acasunlimab (GEN1046) / Genmab - LARVOL DELTA

GCT1046-04: Safety and Efficacy Study of GEN1046 as a Single Agent or in Combination With Pembrolizumab for Treatment of Recurrent (Non-small Cell) Lung Cancer (clinicaltrials.gov) - P2 | N=125 | Terminated | Sponsor: Genmab | Active, not recruiting ➔ Terminated; Genmab has decided to discontinue further clinical development of acasunlimab following strategic portfolio prioritization. The decision was not related to safety concerns.

Checkpoint inhibition • Monotherapy • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

GEN1046 Safety Trial in Patients With Malignant Solid Tumors (clinicaltrials.gov) - P1/2 | N=429 | Terminated | Sponsor: Genmab | Active, not recruiting ➔ Terminated; Genmab has decided to discontinue further clinical development of acasunlimab following strategic portfolio prioritization. The decision was not related to safety concerns.

First-in-human • Trial termination • Oncology • Solid Tumor

A phase 1 dose-finding and pharmacokinetic study of acasunlimab alone or in combination with pembrolizumab in Japanese patients with advanced or metastatic solid tumors. (PubMed, Int J Clin Oncol) - "Acasunlimab demonstrated a manageable safety profile, with comparable pharmacokinetics in Japanese and non-Japanese patients. Antitumor activity was demonstrated in a small number of patients with diverse tumor types."

Journal • P1 data • PK/PD data • Oncology • Solid Tumor

Study of the Effectiveness and Safety of Acasunlimab Alone and With Pembrolizumab to Treat Advanced Melanoma of the Skin That Has Returned After Treatment With an Approved Checkpoint Inhibitor Therapy (ABBIL1TY MELANOMA-07) (clinicaltrials.gov) - P2 | N=1 | Terminated | Sponsor: Genmab | Trial completion date: Jul 2029 ➔ May 2026 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jul 2027 ➔ May 2026; Genmab has decided to discontinue further clinical development of acasunlimab following strategic portfolio prioritization. The decision was not related to safety concerns.

Checkpoint inhibition • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

Cross-presentation and PD-L1 expression by cDC1s are key for efficacy of a PD-L1×4-1BB bispecific (CIMT 2026) - "Acasunlimab (GEN1046), a PD-L1×4-1BB bispecific antibody, has shown promising clinical activity in non-small cell lung cancer patients refractory to immune checkpoint inhibitors...As a consequence, CD8 T cells abundantly infiltrate the tumor microenvironment and when contacted by cDC1 are transcriptionally poised to proliferate. Expanding dendritic-cell numbers with Fms-like tyrosine kinase 3 ligand (Flt3L) treatment in combination with the PD-L1×4- 1BB bispecific antibody achieved remarkable synergistic tumor control."

Bispecific • Clinical • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • CD40LG • CD8 • FLT3 • IL12A • PD-L1

GCT1046-04: Safety and Efficacy Study of GEN1046 as a Single Agent or in Combination With Pembrolizumab for Treatment of Recurrent (Non-small Cell) Lung Cancer (clinicaltrials.gov) - P2 | N=125 | Active, not recruiting | Sponsor: Genmab | Trial completion date: May 2027 ➔ Aug 2026

Checkpoint inhibition • Monotherapy • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

GEN1046 Safety Trial in Patients With Malignant Solid Tumors (clinicaltrials.gov) - P1/2 | N=429 | Active, not recruiting | Sponsor: Genmab | Trial completion date: Feb 2026 ➔ Aug 2026

First-in-human • Trial completion date • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

Molecular profiling of NSCLC patients associates CT-based radiomic features with a tumor microenvironment favorable for immunotherapy (AACR 2025) - P1/2, P2 | "Here, we integrate radiomics with tumor transcriptomic profiles to enhance biological interpretation of CT-based features linked to an immune-responsive tumor microenvironment (TME), in non-small cell lung cancer (NSCLC) treated with acasunlimab, a DuoBody® PD-L1×4-1BB bispecific antibody, +/- pembrolizumab.This study used contrast-enhanced CT images (n=62) and gene expression (HTG EdgeSeq) from tumor biopsies (n=25) of advanced NSCLC subjects in GCT1046-01 (NCT03917381) and GCT1046-04 (NCT05117242). Gabor was negatively correlated with cancer associated fibrosis and extracellular matrix remodeling.These results show that integrating radiomics with tumoral mRNA data identified key characteristics of a TME conducive for immunotherapy, advancing the interpretability of AI-derived imaging features. The composite radiomics score was independent of traditional prognostic factors and reflected immunotherapy-specific mechanisms, highlighting its potential..."

