On May 26, 2022 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported initial dose-escalation data from the Phase 1 study evaluating XmAb104, a PD-1 x ICOS bispecific antibody, in patients with advanced solid tumors (DUET-3) (Press release, Xencor, MAY 26, 2022, View Source [SID1234615122]). These results will be presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), during the poster session "Developmental Therapeutics—Immunotherapy" on Sunday, June 5, 2022, from 8:00 a.m. to 11 a.m. CDT in Hall A at McCormick Place in Chicago.
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DUET-3 is an ongoing Phase 1 study of XmAb104 to assess the candidate’s safety and tolerability profile in patients with advanced solid tumors and to determine the maximum tolerated dose (MTD). The expansion portion of the study is currently enrolling patients with colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), non-squamous non-small cell lung cancer (NSCLC), sarcoma, melanoma and clear-cell renal cell carcinoma (RCC) and is randomizing patients 1:1 to receive 10 mg/kg intravenous XmAb104 every two weeks as monotherapy or in combination with ipilimumab.
"XmAb104 is engineered to selectively engage T cells that express both PD-1 and ICOS, important regulators of T cell activity, and we have observed biomarker activity consistent with engagement of both receptors. XmAb104 has been well tolerated and is exhibiting a distinct safety profile compared to other clinical ICOS programs, which, along with early anti-tumor activity in patients, supports its evaluation in expansion cohorts," said Allen Yang, M.D., Ph.D., senior vice president and chief medical officer at Xencor. "The ongoing expansion portion of the study is testing XmAb104, with or without the anti-CTLA-4 antibody ipilimumab, as CTLA-4 blockade has been found to increase the frequency of ICOS-expressing T cells in multiple solid tumor types."
Additionally, a trial-in-progress poster, "A phase 2, multicenter, parallel-group, open-label study of vudalimab (XmAb20717), a PD-1 x CTLA-4 bispecific antibody, alone or in combination with chemotherapy or targeted therapy in patients with molecularly defined subtypes of metastatic castration-resistant prostate cancer," will be presented during the session "Genitourinary Cancer—Prostate, Testicular, and Penile" on Monday, June 6, 2022, from 1:15 p.m. to 4:15 p.m. CDT in Hall A.
Posters will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com, at the time of the formal presentations at ASCO (Free ASCO Whitepaper).
Key Highlights from DUET-3 (Abstract #2604)
At the data cut off on April 15, 2022, 62 patients had been treated in nine dose-escalation cohorts escalating from 0.002 to 15 mg/kg of XmAb104 administered every other week in four-week cycles. Patients were a median age of 63 years and had a median of three prior systemic therapies. 62.9% of patients had received at least one prior checkpoint therapy, and 91.9% of patients had Stage IV disease.
Patients presented with the following primary tumor types: CRC (n=14), pancreatic adenocarcinoma (n=8), soft tissue sarcoma (n=8), melanoma (n=6), HNSCC (n=5), RCC (n=4), endometrial cancer (n=2), NSCLC (n=2) and other solid tumor types (n=8). Of the patients with CRC, eight were microsatellite stable (MSS), three were microsatellite instable (MSI) and three were not defined. Most patients had tumors generally not considered to be sensitive to checkpoint inhibition.
Safety and Tolerability
Safety was evaluated in all 62 patients. XmAb104 was well tolerated through the highest tested dose cohort, and treatment-related adverse events (TRAE) were mostly mild. The most common TRAEs (>5 patients) were decreased appetite (9.7%), diarrhea (9.7%), fatigue (9.7%) and maculopapular rash (8.1%). Immune-related adverse events were reported for a limited number of patients, were predominantly Grade 1 or 2, and showed no relationship to dose level. Two patients (3.2%) experienced serious TRAEs, including a Grade 3 hyperbilirubinemia and a Grade 4 asymptomatic lipase increase; both events resolved with prednisone. Four patients (6.5%) discontinued from the study due to an adverse event.
No dose-limiting toxicities were observed, and the MTD was not reached. The recommended dose for continued study, based on feasibility of administration at higher dose levels and a review of safety data with investigators, was determined to be 10 mg/kg.
Clinical Activity Highlights
The efficacy analysis included 51 evaluable patients who received any amount of XmAb104 and had at least one post-baseline assessment by RECIST 1.1. At the data cut off, two confirmed partial responses (PR), one unconfirmed PR, and stable disease have been observed:
A patient with undifferentiated pleomorphic sarcoma, who was immunotherapy naïve, presented with two target lesions in the lung and a subpleural lingular nodule. The patient was enrolled into the 0.2 mg/kg cohort and dose escalated to 0.6 mg/kg. The nodule completely resolved, and a single non-target lesion remained in the lung. The confirmed partial response continued at the time of the data cut (28 months).
A patient with clear cell RCC, who had previously received treatment with pembrolizumab/axitinib, presented with two target lesions in the ribs, one target lesion in a lymph node, and a non-target lesion in bone. The patient was treated at the 10 mg/kg dose. A partial response was observed at the end of Cycle 2, and the patient remained in response at the time of the data cut (8 months).
A patient with HNSCC, who had recently received treatment with pembrolizumab, was enrolled into the 1.8 mg/kg dose cohort. Prior therapies also included neo-adjuvant nivolumab, cisplatin, nivolumab and a GAL-3 inhibitor, and the patient experienced disease progression on all prior therapies. Two target lesions in the lung were identified, and the patient experienced a partial response at the end of Cycle 2.
Two patients with CRC have experienced durable stable disease for over 20 months, both ongoing at the time of data cut. A patient with microsatellite instability high (MSI-H)-CRC was treated at an initial dose of 1.8 mg/kg and dose escalated to 10 mg/kg. Laboratory results indicated a decrease in the tumor marker CEA over time. A second patient, with MSI-H CRC, was treated at the 10 mg/kg dose, and at the time of the data cut, continued to experience stable disease in Cycle 22.
Pharmacokinetics/Pharmacokinetics Assessments
Data from assessments of pharmacokinetics (PK) and pharmacodynamics (PD) will not be shown in the poster presentation. The PK analysis indicated a linear and dose-proportional profile. Biomarker analyses indicated complete receptor saturation on peripheral T cells beginning at the 0.6 mg/kg dose level.
About XmAb104
XmAb104 is an investigational XmAb bispecific antibody designed to promote tumor-selective T-cell activation by simultaneously targeting immune checkpoint receptor PD-1 and the immune co-stimulatory receptor ICOS. Xencor’s approach to dual checkpoint inhibition and co-stimulation reduces the need for multiple antibodies and allows for more selective targeting of T cells with high target expression, which may potentially improve the therapeutic index of combination immunotherapies. In preclinical studies, dual blockade of PD-1 and ICOS with XmAb104 significantly enhanced T cell proliferation and activation, and anti-tumor activity in vivo. XmAb104 is currently being evaluated, as a monotherapy and in combination with ipilimumab, in the expansion portion of a Phase 1 clinical study for the treatment of patients with advanced solid tumors.