BT7480 Shows Preliminary Activity in Nectin-4+, CD137+ Tumors

BT7480, a Nectin-4/CD137 Bicycle tumor–targeted immune cell agonist, showcased clinical activity as a single agent in patients with varying levels of Nectin-4– and CD137-expressing tumors, according to biomarker findings from a phase 1/2 trial (NCT05163041) that were presented at the 2024 SITC Annual Meeting.¹

Findings showed that, as of April 29, 2024, of the 33 evaluable patients who had received BT7480, most were found to be Nectin-4–positive (76%; n = 25/33) and CD137-positive (73%; n = 22/30) at baseline, with 63% of patients being both Nectin-4– and CD137-positive (n = 19/30).

Of the small sample size, investigators noted there were varying levels of Nectin-4 expression, CD137 expression, and immune cell infiltrate across tumor types at baseline. When 33 patients were evaluated via immunohistochemistry (IHC), Nectin-4 expression was identified in 8 patients with non–small cell lung cancer (NSCLC; 24%), 3 patients with cervical cancer (9%), 3 patients with transitional cell urothelial cancer (9%), 2 patients with breast cancer (6%), 2 patients with head and neck squamous cell carcinoma (6%), and 2 patients with ovarian cancer (6%). Thirteen patients with other tumor types also had Nectin-4 expression (39%), including 5 with colorectal cancer (CRC; 15%) and 1 each with bladder adenocarcinoma, esophageal cancer, hepatocellular cancer (HCC), intrahepatic bile duct cholangiocarcinoma, pancreatic cancer, peripheral nerve sheath tumor, squamous cell carcinoma of the anus, and thyroid cancer (3% each).

CD137/immune markers expression was identified in 30 evaluable patients, including 8 with NSCLC (27%), 3 with cervical cancer (10%), 3 with transitional cell urothelial cancer (10%), 2 with breast cancer (7%), 2 with head and neck squamous cell carcinoma (7%), and 2 with ovarian cancer (7%). Ten patients had other tumor types with CD137/immune markers (33%), including CRC (7%) and bladder adenocarcinoma, esophageal cancer, HCC, intrahepatic bile duct cholangiocarcinoma, pancreatic cancer, peripheral nerve sheath tumor, squamous cell carcinoma of the anus, and thyroid cancer (3% each).

“Key clinical biomarker findings were consistent with preclinical mechanism of action observations and offer new mechanistic insights not previously reported for other CD137 agonists in the clinic,” lead study author, Kyriakos P. Papadopoulos, MD, of the Clinical Research Department of START San Antonio in Texas, and coinvestigators, wrote in a poster presented during the meeting. “These data collectively indicate that BT7480 is a pharmacologically active CD137 agonist that induces innate and adaptive immune cell activation, thus supporting clinical activity as monotherapy in patients with tumors associated with Nectin-4 expression.”

Phase 1/2 Trial Rationale and Design

Bicycle molecules are described as being part of a novel, investigational class of agents that offer manufacturing and pharmacokinetic properties of a small molecule, and comprise high binding specificity of a biologic.² BT7480 is a novel, synthetic Bicycle tumor–targeted immune cell agonist that includes 3 bicyclic peptides: 1 that targets Nectin-4 and 2 that target CD137, conjugated by a 3-arm branched trimeric polyethylene glycol linker. Preclinical data demonstrated that Nectin-4 and CD139 co-ligation may create tumor-localized CD137 agonism.

In the open-label, ongoing phase 1/2 trial, BT7480 is being evaluated with or without nivolumab (Opdivo) in patients with Nectin-4–expressing advanced solid tumors.³ Initial data showed that the agent alone was well tolerated and demonstrated early clinical activity; 3 patients treated with the agent had prolonged stable diseases (> 8 months), including 2 with NSCLC and 1 with anal squamous cancer. Two patients with cervical cancer had unconfirmed partial responses.