Biomarker • Clinical • IO biomarker • Tumor microenvironment • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

PRO-CTCAE item selection to assess patient-reported tolerability in the context of a phase III clinical trial of patients with non-small cell lung cancer (NSCLC) (ELCC 2026) - P2 | "Symptomatic AEs were selected based on their frequency in an unbiased manner so as to not favor one treatment regimen over another.Conclusions This study systematically identified the most relevant symptomatic AEs in patients with NSCLC receiving acasunlimab, pembrolizumab, and/or docetaxel, balancing comprehensive symptom capture with reduction of patient-reported burden. These findings support the targeted use of PROs to enhance benefit-risk evaluation and better inform clinical decision-making in lung cancer trials."

Clinical • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Translational analysis of acasunlimab in combination with pembrolizumab in CPI-treated metastatic NSCLC (ELCC 2026) - P2, P3 | "Intermittent 4-1BB target engagement with Q6W provided a T-cell rest period that was associated with reduced on-treatment frequency of CD8 effector memory T cell subsets expressing exhaustion markers (LAG3, TIM3, CD39) in patients treated with Q6W vs Q3W combo regimen. Greater induction of pro-inflammatory markers (CXCL10, TNFA) in cycle 2 was seen in patients with OS >12 m vs those with OS <12 m on Q6W combo (p<0.1; n=10), indicating better T-cell functionality in patients with durable benefit.Conclusions These translational results indicate biological and clinical activity of acasunlimab + pembro in PD-L1+ mNSCLC, supporting a less frequent dosing paradigm (Q6W) to reinvigorate and maintain T-cell functionality post-CPI."

Combination therapy • IO biomarker • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • CD8 • CXCL10 • ENTPD1 • HAVCR2 • KEAP1 • KRAS • LAG3 • TNFA

Proactive management of immune-related hepatic events in a phase II trial of acasunlimab plus pembrolizumab in patients with mNSCLC (ELCC 2026) - P2 | "Similar trends were observed in Arm C. Table: 111P Baseline characteristics of patients included in the PMIR Total at risk, N (%) Variable Category Pre PMIR Post PMIR Total patients - 84 (100) 41 (100) Baseline ECOG PS 0 28 (33.3) 16 (39.0) 1 56 (66.7) 25 (61.0) Sex F 36 (42.9) 15 (36.6) Age group ≥65 yrs 45 (53.6) 20 (48.8) ECOG PS, Eastern Cooperative Oncology Group performance status; PMIR, Proactive Management of Immune-Related Risk. Conclusions PMIR implementation resulted in lower rates of Grade ≥3 hepatic events in this ph 2 study of Aca, suggesting increased awareness and proactive management may translate to better safety outcomes."

Clinical • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • PD-L1

Patient-reported outcomes with acasunlimab monotherapy and in combination with pembrolizumab: Results from a phase II study of PD-L1+ mNSCLC (ELCC 2026) - P2 | "Table: 109P Changes in global HRQoL and mean symptom scores from baseline to wk 12 in arms A, B, and C Change (Mean ± SD) Arm A Arm B Arm C Global HRQoL –16.7 ± 52.7 –18.3 ± 12.4 +1.8 ± 20.7 Symptom scales Cougha 0.0 ± 27.2 0.0 ± 27.2 –5.1 ±18.5 Dyspneaa,b –5.6 ± 11.1 0.0 ± 18.1 –10.3 ± 25.8 Sore moutha 41.7 ± 31.9 0.0 ± 0.0 –2.6 ± 9.2 Appetite lossc 16.7 ± 19.2 13.3 ± 29.8 –2.4 ±15.8 Pain in chesta 0.0 ± 0.0 0.0 ± 27.2 7.7 ±14.6 Fatiguec 16.7 ± 21.3 13.3 ± 12.2 7.1 ± 30.4 Constipationc –8.3 ± 31.9 0.0 ± 23.6 7.1 ± 29.8 aEvaluated through QLQ-LC-13; bOnly dyspnea reached the threshold for clinically meaningful improvement; cEvaluated through QLQ-C30. Conclusions The PRO results corroborate the clinical findings demonstrating that the Q6W combination regimen (ACA + PEM, Arm C) showed more favorable outcomes compared with the Q3W combination..."

Clinical • Combination therapy • Monotherapy • P2 data • Patient reported outcomes • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • PD-L1

GCT1046-07: Study of the Effectiveness and Safety of Acasunlimab Alone or With Pembrolizumab in treating Advanced Melanoma of the Skin That Has Returned After or did not respond to Cancer Immunotherapy (ABBIL1TY MELANOMA-07) (clinicaltrialsregister.eu) - P1/2 | N=129 | Completed | Sponsor: Genmab A/S

Checkpoint inhibition • Monotherapy • New P1/2 trial • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06) (clinicaltrials.gov) - P3 | N=190 | Active, not recruiting | Sponsor: Genmab | N=702 ➔ 190 | Trial completion date: Oct 2029 ➔ Sep 2028 | Trial primary completion date: Jun 2028 ➔ Jul 2027

