Safety and Efficacy Study of GEN1046 as a Single Agent or in Combination With Pembrolizumab for Treatment of Recurrent (Non-small Cell) Lung Cancer

A Phase 2, Multicenter, Randomized, Open-Label Trial of GEN1046 as Monotherapy and in Combination Pembrolizumab Therapy in Subjects With Relapsed/Refractory Metastatic Non-Small Cell Lung Cancer After Treatment With Standard of Care Therapy With an Immune Checkpoint Inhibitor

The goal of this clinical trial is to compare the safety and efficacy (how well the drug works) of acasunlimab (also known as GEN1046) when it is used alone (monotherapy) versus when it is combined with a cancer drug (pembrolizumab) for participants with relapsed/refractory (disease has returned after treatment or did not respond to treatment) non-small cell lung cancer (NSCLC; the most common type of lung cancer).

This trial has 2 parts. The purpose of the first part is to find out if the combination of acasunlimab and pembrolizumab is safe and to find out the best doses to use. The purpose of the second part is to give acasunlimab and pembrolizumab to more participants to evaluate efficacy. In the second part of the trial, participants will be randomized to participate in 1 of the 3 arms of the trial. Randomized means that the participant will be randomly assigned to a treatment arm based on chance; no one chooses their treatment arm.

Participants will receive either acasunlimab alone (100 followed by 500 mg into the vein) or acasunlimab with pembrolizumab (200 or 400 mg into the vein) once every 3 or 6 weeks, depending on which arm the participant is randomized into. All participants will receive active drug; no one will receive placebo.

Trial details include:

• The average trial duration for an individual participant will be about 10 months.
• The average treatment duration for an individual participant will be about 6 months.
• The visit frequency will be weekly at first and lessening over time until visits are only once every 3 weeks.

Study Overview

• Status: Active, not recruiting
• Conditions: Non Small Cell Lung Cancer Metastatic
• Intervention / Treatment: Biological: Acasunlimab; Biological: Pembrolizumab

Detailed Description

This trial is a randomized, open-label trial evaluating the safety and efficacy of acasunlimab (GEN1046) as monotherapy and in combination therapy with pembrolizumab.

The trial consists of two parts; a safety phase and an extension phase. The extension phase will be initiated once the safety phase is completed.

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bordeaux, France
    • Institut Bergonie
  • Brest, France
    • Hopital Morvan CHU de Brest
  • Rouen, France
    • Hopital Charles Nicolle Chu Rouen
  • Saint-Mandé, France
    • Hopital dInstruction Des Armees Begin
  • Strasbourg, France
    • Institut de Cancerologie Strasbourg Europe (ICANS)
  • Suresnes, France
    • Hôpital Foch
  • Villejuif, France
    • Gustave Roussy
• Germany
  • Hanover, Germany
    • Med.Hochschule Hannover Klinik für Pneumologie
  • Hessen, Germany
    • Universitatsklinik Giessen und Marburg Standort Giessen
  • Immenhausen, Germany
    • LKI Lungenfachklinik Immenhausen
  • Regensburg, Germany
    • Department of Internal Medicine II
• Italy
  • Catania, Italy
    • Azienda Ospedaliera Universitaria Policlinico G Rodolico San Marco
  • Milan, Italy
    • IRCCS Istituto Europeo di Oncologia
  • Naples, Italy
    • UOC Oncoematologia AOU L.Vanvitelli
  • Palermo, Italy
    • La Maddalena SPA
  • Roma, Italy
    • IFO Regina Elena
• Netherlands
  • Amsterdam, Netherlands
    • VU University Medical Center
  • Amsterdam, Netherlands
    • Netherlands Cancer Institute
  • Leiden, Netherlands
    • Leids Universitair Medisch Centrum
  • Rotterdam, Netherlands
    • Erasmus MC
• Poland
  • Olsztyn, Poland
    • Samodzielny Publiczny Zespol Gruzlicy i Chorob Pluc
  • Warsaw, Poland
    • Maria Sklodowska-Curie National Research Institute of Oncology
• Portugal
  • Lisbon, Portugal
    • Centro Clinico Champalimaud
  • Porto, Portugal
    • Centro Hospitalar Universitario do Porto - Hospital de Santo Antonio
• Spain
  • Barcelona, Spain
    • Hospital Universitari Vall dHebron
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital Universitario Fundación Jiménez Díaz
  • Madrid, Spain
    • MD Anderson Cancer Center
  • Madrid, Spain
    • Clinica Universidad de Navarra CUN
  • Málaga, Spain
    • Hospital Universitario Virgen de la Victoria
  • Pamplona, Spain
    • Clinica Universidad de Navarra
  • Valencia, Spain
    • Fundación Instituto Valenciano de Oncología
• United Kingdom
  • Cheltenham, United Kingdom
    • Cheltenham General Hospital
  • Manchester, United Kingdom
    • The Christie Hospital
• United States
  • California
    • Santa Rosa, California, United States, 95403
      • St. Joseph Heritage Healthcare
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists - FCS South
    • St. Petersburg, Florida, United States, 33705
      • Florida Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Cancer Institute
    • Grand Rapids, Michigan, United States, 49503
      • Cancer & Hematology Centers of Western Michigan CHCWM P.C.
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Have signed an informed consent form (ICF)
• Be at least 18 years of age.
• Have histologically or cytologically confirmed diagnosis of stage 4 NSCLC with at least 1 prior line of systemic therapy containing an anti-PD-1/PD-L1 mAb for metastatic disease
• Have a tumor PD-L1 expression result available prior to first treatment demonstrating PD-L1 expression in ≥1% of tumor cells as assessed by a central or local laboratory during screening.
• Have measurable disease per RECIST v1.1.
• Have Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1.
• Have life expectancy of at least 3 months.
• Have adequate organ and bone marrow function as defined in the protocol.

