A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors

Abstract

P-cadherin is a cell-cell adhesion molecule that is overexpressed in several solid tumors. PF-06671008 is a T-cell–redirecting bispecific antibody that engages both P-cadherin on tumors and CD3ϵ on T cells and induces antitumor activity in preclinical models. We conducted a phase 1, open-label, first-in-human, dose-escalation study to characterize the safety and tolerability of PF-06671008, towards determining the recommended phase 2 dose. Adult patients with treatment-refractory solid tumors received PF-06671008 (1.5–400 ng/kg) as a weekly intravenous (IV) infusion on a 21-day/3-week cycle. Parallel cohorts evaluated dosing via subcutaneous injection (SC) or an IV-prime dose. Of the 27 patients enrolled in the study, 24 received PF-06671008 IV in escalating doses, two received SC, and one IV-prime. A dose-limiting toxicity of cytokine release syndrome (CRS) occurred in the 400-ng/kg IV group, prompting evaluation of SC and IV-prime schedules. In all, 25/27 patients who received PF-06671008 reported at least one treatment-related adverse event (TRAE); the most common were CRS (21/27), decreased lymphocyte count (9/27), and hypophosphatemia (8/27). Seven patients permanently discontinued treatment due to adverse events and no treatment-related deaths occurred. Cytokine peak concentrations and CRS grade appeared to positively correlate with Cmax. Although the study was terminated due to limited antitumor activity, it provides important insights into understanding and managing immune-related adverse events resulting from this class of molecules.Clinical Trial RegistrationURL: https://clinicaltrials.gov/ct2/show/NCT02659631, ClinicalTrials.gov Identifier: NCT02659631.

Nonclinical Investigation of Cytokine Mitigation Strategies for T-cell–Engaging Bispecifics in the Cynomolgus Macaque

“…Overall, our monkey study results with the P-cadherin TCB suggest that both the priming dose and subcutaneous dosing strategies can reduce cytokine release without affecting intended T-cell responses. Our findings are consistent with previous nonclinical and clinical studies, 15–22 and these dosing strategies explored in our nonclinical studies were recently employed in a phase 1 clinical study with the P-cadherin TCB or P-cadherin LP DART 49 …”

“…Our findings are consistent with previous nonclinical and clinical studies, [15][16][17][18][19][20][21][22] and these dosing strategies explored in our nonclinical studies were recently employed in a phase 1 clinical study with the P-cadherin TCB or P-cadherin LP DART. 49 Dosing strategies may reduce cytokine responses but may not be enough on their own to prevent dose-limiting CRS. To identify additional tools for mitigating cytokine release, we tested agents that directly block cytokine production or responses to cytokines in the monkey.…”

A model‐based approach leveraging in vitro data to support dose selection from the outset: A framework for bispecific antibodies in immuno‐oncology

“…Treatment with CD3 T‐cell bispecific antibodies (TCBs) has the potential to redirect cytotoxic T‐cells against tumor‐specific antigens. Although TCBs are active in the preclinical setting, 4,5 clinical monotherapy with TCBs in solid tumors has proven challenging 6,7 . To this respect, combination of TCBs with other cancer immunotherapies have the potential to increase TCB effect and patient benefit 8,9 …”

“…Although TCBs are active in the preclinical setting, 4,5 clinical monotherapy with TCBs in solid tumors has proven challenging. 6,7 To this respect, combination of TCBs with other cancer immunotherapies have the potential to increase TCB effect and patient benefit. 8,9 In this work, we aim to optimize the combination of the TCB cibisatamab (RO6958688) 4,10 with the bispecific fusion protein FAP-4-1BBL (RO7122290) 9,11 by combining in vitro data with modeling and simulation.…”