XmAb18087 Shows Encouraging Preliminary Activity in NETs

Preliminary data from the phase 1 Duet-1 study of XmAb18087 (tidutamab), a humanized, anti–somatostatin receptor 2 (SSTR2), anti–CD3 bispecific antibody, demonstrated a disease control rate (DCR) of 43% across dose levels in patients with neuroendocrine tumors (NETs) and a favorable safety profile, supporting further study of the agent, according to Bassel El-Rayes, MD.¹

“XmAb18087 induced acute and sustained T-cell activation and proliferation in proliferation in peripheral blood and was generally well-tolerated at the [0.3 -> 1.0 μg/kg] expansion dose,” El-Rayes said during a presentation at the North American Neuroendocrine Tumor Society 2020 Annual Symposium.

Duet-1 (NCT03411915) enrolled 27 patients with low- and intermediate-grade well-differentiated NETs. Patients were spread across 4 dosing groups and received XmAb18087 at the following levels: group 1 (n = 5), 0.1 -> 0.1 μg/kg; group 2 (n = 5), 0.1 -> 0.3 μg/kg; group 3 (n = 12), 0.3 -> 1.0 μg/kg; and group 4 (n = 5), 1.0 -> 2.0 μg/kg. The determined maximum tolerated dose (MTD) of XmAb18087 was 0.3 -> 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 evaluated 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. Best overall response among the was stable disease, with a median treatment duration of 7 months.

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, CRS was reported in 41% of patients and started at the 0.3 μg/kg dose.¹ Notably, 2 dose limiting toxicities—nausea and vomiting—were observed at the group 4 dose level and each affected 60% of patients treated at this dose.¹

“These events may be related to engagement of SSTR2 receptors that have been identified in the gastrointestinal [GI] tract,” said El-Rayes, associate director for clinical research at the 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; reported for ≥2 patients) in the overall population showed that lymphopenia/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/decreased lymphocyte count, El-Rayes said, adding that “transient cytopenia is characteristic of CD3 antibody therapy after the first dose.

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

The 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

Duet-1

The Duet-1 study was initiated to test the safety and tolerability of XmAb18087 in patients with NETs of pancreatic cancer, gastrointestinal cancers, lung cancer, and undetermined origin, and the dual primary end points were to identify the MTD and/or recommended dose of XmAb18087 and schedule. Secondary end points included characterization of PK 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, 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 Duet-1 study.¹

Regarding dosing, XmAb18087 was administered 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

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 analogues and at least 1 other targeted therapy, and had an ECOG performance status of 0 or 1. Malignancies with central nervous system involvement were excluded from Duet-1 enrollment.¹

Most patients (56%) initially presented with a lesion in the pancreas. Initial intestinal and pulmonary lesions were reported in 15% of patients each, with other gastroenteropancreatic-NET and unknown accounting for 7% each.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: North American Neuroendocrine Tumor Society 2020 Annual Symposium; October 1-3, 2020; virtual. C-1.
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.0000000000000700