Key Exclusion Criteria:

• Documentation of known EGFR, KRAS, RET, ROS1, BRAF mutations, NTRK gene infusions, RET arrangement, ALK gene rearrangements, high-level MET amplification, or METex 14 skipping. Note: Subjects harboring such mutations, gene rearrangements or amplifications may be enrolled in the trial, if subjects have received prior approved targeted therapy for such mutations, the subject may still be eligible for this trial.
• Treatment with an anti-cancer agent within 28 days prior to acasunlimab administration.
• Any investigational agent (including investigational vaccines).
• Radiotherapy within 14 days prior to first dose of acasunlimab. Note: palliative radiotherapy will be allowed for local pain control under certain conditions.
• Chronic systemic immunosuppressive corticosteroid doses, ie, prednisone >10 mg daily or a cumulative dose >150 mg prednisone within 14 days before the first acasunlimab administration.
• Subject has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Subject has contraindications to the use of pembrolizumab per local prescribing information.
• Subject has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis (interstitial lung disease).
• Ongoing or active infection requiring intravenous treatment with anti-infective therapy or any ongoing systemic inflammatory condition requiring further diagnostic work-up or management during screening.
• Symptomatic congestive heart failure (grade III or IV as classified by the New York Heart Association), unstable angina pectoris, or cardiac arrhythmia.
• Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, despite optimal medical management.
• Ongoing or recent (within 6 months) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for irAEs.

• Subject has a known history of any of the following:

  1. Grade 3 or higher irAEs that led to treatment discontinuation of a prior immunotherapy treatment.
  2. Myositis, Guillain-Barré syndrome, or myasthenia gravis of any grade.
  3. Liver disease (eg, alcoholic hepatitis or non-alcoholic steatohepatitis, drug-related or autoimmune hepatitis, or evidence of hepatic cirrhosis).
  4. Organ allograft (except for corneal transplant) or autologous or allogeneic bone marrow transplant, or stem cell rescue within 3 months prior to the first dose of acasunlimab.
  5. Grade 3 or higher allergic reactions to monoclonal antibody therapy as well as known or suspected allergy or intolerance to any agent given in the course of this trial.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Treatment with acasunlimab once every 21 days for the first 2 cycles and then every 42 days in subsequent cycles	Biological: Acasunlimab; Acasunlimab will be administered intravenously (IV); Other Names: DuoBody®-PD-L1×4-1BB; GEN1046
Experimental: Arm B; Treatment with acasunlimab + pembrolizumab once every 21 days	Biological: Acasunlimab; Acasunlimab will be administered intravenously (IV); Other Names: DuoBody®-PD-L1×4-1BB; GEN1046; Biological: Pembrolizumab; Pembrolizumab will be administered IV; Other Names: KEYTRUDA®
Experimental: Arm C; Treatment with acasunlimab + pembrolizumab once every 42 days	Biological: Acasunlimab; Acasunlimab will be administered intravenously (IV); Other Names: DuoBody®-PD-L1×4-1BB; GEN1046; Biological: Pembrolizumab; Pembrolizumab will be administered IV; Other Names: KEYTRUDA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	ORR will be measured as the proportion of subjects with a confirmed response of complete response (CR) or partial response (PR) as per RECIST v1.1	From first treatment to approximately 27 weeks after last subject's first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response (DOR)	DOR will be measured as the time from initial onset of CR or PR to first radiographic progression as per RECIST v. 1.1 or death from any cause, whichever occurs first.	From onset date of response until disease progression/death/lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first (an expected average of 6 months)
Time to response (TTR)	TTR will be measured as the time from first treatment to onset of initial response (CR or PR) as per RECIST v.1.1	From first treatment to date of onset of initial response (CR or PR) as per RECIST v.1.1 (an expected average of 6 months)
Progression-free survival (PFS)	PFS will be measured from date of first treatment until date of radiographic progression as per RECIST v.1.1 or until death from any cause, whichever occurs first	From first treatment to first documented progression or death due to any cause (an expected average of 6 months)
Overall survival (OS)	Defined as time to death from of any cause	From first treatment to date of death (assessed up to 3 years after the last participant's first dose in the trial)
Incidence and severity of adverse events (AEs) and laboratory abnormalities	Incidence of treatment-emergent AEs as assessed by CTCAE v5.0. Laboratory parameters graded by CTCAE v5.0	Throughout the trial until end of safety follow-up period (60 days or 90 days after last dose)

Collaborators and Investigators

• Sponsor: Genmab
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Study Official, Genmab

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2021
• Primary Completion (Actual): December 2, 2024
• Study Completion (Estimated): August 30, 2026

Study Registration Dates

• First Submitted: November 1, 2021
• First Submitted That Met QC Criteria: November 10, 2021
• First Posted (Actual): November 11, 2021

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: PD-L1; Bispecific antibody; 4-1BB; DuoBody®
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab
• Other Study ID Numbers: GCT1046-04; 2021-001928-17 (EudraCT Number); 1004314 (Other Identifier: IRAS ID; UK Research Summaries Database); NL-OMON54259 (Registry Identifier: CCMO (The Netherlands)); 2024-513770-22-00 (Other Identifier: EU Trial (CTIS) Number); RECF-005102 (Registry Identifier: National Institute of Cancer France); 15582 (Registry Identifier: Portugal RNET)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No