Enrollment change • Head-to-Head • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06) (clinicaltrials.gov) - P3 | N=702 | Active, not recruiting | Sponsor: Genmab | Recruiting ➔ Active, not recruiting

Enrollment closed • Head-to-Head • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of the Effectiveness and Safety of Acasunlimab Alone and With Pembrolizumab to Treat Advanced Melanoma of the Skin That Has Returned After Treatment With an Approved Checkpoint Inhibitor Therapy (ABBIL1TY MELANOMA-07) (clinicaltrials.gov) - P2 | N=1 | Active, not recruiting | Sponsor: Genmab | N=90 ➔ 1

Checkpoint inhibition • Enrollment change • Monotherapy • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06) (clinicaltrials.gov) - P3 | N=702 | Recruiting | Sponsor: Genmab | Trial primary completion date: Jan 2027 ➔ Jun 2028

Head-to-Head • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Genmab Portfolio Prioritization Update (Businesswire) - "Genmab...announced today that it will discontinue further clinical development of acasunlimab. This decision was made as part of Genmab’s strategic focus on the most value‑creating opportunities in its late‑stage portfolio and following a thorough assessment of the evolving competitive landscape. While the clinical profile observed to date has been encouraging, Genmab will concentrate resources on programs with the highest potential impact, including EPKINLY (epcoritamab), petosemtamab and rinatabart sesutecan (Rina‑S), which are advancing in late‑stage development."

Discontinued • Pipeline update • Diffuse Large B Cell Lymphoma • Endometrial Cancer • Follicular Lymphoma • Melanoma • Non Small Cell Lung Cancer • Ovarian Cancer • Squamous Cell Carcinoma of Head and Neck

Acasunlimab monotherapy or with pembrolizumab in CPI-treated mNSCLC: Primary Phase 2 results (ESMO-IO 2025) - P2, P3 | "Safety was manageable, with generally reversible hepatic events. The Q6W regimen offered better tolerability, durability of response, and survival, supporting its evaluation in the ongoing Ph3 trial (NCT06635824).Editorial acknowledgement Editorial writing support provided by Suparna Mukherjee, PhD of Syneos Health."

Monotherapy • P2 data • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of the Effectiveness and Safety of Acasunlimab Alone and With Pembrolizumab to Treat Advanced Melanoma of the Skin That Has Returned After Treatment With an Approved Checkpoint Inhibitor Therapy (ABBIL1TY MELANOMA-07) (clinicaltrials.gov) - P2 | N=90 | Active, not recruiting | Sponsor: Genmab | Recruiting ➔ Active, not recruiting

Checkpoint inhibition • Enrollment closed • Monotherapy • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

Study of the Effectiveness and Safety of Acasunlimab Alone and With Pembrolizumab to Treat Advanced Melanoma of the Skin That Has Returned After Treatment With an Approved Checkpoint Inhibitor Therapy (ABBIL1TY MELANOMA-07) (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Genmab | Not yet recruiting ➔ Recruiting

Checkpoint inhibition • Enrollment open • Monotherapy • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

Study of the Effectiveness and Safety of Acasunlimab Alone and With Pembrolizumab to Treat Advanced Melanoma of the Skin That Has Returned After Treatment With an Approved Checkpoint Inhibitor Therapy (ABBIL1TY MELANOMA-07) (clinicaltrials.gov) - P2 | N=90 | Not yet recruiting | Sponsor: Genmab

Checkpoint inhibition • Monotherapy • New P2 trial • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

GEN1046 Safety Trial in Patients With Malignant Solid Tumors (clinicaltrials.gov) - P1/2 | N=429 | Active, not recruiting | Sponsor: Genmab | Trial primary completion date: Feb 2026 ➔ Apr 2025

Trial primary completion date • Breast Cancer • Cervical Cancer • Endometrial Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer

Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity via complementary immune modulatory effects. (PubMed, J Immunother Cancer) - P2, P3 | "These preclinical results demonstrate that conditional 4-1BB stimulation combined with complete PD-1 blockade enhances antitumor immunity through complementary mechanisms. The acasunlimab and pembrolizumab combination is being evaluated in Phase 2 (NCT05117242) and pivotal Phase 3 (NCT06635824) trials in patients with metastatic non-small cell lung cancer after checkpoint inhibitor therapy failure."

Journal • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • GZMB • IFNG • IL2 • PD-L2

ABBIL1TY NSCLC-06: A global, randomized, open-label, phase III trial of acasunlimab in combination with pembrolizumab (Pembro) vs docetaxel in checkpoint inhibitor (CPI)-experienced patients with PD-L1+ metastatic non-small cell lung cancer (mNSCLC) (ELCC 2025) - P2, P3 | "Secondary endpoints include progression-free survival, objective response rate, duration of response, patient-reported outcomes, and occurrence of AEs. The trial is currently enrolling."

Checkpoint inhibition • Clinical • Combination therapy • IO biomarker • Metastases • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • PD-L1 • ROS1