493 First-in-human phase 1/2 trial to evaluate the safety and initial clinical activity of DuoBody®-CD40×4–1BB (GEN1042) in patients with advanced solid tumors (2021)

<h3>Background</h3> Despite the preclinical promise of CD40 and 4-1BB as immuno-oncologic targets, clinical efforts evaluating these agonists as monotherapy have had limited success due to minimal efficacy and/or severe toxicity. DuoBody-CD40×4-1BB (GEN1042) is a first-in-class, bispecific, agonistic antibody that combines targeting and conditional activation of CD40 and 4-1BB on immune cells, resulting in enhanced priming and (re-)activation of tumor-specific immunity. Furthermore, preclinical data suggest that combination with anti–PD-1 can enhance antitumor activity. We present preliminary data from the ongoing, first-in-human, open-label, phase 1/2 trial of DuoBody-CD40×4-1BB in advanced solid tumors (NCT04083599). <h3>Methods</h3> During dose escalation, patients with metastatic/unresectable non-CNS solid tumors who had exhausted standard therapies received flat-dose DuoBody-CD40×4-1BB (0.1–400 mg) intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included adverse events (AEs), pharmacokinetic parameters, and preliminary antitumor activity (RECIST v1.1). Pharmacodynamic biomarkers were assessed as exploratory endpoints. <h3>Results</h3> As of June 11, 2021, 50 patients were enrolled (median age, 57 years). The most common cancer types were colorectal (22%), melanoma (20%), and non–small-cell lung cancer (8%). Patients received a median (range) of 2.5 (1–21) treatment cycles; Cmax was observed shortly after end of infusion. Treatment-related AEs occurring in ≥10% of patients (all grades; grade ≥3) were fatigue (22%; 0%), pyrexia (16%; 0%), nausea (10%; 0%), and transaminase elevation (10%; 6%). Maximum tolerated dose was not reached. One DLT of elevated transaminases (grade 4) was observed at the 200-mg dose that resolved upon corticosteroid administration. No drug-related grade ≥3 thrombocytopenia events were reported. Disease control, defined as best overall response of complete/partial response and stable disease, was achieved in 51% of patients (25/49), including 2 confirmed partial responses per RECIST v1.1 in melanoma and neuroendocrine lung cancer. Modulation of pharmacodynamic endpoints was observed across dose levels, with more pronounced effects near the 100-mg dose. Increases in peripheral IFN-y, TARC (monocyte/DC chemokine), and proliferating CD8+ total and effector memory T cells were observed during cycle 1. Using physiologically based pharmacokinetic/pharmacodynamic modeling and available safety, efficacy, and pharmacodynamic data, 100 mg every 3 weeks was identified as the expansion dose for further evaluation. <h3>Conclusions</h3> DuoBody-CD40×4-1BB demonstrated biologic and early antitumor activity with a favorable safety profile in patients with advanced solid tumors. Expansion cohorts, including combination therapy with PD-1 inhibitors, are currently enrolling. <h3>Acknowledgements</h3> This trial was funded by Genmab A/S and BioNTech SE. <h3>Trial Registration</h3> NCT04083599 <h3>Ethics Approval</h3> This trial is undertaken following full approval of the final protocol, amendments, informed consent form, applicable recruiting materials, and subject compensation programs by the Independent Ethics Committee/Institutional Review Board.