Preliminary results of the first-in-human, dose-finding PROCLAIM-CX-072 trial of the PD-L1 Probody therapeutic CX-072 as monotherapy in patients (pts) with advanced solid tumors.

Abstract

BACKGROUND • Programmed cell death ligand 1 (PD-L1) is expressed on many cancer and immune cells; by binding the receptor programmed cell death 1 (PD-1), a negative regulator of T-lymphocyte activation, it can block cancer immune detection 1 • Monoclonal antibodies targeting the PD-pathway and other immunecheckpoint inhibitors have shown anticancer activity in different tumor types 2 • Immune-related adverse events (AEs), including interstitial pneumonitis, colitis, and transaminitis, are known toxicities of PD-1/PD-L1 axisblocking antibodies. These toxicities are considerably higher when dual checkpoint inhibition is implemented 2-6

Model‐Informed Drug Development of the Masked Anti‑PD‑L1 Antibody CX‐072

“…The PROCLAIM studies discussed herein are conducted in accordance with the current institutional review board / independent ethics committee–approved clinical protocol. Both the clinical and PK data reported in this evaluation originate from preliminary monotherapy data available as of August 2019 from PROCLAIM‐CX‐072‐001 2 ( Tables and ). For patients enrolled in dose escalation and biomarker and dose–effect parts, intensive PK were collected following the first dose with sparse collection thereafter; sparse PK was collected for patients enrolled in cohort expansion.…”

“…The immune checkpoint inhibitors (ICI) targeting CTL‐associated antigen‐4 (CTLA‐4), anti–programmed death receptor 1 (PD‐1), and anti–programmed death ligand 1 (PD‐L1) are now approved for the treatment of multiple cancers 1 . Unfortunately, the use of ICIs as monotherapy often leads to responses only in a minority of patients and has been associated with immune‐related adverse events, likely due to indiscriminate immunostimulatory action in both healthy tissue and the tumor 2 . Combination therapy promises to increase the fraction of patients who respond to ICI; however, this can come with a corresponding increase in the proportion of patients who experience severe toxicities 3 …”

“…CX‐072 is a Pb‐Tx directed against PD‐L1 currently under investigation in multiple cancer types as both monotherapy and combination in the first‐in‐human, phase I‑IIa study Probody Clinical Assessment In Man (PROCLAIM)‑CX‑072‐001 (NCT03013491) and again in combination with the anti‐CTLA‐4 mAb ipilimumab in the phase II study PROCLAIM‑CX‑072‐002 (NCT03993379). Preliminary results from PROCLAIM‑CX‑072‐001 suggest both an encouraging safety profile and antitumor activity 2,9 …”

“…1 Unfortunately, the use of ICIs as monotherapy often leads to responses only in a minority of patients and has been associated with immune-related adverse events, likely due to indiscriminate immunostimulatory action in both healthy tissue and the tumor. 2 Combination therapy promises to increase the fraction of patients who respond to ICI; however, this can come with a corresponding increase in the proportion of patients who experience severe toxicities. 3 While exploration of dose and schedule can provide an avenue for increased tolerability of ICI especially in the combination setting, this approach may necessitate an exhaustive clinical evaluation in an attempt to avoid compromising efficacy.…”

Probody Therapeutics: An Emerging Class of Therapies Designed to Enhance On-Target Effects with Reduced Off-Tumor Toxicity for Use in Immuno-Oncology

“…Launched in 2017, PROCLAIM-CX-072 (PRObody Clinical Assessment In Man; NCT03013491) is a proof-of-concept phase I/IIa, open-label, multicenter, dose-escalation study to evaluate tolerability and antitumor activity of CX-072 as monotherapy or in selected combinations in patients with advanced, unresectable solid tumors or lymphoma for which a PD-1 or PD-L1 inhibitor was not approved by the FDA or other regulatory body (39,40). Patients were required to be na€ ve to ICI therapies.…”