Phase I Study of P-cadherin–targeted Radioimmunotherapy with 90Y-FF-21101 Monoclonal Antibody in Solid Tumors

Abstract

Purpose: 90 Y-FF-21101 is an Yttrium-90-conjugated, chimeric mAb that is highly specific for binding to human placental (P)cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90 Y-FF-21101 in a firstin-human phase I study in patients with advanced solid tumors. Patients and Methods: The safety and efficacy of 90 Y-FF-21101 were evaluated in a phase I 3þ3 dose-escalation study in patients with advanced solid tumors (n ¼ 15) over a dose range of 5-25 mCi/m 2. Dosimetry using 111 In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90 Y-FF-21101 administration every 4 months. Results: 111 In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (AE12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without doselimiting toxicity. Conclusions: The favorable safety profile and initial antitumor activity observed for 90 Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.

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

“…Indeed, other monoclonal antibodies targeting P-cadherin have shown lackluster efficacy, with low objective response rates. This is reinforced by the findings from a phase 1 study of an Yttrium-90-conjugated, P-cadherin–targeted chimeric monoclonal antibody for the treatment of advanced solid tumors, in which a single complete response and no partial responses were observed ( 21 ). Enrichment strategies and prescreening for P-cadherin high tumors (not required in the phase 1 dose-escalation portion of this study) may also be needed for observation of antitumor activity in treatments targeting P-cadherin.…”

Antibody–drug conjugates: Smart chemotherapy delivery across tumor histologies

“…For instance, early clinical trials are ongoing with radionuclide‐conjugated MoAbs, aiming to deliver radioactive payloads selectively. In this regard, phase 1 data were reported with the Yttrium‐90–conjugated, P‐cadherin–targeting antibody 90Y‐FF‐21101, showing a favorable toxicity profile and clinical activity in several tumor types, with an observed clinical benefit rate of 73% 117 . Moreover, attempts are being made to conjugate ADCs with immune‐stimulant molecules 118 to induce targeted antitumoral immune responses and/or to synergize with immune checkpoint inhibition.…”

Breast Cancer Stem Cell Membrane Biomarkers: Therapy Targeting and Clinical Implications

“…P-cadherin constitutes an attractive target with therapeutic potential to treat tumours that highly express this protein, with several studies addressing its target using different approaches [116][117][118][119]. In fact, for breast cancer, PCA062, a P-cadherin-targeting antibody-drug conjugate may have clinical potential, since it has been shown to have potent antitumour activity with acceptable efficacy and tolerability in preclinical studies in primates [120].…”

“…However, PCA062 administration in phase I clinical trial (NCT02375958) has been discontinued, since the efficacy signals were limited during dose escalation [120], suggesting that further studies using this molecule need to be performed in order to successfully target P-cadherin. Moreover, further phase I clinical trials (NCT02454010) studies suggest the use of P-cadherin-targeted radioimmunotherapy with Y-FF-21101 monoclonal antibody in the treatment of solid tumours as showing promising results [119]; however, this treatment has not been tested in breast cancer patients, which might be an interesting approach for the future since P-cadherin overexpression is a common feature of breast cancer patients. PF-06671008 is a CD3-bispecific molecule-targeting P-cadherin that was able to promote T-cell-mediated regression of established tumours in mice models.…”