Antibodies (Abs) against programmed cell death ligand-1 (PD-L1) have improved survival in many types of cancer when used as monotherapy. However, anti–PD-L1 agents can be associated with high-grade immune-related adverse events (irAEs), particularly when used in combination with other anticancer agents. CX-072 is an anti–PD-L1 Probody™ therapeutic (Pb-Tx) designed to be preferentially activated by proteases in the tumor microenvironment and not in healthy tissue. Preclinically, Pb-Tx exhibited anticancer activity of the parent Ab with reduced toxicities in models of autoimmunity.
In parts A and A2 of the ongoing phase 1/2 Probody Clinical Assessment In Man (PROCLAIM)-CX-072 study (NCT03013491), CX-072 monotherapy is evaluated in a dose-escalation cohort of pts with advanced, heavily pretreated solid tumors. Part A2 required PD-L1-positive tumors and paired biopsies. Eligible pts were PD-1, PD-L1, and CTLA-4 inhibitor naive, with immunotherapy (IMT) unavailable as a standard of care. CX-072 is given every 14 days in cohorts of intravenous doses ranging from 0.03-30 mg/kg.
As of April 20, 2018, part A/A2 had enrolled 37 pts. Pts had a median (range) of 3 (1-13) prior anticancer treatments. 14 (37.8%) pts are still on treatment at time of data cut. Median (range) time on treatment was 2.1 months (1-10). One DLT was observed (grade 3 febrile neutropenia; 3 mg/kg); MTD was not reached. Grade 3-4 treatment-related events were observed in 4 (10.8%) pts. irAEs with reversible grade 3 events occurred in 3 patients: thrombocytopenia, aminotransferase increases, and dyspnea. Two subjects discontinued CX-072 due to AEs. Across all dose levels, best response based on investigators’ assessment in 23 evaluable pts included 2 partial response (thymoma, 3 mg/kg; TNBC, 10 mg/kg), 10 stable disease, and 11 progressive disease.
Preliminary data suggest that CX-072 demonstrates the characteristics of an antibody prodrug with antitumor activity and an acceptable safety profile in heavily pretreated pts with IMT-naive solid tumors. These data warrant further exploration of CX-072 as monotherapy and in combination with other anti-cancer agents.
Clinical trial identification
Legal entity responsible for the study
CytomX Therapeutics, Inc.
CytomX Therapeutics, Inc.
Editorial support was provided by Andrew Occiano (ApotheCom, San Francisco, CA).
P.A. Ott: Research grant: BMS, Merck, Celldex, MedImmune, CytomX, ArmoBiosciences, Neon Therapeutics; Consulting: BMS, Merck, Celldex, CytomX, Roche/Genentech, Pfizer, Novartis, Neon Therapeutics; Nonremunerative positions of influence: NCCN melanoma guidelines board member. D.C. Cho: Consulting: BMS, Pfizer, Exelixis, Genentech, Prometheus. K.A. Autio: Research funding: CytomX, Pfizer, Lilly, GSK, Merck, ARMO Biosciences. N. Uboha: Consulting: EMD Serono, Lilly, FlatIron, GLG. A.I. Spira: Research grant: AbbVie; Consulting: AbbVie. R. Humphrey, M. Will: Employee: CytomX. A. Naing: Research funding: NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO Biosciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Baxter (spouse). F. Thistlethwaite: Research grant: Novartis; Consulting: Pfizer, BMS, Octimet, Achilles Therapeutics, Evelo Biosciences; Honorarium: Novartis; Speakers' bureau: BMS. E.G.E. de Vries: Research grant (institution): Amgen, Genentech, Roche, Chugai, Synthon, CytomX, Nordic Nanovector, Regeneron, G1 Therapeutics, AstraZeneca, Radius Health; Consulting (institution): Pfizer, Sanofi. All other authors have declared no conflicts of interest.