GCT1046-04

Key outcome parameters

Primary endpoints:

• Objective response rate (ORR) per RECIST v1.1

Secondary endpoints:

• Duration of response (DOR) per RECIST v1.1
• Time to response (TTR) per RECIST v1.1
• Progression-free survival (PFS) per RECIST v1.1
• Overall survival (OS)
• Incidence and severity of adverse events (AEs)
• Incidence and severity of laboratory abnormalities

Exploratory endpoints

• Exploratory analyses of biomarkers associated with clinical benefit of GEN1046 as monotherapy and in combination with pembrolizumab
• GEN1046 PK concentrations and antidrug antibodies associated with GEN1046
• Change from baseline in all domain and single-item scores of:
  • EORTC QLQ-C30
  • EORTC QLQ-LC13
  • EQ-5D-5L
• EQ-5D Index
• Progression-free survival 2: Time from first infusion to objective tumor progression on next-line treatment or death from any cause
• iORR, iPFS, and iDOR per Irecist
• Reasons selected for choice of opting-in/opting-out of remote visits at baseline
• Subject scores assessing experience, understanding, satisfaction, comfort, and burden of remote visits and clinic/hospital visits at Cycle 3 and Cycle 4
• Subject scores of preference and likelihood to recommend clinic/hospital vs remote visit at end of Cycle 4
• Subject scores assessing expectations at Cycle 3 and Cycle 4

Intervention

• ARM A – GEN1046 100 mg Q3W for the first 2 cycles followed by GEN1046 500 mg Q6W for vthe subsequent cycles
• ARM B -GEN1046 100 mg Q3W in combination with pembrolizumab 200 mg Q3W
• ARM C – GEN1046 100 mg Q6W in combination with pembrolizumab 400 mg Q6W

Key inclusion criteria

Inclusion criteria:

• Subject must be at least 18 years of age
• Subject has 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 monoclonal antibody (mAb). Subjects must have demonstrated disease progression (PD) as defined by RECIST v1.1. For the subjects whose most recent anti-cancer therapy contained an anti-PD-1/PD-L1 mAb, their recent evidence of PD must be confirmed by a second assessment no less than 4 weeks from the date of the initial documented PD. Note: Subject must have received at least 2 doses of an approved anti PD-1/PD-L1 mAb approved in NSCLC
• Subject has progressed during or after treatment with 1 anti-PD-1/PD-L1 nmAb administered either as monotherapy, or as SOC combination (subjects who have received only anti-PD-1/PD-L1 mAb monotherapy as first-line therapy, are eligible for this study if the investigator determines treatment with platinum-containing chemotherapy is not appropriate, in line withlocal treatment guidelines) or
• Subject has progressed during or after platinum doublet chemotherapy following an anti-PD-1/PD-L1 mAb or
• Subject has progressed during or after an anti-PD-1/PD-L1 following platinum doublet chemotherapy
• Subject must have a tumor PD-L1 expression result available prior to C1D1 demonstrating PD-L1 expression in ≥1% of tumor cells as assessed by a sponsor designated central laboratory using the Dako PD-L1 IHC 22C3 pharmDx assay (TPS≥1%), or per site local assessment with the Dako PD-L1 IHC 22C3 pharmDx assay (TPS≥1%) or the VENTANA PD-L1 (SP263) assay (TC ≥1%) adhering to the manufacturer’s instructions. Note: Local PD-L1 result needs to be performed on fresh tumor tissue (obtained within 3 months prior to enrollment and after failure/stop of last prior treatment) or, if not feasible, archival tissue (obtained within 12 months prior to enrollment)
• Subject must have measurable disease per RECIST v1.1 as assessed by the investigator
• Subject must have ECOG PS ≤1
• Subject must have life expectancy of at least 3 months.
• Subject must have adequate organ and bone marrow function as described in the protocol.

Key exclusion criteria

Exclusion criteria:

• Documentation of known EGFR sensitizing mutations, KRAS, RET, ROS1, BRAF mutations, NTRK gene infusions, RET rearrangement, ALK gene rearrangements, high level MET amplification, or METex 14 skipping. If documentation of mutation status is not available, for subjects with non-squamous histology or a mixed histology of non-squamous and squamous, a formalin-fixed, paraffin-embedded tumor tissue should be tested for biomarker panel analysis (which may include, but is not limited to, EGFR,ALK, ROS1, BRAF, KRAS mutations, RET rearrangement, or NTRK gene infusions,etc.). Subjects must not be randomized until biomarker status is available in source documentation at the site

Note: Subjects with tumors harboring such targetable mutations, gene rearrangements, or gene amplifications as described above may enroll              in the trial, if such subjects have also received an approved targeted therapy for this indication assuming satisfactory fulfilment of all other                  eligibility criteria (especially, at least 1 prior line of systemic therapy containing an anti-PD-1/PD-L1 mAb for metastatic NSCLC disease)

• Subject has been exposed to any of the following prior therapies:
  • Prior treatment with docetaxel for NSCLC
  • Prior treatment with a 4-1BB (CD137) targeted agent, any type of antitumor vaccine, or autologous cell immunotherapy
  • Treatment with an anti-cancer agent within 28 days prior to GEN1046 administration
• Subject discontinued treatment due to disease progression within the first 6 weeks of a CPI-containing treatment