Clinical trials corner: Take a BiTE out of kidney cancer

Dear Readers,

The Clinical Trials Corner of Kidney Cancer highlights planned or ongoing high-impact studies in renal cell carcinoma (RCC). In this issue, we highlight a Phase I trial evaluating the novel bispecific T-cell engager antibody, XmAb819 in patients with clear cell RCC (ccRCC).

In the future, if you feel that you would like to draw attention to a specific trial, please feel free to email us at [e-mail] or [e-mail]

Sincerely,

Mamta Parikh, MD, MS

Associate Editor, Kidney Cancer

Associate Professor, University of California Davis School of Medicine

Medical Director of Genitourinary Malignancies

Department of Internal Medicine

Division of Hematology Oncology

Sacramento, California

A Phase I Multiple Dose Study to Evaluate the Safety and Tolerability of XmAb819 in Subjects With Relapsed or Refractory Clear Cell Renal Cell Carcinoma

Status: Recruiting

Clinicaltrials.gov identifier: NCT05433142

Sponsor: Xencor, Inc

Enrollment: 95

Rationale: The role of immunotherapy has been long-established in the treatment of metastatic renal cell carcinoma (mRCC), evolving from the early days of treatment with interferon to IL-2 to single agent checkpoint inhibitor (ICI) to the present day in which most patients with mRCC are treated with either dual ICI or an ICI in combination with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). While front-line treatment for mRCC involves robust therapies with improvement in overall survival compared to prior, only a small portion of patients enjoy a durable response. Furthermore, rechallenge with ICIs in combination with other VEGF TKIs has been unsuccessful in improving outcomes for patients with prior ICI exposure in the two prospective Phase III TiNivo-2 and CONTACT-03 trials. Thus, other modalities exploiting the immunogenic nature of RCC are needed.

Bispecific T-cell engager (BiTE) antibodies have established clinical utility in a number of hematologic malignancies and more recently solid tumors. These antibodies simultaneously blind cluster of differentiation (CD) 3 on T-cells as well as a tumor-associate antigen (TAA) to promote T-cell mediated lysis of tumor cells. XmAb819 utilizes the TAA ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3), underexplored but described in ccRCC and restricted in most normal tissues. Given the difference in how BiTE therapies activate the tumor microenvironment, this study of XmAb819 evaluates safety and preliminary efficacy in patients with refractory ccRCC.

Study Design: This Phase I, multi-center, global study involves a dose escalation (Part A) and dose expansion (Part B) phase. In both parts of the study, patients with relapsed or refractory ccRCC with measurable disease with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with adequate end organ function and without autoimmune conditions requiring immunosuppressive therapy are eligible to participate. In Part A of the study, patients should have progressed on standard-of-care therapies with no maximum prior lines of therapy, while patients in Part B can have been treated with up to 4 prior lines of therapy for locally advanced or metastatic disease. During dose escalation, intravenous and subcutaneous dosing of XmAb819 will be examined in two separate parallel cohorts to establish the optimal dosing schedule. Part B will examine the recommended dose from Part A. Treatment will be given on Day 1, 8 and 15 of 21-day cycles until progression or unacceptable toxicity.

Endpoints: The co-primary endpoints of this study are to assess the safety and tolerability of XmAb819 administered either subcutaneously or intravenously, as well as to identify the minimum safe and biologically effective dose. Secondary objectives are pharmacokinetic characterization of XmAb819, characterization of the immunogenicity of XmAb819, and preliminary antitumor activity including objective response rate, progression-free survival, duration of response and overall survival.

Comments: While immunotherapy is a long-standing component of treatment of mRCC, only a small portion of patients with mRCC have a durable response to therapy in the front-line setting, despite ICI combinations that have inarguably improved survival. While rechallenge of ICI has been demonstrated to have little clinical benefit, novel approaches to restoring the susceptibility of the tumor microenvironment to immunotherapies remain of interest. This trial studying XmAb819 is in early stages, but represents a different approach by targeting T-cell engagement to mRCC cells. However, much as in the days of interleukin-2 (IL-2) usage, XmAb819 therapy by virtue of its mechanism of action does require close monitoring due to the risk of cytokine release syndrome. Thus far, BiTE therapies seem to be associated with less severe toxicity as compared to those seen previously with IL-2, but this will need to be taken into consideration, as potential toxicity could limit which patients would be able to receive these treatments.