Background ALG.APV-527 is a bispecific antibody targeting costimulatory receptor 4-1BB (CD137) and the oncofetal tumor-associated antigen 5T4. 5T4 is expressed by multiple solid tumor types, such as non-small cell lung cancer, breast cancer, pancreatic, and gastrointestinal cancers with minimal expression in normal tissue. 4-1BB is an activation-induced costimulatory receptor that regulates immune responses of activated tumor-specific CD8 T cells and natural killer cells. ALG.APV-527 is designed to deliver a 5T4-conditional 4-1BB–mediated antitumor activity and minimize systemic immune activation and toxicity. Preclinically, ALG.APV-527 demonstrates robust antitumor activity by inhibiting the growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response,¹ providing a rationale for evaluating ALG.APV-527 in patients with advanced solid tumors with the possibility of combining with immune checkpoint inhibitors (ICI).

Methods The Phase 1 study is a first-in-human, open-label, multicenter trial consisting of up to six cohorts (0.1–15 mg/kg) in a 3+3 dose escalation of ALG.APV-527 monotherapy, administered intravenously Q2W, in adult patients with advanced solid tumors. Eligibility is limited to patients with tumor types identified as likely to express 5T4. Key endpoints include safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamic activity and clinical antitumor activity of ALG.APV-527.

Results ALG.APV-527 has been well tolerated in 18 enrolled patients, including 2 patients enrolled in dose level 5 (12 mg/kg). Enrollment and assessment of dose level 5 is ongoing. Most treatment-emergent adverse events (TEAEs) were mild to moderate and manageable in the clinic; Grade 1 (G1): 31 (41%), G2: 33 (43%), G3: 9 (12%), G4: 3 (4%), G5: 0. One patient experienced a G4 dose limiting toxicity of febrile neutropenia. MTD has not been determined. Pharmacokinetics was favorable: Serum concentrations were consistent with administered doses. Exposure is associated with changes in pharmacodynamic biomarkers reflecting ALG.APV-527 mode of action. Expression of 5T4 and 4-1BB was detected in tumor biopsies. Two heavily pretreated breast cancer patients experienced prolonged stable disease (SD) of over 7 months and 12 months (the second of which escalated to a higher dose level twice without any added adverse events and remains on study).

Conclusions Available data for ALG. APV-527 treatment demonstrates good tolerability, safety, biological activity, and prolonged SD in some patients suggesting clinical benefit of treatment. Upon determining the optimized dose, subsequent development will likely take place as a combination treatment.

Reference

1. Nelson MH, Fritzell S, Miller R, Werchau D, Van Citters D, Nilsson A, Misher L, Ljung L, Bader R, Deronic A, Chunyk AG, Schultz L, Varas LA, Rose N, Håkansson M, Gross J, Furebring C, Pavlik P, Sundstedt A, Veitonmäki N, Ramos HJ, Säll A, Dahlman A, Bienvenue D, von Schantz L, McMahan CJ, Askmyr M, Hernandez-Hoyos G, Ellmark P. The bispecific tumor antigen-conditional 4-1BB x 5T4 agonist, ALG.APV-527, mediates strong T cell activation and potent anti-tumor activity in preclinical studies. Mol Cancer Ther. 2022;22(1).