At the 2024 SITC Annual Meeting, investigators presented a biomarker analysis of patients enrolled on the dose-escalation part of the trial who received single-agent BT7480, to explore the downstream immune effects of CD137 agonism and determine the translation of preclinical pharmacodynamics to patients.¹

BT7480 was administered intravenously with a starting weekly dose of 0.002 mg/kg, and patients were enrolled sequentially to increasing doses in a 3+3 design to a 3.5-mg/kg weekly dose.

To be eligible for enrollment, patients needed to be refractory to or ineligible for standard therapy but could not have received prior CD137-targeted therapy.

The primary end point was safety; secondary outcome measures were efficacy, pharmacokinetics, and CD137 target engagement in the peripheral blood. Additional biomarker analyses served as exploratory end points.

To inform BT7480 dose selection and proof-of-mechanism data, archival or fresh tumor tissue was collected at baseline for retrospective assessment of Nectin-4 and CD137 expression and measurement of immune cell infiltration as part of the biomarker strategy. Tumor biomarkers included Nectin-4 protein expression, CD137 protein expression and immune cell infiltration, immune activation profiling and gene expression signatures, and immune cell/tumor spatial proteomics; peripheral biomarkers comprised CD137 receptor occupancy, transcriptomic and proteomic immune cell activation, cytokines and soluble mechanistic proteins, antidrug antibody incidence monitoring, and pharmacogenomics and circulating tumor DNA.

Additionally, peripheral blood samples were collected before and after dosing to evaluate biomarkers linked with pharmacological activity and target engagement. Investigators utilized IHC and multiplex immunofluorescence to assess Nectin-4 and CD137 expression, along with flow cytometry for CD137 receptor occupancy and activated CD4-positive T-cell levels, Olink for profiling soluble CD137 and CXCL9, and NanoString for mRNA profiling of peripheral blood samples.

The immune activation profiling and gene expression signatures, immune cell/tumor spatial proteomics antidrug antibody incidence monitoring, and pharmacogenomics and circulating tumor DNA biomarkers will be presented at a later date.

Additional Findings

The receptor occupancy of circulating CD137 was identified in a dose-dependent manner, with target saturation in peripheral blood at doses of 0.15 mg/kg and higher. Robust induction of activated CD4-positive T cells, sCD137, and CXCL9 was observed across 2 cycles; there was no hook effect seen at higher doses. Also, transient increases in immune activation markets occurred within the first 2 cycles at doses of 1.3 mg/kg and higher.

RNA profiling of circulating immune cells demonstrated that BT7480 administration led to immune cell reprogramming, thereby promoting immune activation gene expression over baseline pretreatment samples that included FOXP3, IL2RA, CCR4, and CTLA4 genes.

At weekly doses of 1.3 mg/kg to 3.5 mg/kg, the BT7480-induced pharmacodynamic changes reached a biological plateau within the peripheral blood, the authors wrote.

Investigators noted that additional cohorts are planned to evaluate BT7480 in combination with nivolumab.

References

1. Papadopoulos KP, Cohen H, Dowlati A, et al. Mechanistic biomarker analyses following administration of BT7480, a novel Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist, in a phase 1/2 study in patients with advanced solid tumors. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 53.
2. Hurov K, Lahdenranta J, Upadhyaya P, et al. BT7480, a novel fully synthetic Bicycle tumor- targeted immune cell agonist (Bicycle TICA) induces tumor localized CD137 agonism. J Immunother Cancer. 2021;9:e002883. doi:10.1136/jitc-2021-002883
3. Papadopoulos KP, Dowlati A, Lopez JS, et al. Initial results from a phase I/II study of BT7480, a novel nectin-4/CD137 bicycle tumor-targeted immune cell agonist, in patients (pts) with advanced solid tumors. Ann Oncol. 2024;35(2_Suppl):S513-S514. doi:10.1016/j.annonc.2024.08.716