Tidutamab Shows Early Tolerability, Active Immune Profile in Advanced Neuroendocrine Tumors

Tidutamab (previously XmAb18087) was found to be well tolerated with a best overall response of stable disease in patients with advanced, well-differentiated neuroendocrine tumors (NETs) of pancreatic, gastrointestinal (GI), lung and undetermined origin, according to preliminary data from a phase 1 trial (NCT03411915) presented during the 2021 NANETS Annual Symposium.¹

Results showed that of the 41 patients who received at least 1 dose of the bispecific antibody and who had undergone at least 1 post-baseline RECIST v1.1 assessment, 26.8% achieved stable disease. Moreover, tidutamab was found to induce acute and sustained T-cell activation and cytokine release.

“Tidutamab was generally well tolerated,” Bassel El-Rayes, MD, lead study author and professor and vice chair for clinical research in the Department of Hematology and Medical Oncology at Emory University School of Medicine, said in a presentation on the data. “Tidutamab monotherapy showed an active immune profile. Additional studies in other tumors that express SSTR2 are warranted and given poor outcomes in patient with higher PD(L)-1 expression, combinations with checkpoint inhibitors should be considered.”

It is known that somatostatin receptor 2 (SSTR2) is overexpressed in NETs, gastrointestinal stromal tumor (GIST), and other malignancies. The humanized, anti-SSTR2 x anti-CD3 bispecific antibody tidutamab was designed to direct T-cell–mediated cytotoxicity to cells with SSTR2 positivity.

In the ongoing, first-in-human phase 1 trial, investigators set out to examine the agent in patients with NETs and GIST. At the meeting, El-Rayes, who is also the John Kauffman Family Professor for Pancreatic Cancer Research, the associate director for clinical research, and the director of the Gastrointestinal Oncology Program at Winship Cancer Institute of Emory University, reported updated preliminary findings from the NETs cohorts.

The trial enrolled patients with histologically or cytologically confirmed grade 1 or 2 NETs of pancreatic, GI, lung or undetermined origin that was locally advanced or metastatic and had progressed within the past 12 months.

To be eligible for enrollment, participants must have progressed on, or been ineligible for, somatostatin analogues (SSAs) and 1 or more other targeted therapies. If they were on a stable dose for at least 3 months, they were allowed to continue treatment with SSAs. Moreover, patients needed to have measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1. They could not have central nervous system involvement.

For the trial, patients received tidutamab via a 2-hour intravenous infusion on days 1, 8, 15, and 22 of each 28-day treatment cycle. Dosing included a priming dose on day 1 of cycle 1; this was followed by a higher, repeated dose on subsequent dosing days. At least through cycle 1, patients were permitted to receive prophylaxis for cytokine release syndrome (CRS), nausea, and vomiting.

Imaging was done at the time of screening and then at the end of every third cycle of treatment to evaluate response to treatment. Investigators collected samples from the patients to examine the pharmacokinetics (PK) and pharmacodynamics of tidutamab in the peripheral blood at several time points throughout treatment. Moreover, tumor biopsies were performed at the time of screening and between 1 and 3 weeks following the first dose of the investigative agent.

The primary objective of the study was to evaluate the safety and tolerability of tidutamab in this patient population, and to determine the maximum tolerated dose (MTD) and/or recommended dose and schedule of the agent.

Secondary objectives included characterization of PK and immunogenicity, and evaluation of the preliminary antitumor activity of the drug based on overall response rate and progression-free survival. Exploratory objectives included the assessment of biomarkers of CRS, and the characterization of immune responses in peripheral blood based on changes in lymphocyte subsets and markers of T-cell activation and exhaustion.

At a data cutoff of August 26, 2021, a total of 42 patients had been enrolled to the trial and 41 patients had received treatment with the bispecific antibody. The median age among those who received tidutamab was 64 years (range, 34-85) and 46.3% were male. The most common primary tumor site was the pancreas (46.3%), followed by intestinal (22.0%), pulmonary (19.5%), other gastroenteropancreatic NETs (7.9%), and unknown (4.9%). For 57.9% of patients, their initial lesion was grade 2.

Additionally, the median number of prior lines of disease-specific systemic therapies was 4 (range, 0-11), 50.0% of patients had previously received peptide receptor radionuclide therapy, and 41.5% continued to receive an SSA on the study, in the form of either lanreotide (Somatuline Depot) or octreotide (Sandostatin LAR Depot).

Of the 41 patients who received treatment, 21 did so at 4 dose levels in the dose-escalation portion of the research, and 20 did so in the dose-expansion portion. The latter received tidutamab at the MTD, which had been determined to range from 0.3 μg/kg to 1.0 μg/kg.

A total of 40 patients discontinued treatment, and the most common reason was disease progression (n = 17), followed by toxicity (n= 13), withdrawn consent (n = 7), physician decision (n = 1), loss to follow-up (n = 1), or another undisclosed reason (n = 1).

Cohort 1 (n = 5) received tidutamab at a repeated dose of 0.1 μg/kg. The agent was given at a repeated dose of 0.3 μg/kg in cohort 2 (n = 5), 1.0 μg/kg in cohort 3 (n = 6), 2.0 μg/kg in cohort 4 (n = 5), and 1.0 μg/kg in the expansion NET cohort (n = 20).

“The median duration of exposure was 6.3 weeks,” El-Rayes noted. “One subject was continuing therapy at the time of the report, and she is a 73-year-old patient with intestinal NETs who had received a total of 10 cycles [of treatment] and achieved stable disease.”

Additional findings indicated that no complete or partial responses to tidutamab were observed. Twenty-two percent of the 41 total patients experienced disease progression. The duration of response was 85 days.

“Tidutamab is biologically active and inducted T-cell activation in the peripheral blood. Increases in IL-6 were observed only with the first weekly priming dose and the second weekly repeated dose, and not subsequently,” El-Rayes reported. “Acute CD8 proliferation and activation with Ki67 and PD-L1 expression were observed within 48 days after each of the first 2 infusions. Higher PD-L1 expression was associated with shorter time on the study.”

Regarding safety, 65.9% of all 41 patients experienced at least 1 adverse effect (AE). The most frequent grade 3 or 4 treatment-related AE was lymphopenia/decreased lymphocyte count (29.0%), “but this was clinically insignificant,” El-Rayes noted.

Other AEs included increased gamma-glutamyl transferase (19.5%), alanine/aspartate aminotransferase increase (19.5%), vomiting (17.1%), diarrhea (9.8%), hypophosphatemia (9.8%), anemia (7.3%), esophageal motility disorder (7.3%), fatigue (7.3%), lipase increased (7.3%), CRS (4.9%), malnutrition (4.9%), decreased neutrophil count/neutropenia (4.9%), and esophagitis (4.9%).

“Transient cytopenias were observed, which is characteristic of CD3 antibody therapy. No treatment-related deaths were observed,” El-Rayes concluded. “There appeared to be an association between dose and incidence of grade 3 or 4 vomiting, diarrhea, hypophosphatemia, fatigue, and esophageal motility disorder. These events were not observed below dose level 1.0 μg/kg. Three subjects developed grade 3 esophageal motility disorders and they had not resolved at the time of data cutoff; 2 were treated at the 2.0-μg/kg dose, and 1 was treated at the 1.0-μg/kg dose.”

Reference

1. El-Rayes B, Hendifar AE, Pant S, et al. Preliminary safety, pharmacodynamic, and antitumor activity of tidutamab, an SSTR2 x CD3 bispecific antibody, in subjects with advanced neuroendocrine tumors. Presented at: 2021 NANETS Annual Symposium; November 3-6, 2021; virtual. Abstract 109.