Xencor Presents Early Clinical Data from Combination Study of Vudalimab and New Data from Multiple Preclinical-stage XmAb® Programs at the SITC Annual Meeting
“Evaluating chemotherapy combinations with vudalimab is an important part of our Phase 2 development plan due to the breadth of tumor types we could address with dual PD-1/CTLA-4 blockade and chemotherapy,” said
Posters will be available in the poster hall and virtually to registrants of the SITC Annual Meeting. In the poster hall, odd numbered posters will be displayed on
Abstract 668, “A Phase 2 study of vudalimab, a PD-1 x CTLA-4 bispecific antibody, plus chemotherapy or targeted therapy in patients with molecularly defined subtypes of metastatic castration-resistant prostate cancer”
The trials in progress poster included clinical data from the safety run-in portion of the first Phase 2 study, which enrolled nine patients with mCRPC. Eight of the nine patients received vudalimab plus carboplatin and a taxane (either cabazitaxel or docetaxel). Patients were categorized into five cohorts, depending on their molecularly defined mCRPC subtype: aggressive variant prostate cancer (Cohort A; n=2), prior PARPi progressor (Cohort B; n=1), PARPi naïve (Cohort C; n=1), MSI-high or MMRD (Cohort D; n=0) and no targetable mutations (Cohort E; n=5).
Efficacy Analysis
As of the data cut on
Safety Analysis
The review of data from the safety run-in portion of the study guided the Company to revise the chemotherapy dosing regimens in combination cohorts in the study (Cohorts A, B and E). Vudalimab dosing in all cohorts remains at 10 mg/kg, administered every two weeks. The chemotherapy regimen was changed to taxane alone in Cohorts B and E or reduced dose intensity for the first cycle of treatment in Cohort A, the aggressive variant.
- Eight patients in Cohorts A, B and E received the combination of vudalimab, carboplatin and either cabazitaxel or docetaxel, depending on prior docetaxel exposure. Treatment-related serious adverse events (SAEs) occurring within the first cycle of therapy were reported for five of eight patients. All events resolved with medical management, including steroids when appropriate, treatment interruption or treatment cessation. Overall, four patients discontinued treatment due to AEs. The types of irAEs observed were largely consistent with the Phase 1 vudalimab monotherapy study of 110 patients.
- No immune related adverse events (irAEs) or treatment-related AEs were reported for the patient in Cohort C, who received vudalimab and olaparib, a PARP inhibitor.
Preclinical Program Posters
Abstract 1067, “Synergistic combination of Natural Killer cell engagers (NKEs) with proinflammatory cytokines”
Xencor’s XmAb natural killer cell engagers (NKEs) are multifunctional antibodies that target multiple activating receptors on the surface of NK cells and bind to tumor associated antigens.
In parallel,
In vitro, B7-H3 x NKG2D and MICA/B x B7H3 NKEs activated NK cells and enhanced NK cell mediated lysis of tumor cells. Additionally, in vitro anti-tumor activity was enhanced when combined with an analog of the proinflammatory IL15-Fc cytokine, XmAb306.
Abstract 1073, “Costimulatory CD28 trispecific antibodies targeting PDL1 and PDL2 enhance T cell activation in solid tumors”
T cells in the tumor microenvironment require both T cell receptor (TCR) and co-stimulatory receptor engagement to achieve full activation. CD28 is a key immune co-stimulatory receptor on T cells; however, the ligands that activate T cells through CD28 are usually not expressed on tumor cells.
Abstract 1079, “LAG3-targeted IL15/IL15Rα-Fc (LAG3 x IL15) fusion proteins for preferential TIL expansion via cis delivery of IL15 to LAG3+ cells”
IL-2 and IL-15 are cytokines that cause the activation and proliferation of T cells and NK cells. Their therapeutic potential has been well established in preclinical models and clinical studies; however, when given systemically, these potent cytokines have historically provided a poor therapeutic window, as they are not well tolerated and are quickly cleared from circulation. LAG-3 is an immune checkpoint expressed on tumor-infiltrating lymphocytes (TILs), is frequently co-expressed with PD-1 and has limited expression in non-activated T cells.
Abstract 1372, “XmAb143, an engineered IL18 heterodimeric Fc-fusion, features improved stability, reduced potency, and insensitivity to IL18BP”
IL-18 is a proinflammatory cytokine that modulates both the innate and adaptive immune responses. IL-18 receptor 1, the primary co-receptor for IL-18, is expressed on activated T cells and NK cells, which are critical for anti-tumor responses. Additional preclinical studies of IL-18 have demonstrated its anti-tumor activity, including synergy with immune checkpoint inhibitors and CAR-T therapies. In contrast with other potent cytokines, IL-18 has been well tolerated in clinical trials but demonstrated a lack of efficacy despite heavy dosing. IL-18 participates in a negative feedback loop with a high affinity natural inhibitor, IL18BP, which was observed to be upregulated in early phase clinical studies and may have directly resulted in IL-18’s limited clinical performance.
Additional Posters (Clinical Trials in Progress)
Abstract 667, “A Phase 1, multiple-dose study to evaluate the safety and tolerability of XmAb819 (ENPP3 x CD3) in subjects with relapsed or refractory clear cell renal cell carcinoma (RCC)”
Abstract 733, “A Phase 2 study of vudalimab (XmAb717), an anti-PD-1/CTLA-4 bispecific antibody, in patients with selected gynecological malignancies and high-risk metastatic castration-resistant prostate-cancer”
About Vudalimab
Vudalimab is an XmAb bispecific antibody that simultaneously targets immune checkpoint receptors PD-1 and CTLA-4 and is designed to promote tumor-selective T-cell activation. Xencor’s approach to dual checkpoint inhibition reduces the need for multiple antibodies and allows for more selective targeting of T cells with high checkpoint expression of both targets, which may potentially improve the therapeutic index of combination immunotherapies. In preclinical studies, dual blockade of PD-1 and CTLA-4 with vudalimab significantly enhanced T cell proliferation and activation, and anti-tumor activity in vivo.
About XmAb®819
XmAb®819 is a tumor-targeted, T-cell engaging XmAb 2+1 bispecific antibody in development for patients with renal cell carcinoma (RCC). XmAb819 engages the immune system by activating T cells for highly potent and targeted killing of tumor cells expressing ENPP3, an antigen highly expressed on kidney cancers. ENPP3 is differentially expressed between RCC (high expression) and normal tissues (low expression). To attack RCC cells selectively, XmAb819 was engineered as an XmAb 2+1 bispecific antibody with two binding domains against ENPP3 and one cytotoxic T-cell binding domain against CD3, a component of the T-cell receptor (TCR) complex. Xencor’s XmAb Bispecific Fc Domain serves as the scaffold for these binding domains and provides long circulating half-life, stability and ease of manufacture.
About
Forward-Looking Statements
Certain statements contained in this press release may constitute forward-looking statements within the meaning of applicable securities laws. Forward-looking statements include statements that are not purely statements of historical fact, and can generally be identified by the use of words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “seek,” “look forward,” “believe,” “committed,” “investigational,” and similar terms, or by express or implied discussions relating to Xencor’s business, including, but not limited to, statements regarding presentations of clinical trial data for vudalimab generally, planned clinical trials, the quotations from
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