed consent.

P1, N=18, Active, not recruiting, Genmab | Trial completion date: Nov 2024 --> Aug 2025 | Trial primary completion date: Nov 2024 --> Aug 2025

P2, N=125, Active, not recruiting, Genmab | Recruiting --> Active, not recruiting

P1/2, N=429, Active, not recruiting, Genmab | Trial completion date: Dec 2024 --> Oct 2025 | Trial primary completion date: Jun 2024 --> Jan 2025

P2, N=0, Withdrawn, Genmab | N=80 --> 0 | Initiation date: Apr 2024 --> Oct 2023 | Not yet recruiting --> Withdrawn

Given failures of recent trials in this setting, single-agent chemotherapy remains the main tx option despite limited effectiveness (eg, docetaxel ORR 10–14%) and considerable toxicity. In PD-L1+ pts with mNSCLC following progression on prior CPI tx, acasunlimab + pembro combo showed a manageable safety profile and promising efficacy, with deeper responses and durable disease control in pts treated Q6W. Enrollment is ongoing.

P2, N=160, Recruiting, Genmab | Trial completion date: Jun 2024 --> Mar 2027 | Trial primary completion date: Mar 2024 --> Nov 2024

P1/2, N=429, Active, not recruiting, Genmab | N=752 --> 429

P1, N=18, Active, not recruiting, Genmab | Recruiting --> Active, not recruiting | N=39 --> 18

P1/2, N=752, Active, not recruiting, Genmab | Recruiting --> Active, not recruiting

P2, N=160, Recruiting, Genmab

P1/2, N=752, Recruiting, Genmab

P2, N=80, Recruiting, Genmab | Not yet recruiting --> Recruiting

P2, N=80, Not yet recruiting, Genmab

Mechanistically, animals treated with the combination showed a trend for ≥1.5-fold increase in the average density of CD3+ and CD4+ tumor-infiltrating lymphocytes (TILs), as well as proliferating (Ki67+) and cytotoxic (GZMB+) CD8+ TILs relative to each single agent, consistent with an amplified anti-tumor immune response.  Together, these preclinical results suggest that combining GEN1046-induced conditional 4-1BB stimulation with complete PD-1 blockade can improve the anti-tumor immune response via distinct and complementary immune modulatory effects. The combination of GEN1046 with pembrolizumab is currently being investigated in ongoing clinical studies in patients with advanced NSCLC, who are treatment-naïve (NCT03917381) or have progressed on prior CPI-containing therapy (NCT05117242).

These findings support that patient selection and/or anti–PD-1 combination therapy may lead to improved clinical efficacy. Further analyses are ongoing and updated results will be presented.

GEN1046 induced T-cell proliferation, cytokine production, and antigen-specific T-cell-mediated cytotoxicity superior to clinically approved PD-(L)1 antibodies in human T-cell cultures and exerted potent antitumor activity in transplantable mouse tumor models. In dose escalation of the ongoing first-in-human study in heavily pretreated patients with advanced refractory solid tumors (NCT03917381), GEN1046 demonstrated pharmacodynamic immune effects in peripheral blood consistent with its mechanism of action, manageable safety, and early clinical activity (disease control rate: 65.6% [40/61]), including patients resistant to prior PD-(L)1 immunotherapy.

Further analyses are ongoing and updated results will be presented. Trial Registration NCT03917381

Moreover, DuoBody-PD-L1×4-1BB exhibits anti-tumor activity and induces memory immune responses in vivo. DuoBody-PD-L1×4-1BB is currently being evaluated in patients with advanced solid tumors in a first-in-human clinical trial (NCT03917381).

No abstract available

Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented.

Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented.