Davoceticept (ALPN-202), a PD-L1-dependent CD28 costimulator and dual checkpoint inhibitor, in combination with pembrolizumab in patients with advanced malignancies (NEON-2).

Abstract

TPS2683 Background: Despite successes with checkpoint inhibition (CPI) in a wide range of tumors, most demonstrate primary or acquired resistance, warranting better therapeutic strategies. PD-1 is now recognized to effect much of its benefit by disinhibiting CD28 signaling – a mechanism expected to require intra-tumoral engagement of CD28 by its ligands CD80/CD86. Davoceticept (ALPN-202), a variant CD80 vIgD-Fc fusion protein, was engineered to provide tumor localizing PD-L1-dependent CD28 agonism, while inhibiting PD-L1 and CTLA-4. Davoceticept has demonstrated superiority to CPI-only therapies in both in vitro and in vivo tumor models, while also demonstrating additional benefit in combination with targeted PD-1 axis blockade (Lewis et al. (2019) J Immunother Cancer 7(S1): P467). The benefit appeared at least additive in models of poorly immunogenic tumors, suggesting the possibility of meaningful clinical benefit where CPI therapeutic efficacy is limited, such as noninflamed tumors. Single agent safety and tolerability of davoceticept has been demonstrated along with pharmacodynamic evidence of CD28 engagement with immune checkpoint inhibition (Moser et al. (2021) J Clin Oncol 39(s15): 2547). Methods: NEON-2 is an open-label dose escalation and expansion study of davoceticept combined with pembrolizumab in adults with advanced solid tumors or lymphoma that was initiated in June 2021 (NCT04920383). Eligibility includes tumors where single agent PD-(L)1 antagonists are SOC, are refractory or resistant to standard therapies (including approved CPIs), or have no standard or curative therapy. The study employs a standard 3+3 dose escalation design with two schedules, Q1W and Q3W of davoceticept. Pembrolizumab is given per label at 400 mg IV Q6W. Objectives include evaluation of safety and tolerability, identification of the recommended phase 2 dose(s) (RP2D), PK, PD, exploratory predictive biomarker analysis (i.e., PD-L1, CD28, CD80 and CD86 expression, as well as immunophenotyping of immune cell populations on treatment) and preliminary anticancer activity of davoceticept in combination with pembrolizumab. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma. Efficacy endpoints include ORR, duration of response and disease control rate. Once the RP2D combination is identified, tumor-specific expansion cohorts of ̃ 30- 35 patients will be performed, including histologies that have not been demonstrated to be CPI responsive, as well as those where CPIs are approved SOC. The 0.1 mg/kg cohorts have been completed without DLT. Enrollment to the 0.3 mg/kg cohorts began in September 2021. Clinical trial information: NCT04920383.