Clinical Investigation Into Antibody With Activity Against SSTR2 and CD3 Moves Forward

Positive preliminary data from the phase 1 DUET-1 study (NCT03411915) examining XmAb18087 (tidutamab) in patients with neuroendocrine tumors (NETs) demonstrated promising safety and efficacy findings. The humanized anti–somatostatin receptor 2 (SSTR2), anti-CD3 bispecific antibody induced a disease control rate (DCR) of 43% across dose levels, thereby supporting further study of the agent in this patient population.

“XmAb18087 induced acute and sustained T-cell activation and proliferation…in peripheral blood and was generally well tolerated at the [0.3 to 1.0 μg/kg] expansion dose,” said Bassel El-Rayes, MD, during a presentation at the North American Neuroendocrine Tumor Society (NANETS) 2020 Multidisciplinary NET Medical Virtual Symposium.

Investigators enrolled 27 patients with low- and intermediate-grade, well-differentiated NETs in the trial. Patients were spread across 4 dosing groups and received XmAb18087 at the following levels: group 1 (n = 5) at 0.1 μg/kg; group 2 (n = 5) at 0.1 to 0.3 μg/kg; group 3 (n = 12) at 0.3 to 1.0 μg/kg; and group 4 (n = 5) at 1.0 to 2.0 μg/kg. The determined maximum tolerated dose (MTD) of XmAb18087 was 0.3 to 1.0 μg/kg. The pharmacokinetic (PK) profile was dose proportional at priming and repeated doses. The agent’s median half-life was 94 hours or approximately 4 days.¹

Specifically, the DCR among the 14 evaluable patients assessed at the August 26, 2020, data cutoff was 75% in group 1, 33% in group 2, and 29% in group 3. No patients in group 4 met the criteria for the objective response analysis and consequently were not included in the assessment. The best overall response was stable disease, with a median treatment duration of 7 months.¹

Across dosing levels, cytokine release syndrome (CRS) was restricted to grades 1 (22%) and 2 (19%) and limited to the first 2 doses of XmAb18087. In sum, investigators reported CRS in 41% of patients, which began at the 0.3 μg/kg dose.1 Notably, they observed 2 dose-limiting toxicities, nausea and vomiting, at the group 4 dose level, each of which affected 60% of patients treated at this dose.¹

“These events may be related to engagement of the somatostatin receptor 2 that has been identified in the gastrointestinal tract,” said El-Rayes, who is associate director for clinical research at Winship Cancer Institute of Emory University, and professor and vice chair for clinical research in the Department of Hematology and Medical Oncology at Emory University School of Medicine, both in Atlanta, Georgia.

A safety evaluation of grade 3 and 4 adverse effects (AEs) that investigators reported for 2 or more patients in the overall population showed that lymphopenia or decreased lymphocyte count was the most common toxicity affecting 41% of patients.1 However, “no apparent deleterious clinical effects” were observed in patients who experienced lymphopenia or decreased lymphocyte count, El-Rayes said, adding that “transient cytopenia is characteristic of CD3 antibody therapy after the first dose.”

Beyond lymphopenia or decreased lymphocyte count, the most frequently observed AEs were increased g-glutamyl transferase (19%), vomiting (19%), increased alanine aminotransferase/ aspartate transaminase (19%), and nausea (15%). Investigators reported no grade 5 treatment-emergent AEs. Most patients (n = 24) discontinued XmAb18087 monotherapy for various reasons, including disease progression (n = 12), withdrawn consent (n = 6), AEs (n = 4), physician decision (n = 1), and other (n = 1).¹

Anticancer activity seen with XmAb18087 stems from the antibody’s direction of T-cell– mediated cytotoxicity to SSTR2-positive tumor cells.¹ SSTR2 is highly overexpressed in NETs, but existing evidence has shown that high SSTR2 expression correlates with favorable prognoses.²

The DUET-1 study was initiated to test the safety and tolerability of XmAb18087 in patients with NETs of the pancreas, gastrointestinal tract, lungs, and of undetermined origin. The dual primary end points were to identify the MTD and/or recommended dose of XmAb18087 and the schedule. Secondary end points included characterization of PKs and immunogenicity and assessing preliminary antitumor activity via RECIST 1.1 criteria.

Samples were collected for PK and pharmacodynamic evaluation in peripheral blood “at multiple points throughout treatment,” said El-Rayes, who also serves as the director of the Gastrointestinal Oncology Program at Winship Cancer Institute. Antitumor activity was evaluated through objective response rate, duration of response, and progression-free survival PFS), with imaging performed at screening and at the end of every third treatment cycle for response assessment.¹

Examining biomarkers of CRS and characterizing immune response in peripheral blood based on changes in lymphocyte subsets and markers of T-cell activation and exhaustion were key exploratory end points of the study.¹

Regarding dosing, patients received XmAb18087 as a 2-hour intravenous infusion on days 1, 8, 15, and 22 of each 28-day cycle. Investigators administered a priming dose on day 1 of the first cycle and followed this initial dose with a higher, repeated dose of XmAb18087 on subsequent dosing days. All patients received at least 1 dose of XmAb18087. Prophylaxis for CRS, nausea, and vomiting was given to each of the 27 patients through cycle 1 at a minimum.¹

Trial eligibility requirements included histologically or cytologically confirmed grade 1 or 2 NETs that were either locally advanced and unresectable or metastatic. Patients must also have experienced disease progression within the past 12 months, progressed on or demonstrated unsuitability for somatostatin analogs and at least 1 other targeted therapy, and had an ECOG performance status of 0 or 1.

Most patients (56%) initially presented with a lesion in the pancreas. Initial intestinal and pulmonary lesions were each reported in 15% of patients, with other gastroenteropancreatic and NETs of unknown origin each accounting for 7% of patients.¹

Although the preliminary data from DUET-1 are encouraging, completion of enrollment in the MTD expansion cohort, which will enroll a maximum of 20 patients, and longer follow-up are required to evaluate PFS and the clinical utility of XmAb18087 in this patient population, El-Rayes concluded.

_References:

_{1. El-Rayes B, Pant S, Villalobos V, et al. Preliminary safety, PK/PD, and antitumor activity of XmAb18087, an SSTR2 x CD3 bispecific antibody, in patients with advanced neuroendocrine tumors. Poster presented at: NANETS 2020 Multidisciplinary NET Medical Virtual Symposium; October 2-3, 2020. Abstract 111.}

_{2. Qian ZR, Li T, Ter-Minassian, et al. Association between somatostatin receptor expression and clinical outcomes in neuroendocrine tumors. Pancreas. 2016;45(10):1386-1393. doi:10.1097/MPA.000000000000070}