Novel B7-H4 Targeted ADCs Generate Activity and Show Manageable Safety Profile in Breast and Other Cancers

Two novel antibody-drug conjugates (ADCs), HS-20089 and SGN-B7H4V, targeting the highly expressed immune checkpoint ligand B7-H4 have demonstrated manageable safety profiles and shown anti-tumor activity in first-in-human dose-escalation portions of phase 1 trials and will move forward to the next portions of the studies, according to data presented at the 2023 ESMO Congress.^1,2

“The exciting thing about this [development is] having different antibodies with different targets,” Cesar A. Perez, MD, explained in an interview with OncLive^®. “But at the same time, using different payloads [is similar in] the same way we have been sequencing different chemotherapy agents through time. We could possibly overcome resistance to other ADCs by using both different payloads and different antibodies in these ADCs.”

In the interview, Perez, who is the director of drug development at Sarah Cannon Research Institute at Florida Cancer Specialists & Research Institute in Orlando, discussed the significance of B7-H4, which is a transmembrane glycoprotein in the B7 superfamily. It is expressed at low levels in normal tissue and upregulated in solid tumors.¹

“Hopefully we can continue to develop [the ADC SGN-B7H4V] in breast cancer, both in estrogen receptor [ER]–positive and triple-negative [disease] as well as in endometrial or ovarian cancer. It’s a new target and what the combination with other agents will do in the future, how safe it will be, and how much efficacy it will have [is under investigation]. How we can move this agent forward into the whole paradigm [is a next step],” Perez explained.

Early Anti-Tumor Activity With HS-20089

HS-20089 is a novel B7-H4 targeted ADC that conjugates a humanized anti B7-H4 lgG1 monoclonal antibody with a small molecule toxin topoisomerase I inhibitor via a protease-cleavable linker. The agent was evaluated in the dose-escalation portion of an open-label phase 1 study (NCT05263479), which enrolled patients with locally advanced or metastatic tumors that were unselected for B7-H4 expression.²

“[The evolution of ADCs] is very exciting,” Perez said. “There are 252 ADC trials that are now being developed, so there’s a lot to be done. We’ll see a lot of data mature in the next year.”

All patients with triple-negative breast cancer (TNBC; n = 28) treated with HS-20089 experienced an objective response rate (ORR) of 28.6% (95% CI, 13.2%-48.7%) and a disease control rate (DCR) of 75.0% (95% CI, 55.1%-89.3%). Those treated at the 0.7 mg/kg (n = 2), 1.4 mg/kg (n = 2), 4.8 mg/kg (n = 12), 5.8 mg/kg (n = 11), and 7.2 mg/kg (n = 1) doses experienced ORRs of 50.0% (95% CI, 1.3%-98.7%), 0%, 33.3% (95% CI, 9.9%-65.1%), 27.3% (95% CI, 6.0%-61.0%), and 0%, respectively. The potential target therapeutic doses were 4.8 mg/kg and 5.8 mg/kg and patients received HS-20089 intravenously once every 3 weeks.²

Patients with TNBC who previously received PARP inhibitors (n = 4) treated at both the 4.8 mg/kg and 5.8 mg/kg doses achieved an ORR of 75.0% (95% CI, 19.4%-99.4%); those who received prior PD-1 or PD-L1 inhibitors (n = 7) experienced an ORR of 42.9% (95% CI, 9.9%-81.6%). The DCRs were 100.0% (95% CI, 39.8%-100.0%) and 85.7% (95% CI, 42.1%-99.6%), respectively.²

In patients with ovarian cancer (n = 3) treated with the 4.8 mg/kg and 5.8 mg/kg doses, the ORR was 66.7% (95% CI, 9.4%-99.2%) and the DCR was 100.0% (95% CI, 29.2%-100.0%).

The study enrolled a total of 52 patients with either breast (n = 48), ovarian (n = 3), or endometrial (n = 1) cancer; breast cancer tumor types included triple-negative (n = 32), hormone receptor–positive, HER2-negative (n = 12), or HER2-positive (n = 4) disease. Patients were a mean age of 50.9 years (standard deviation [SD], 9.2) and had received a mean of 4.8 prior lines of therapy (SD, 3.6).

HS-20089 Demonstrates Manageable Safety

At a median follow-up of 5.7 months, 2 patients expereinced dose-limiting toxicities (DLTs) at the 7.2 mg/kg dose and 1 patient at the 5.8 mg/kg dose. The maximum tolerated dose of HS-20089 was defined as 5.8 mg/kg and no adverse effects (AEs) led to death on the study. Additionally, serious AEs occurred in 8.7% of the 4.8 mg/kg (n = 23) group, 28.6% of the 5.8 mg/kg (n = 14) group, and 16.7% of the 7.2 mg/kg (n = 6) group; treatment-related AEs (TRAEs) leading to dose reduction occurred in 8.7%, 28.6%, and 33.3% of patients, respectively. No patients treated with 0.7 mg/kg (n = 3), 1.4 mg/kg (n = 3), or 2.8 mg/kg (n = 3) experienced serious AEs or required dose reductions due to AEs.²

Approximately 40% of patients experienced grade 1/2 decreased white blood cell count and approximately 30% reported decreased neutrophil count. Grade 3/4 TRAEs that occurred in more than 20% of patients were decreased white blood cell count, decreased neutrophil count, and decreased platelet count. Grade 3/4 nausea and vomiting were both experienced in less than 5% of patients.

SGN-B7H4V Demonstrates A Tolerable Safety Profile

The vedotin ADC SGN-B7H4V, which was examined in the phase 1 SGNB7H4V-001 study (NCT05194072), comprises a B7-H4 directed monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable linker. Data from part A of the multicenter study revealed that SGN-B7H4V had a manageable safety profile across a variety of doses.¹

“The next steps are continuing to analyze the safety of the drug and we’re looking forward to seeing the efficacy [SGN-B7H4V] from the dose-expansion phase of the trial. In the histology’s included there’s a lot of ADCs [under development] in patients with triple-negative breast cancer, for example. It will be interesting to see in the future how we will sequence these agents and what combinations we can do with ADCs.”

In dose-escalation Part A, investigators administered SGN-B7H4V at 0.75 mg/kg, 1.0 mg/kg, 1.25 mg/kg, or 1.5 mg/kg on day 1 and 8 of a 21-day cycle (n = 41). Additionally, 45 patients received the agent at 1.25 mg/kg, 1.5 mg/kg, 1.75 mg/kg, or 2.0 mg/kg on day 1 and 15 of a 28-day cycle. Histologies included ovarian cancer; hormone receptor–positive, HER2-negative breast cancer; TNBC; endometrial carcinoma; cholangiocarcinoma; non–small cell lung cancer; gallbladder carcinoma; and adenoid cystic carcinoma of the head and neck.

“The treatment was very well tolerated. Most of the AEs that we saw were comparable with other vedotin ADCs including peripheral neuropathy, cytopenias, and nausea,” Perez said.

Any-grade treatment-related treatment-emergent AEs (TEAEs) occurred in 78.0% of patients in the SGN-B7H4V 21-day cycle dose group and 68.9% of those in the 28-day cycle dose group; grade 3 of higher events occurred in 46.3% and 40.0% of patients, respectively. TEAEs led to discontinuation in 2 patients who were enrolled in the 28-day cycle dose group and led to dose reductions in 17.1% of the 21-day cycle group and 13.3% of the 28-day cycle group.

Serious AEs occurred in 26.8% of patients in the SGN-B7H4V 21-day cycle dose group and 22.2% of the 28-day cycle dose group and were treatment-related in 9.8% and 2.2% of patients, respectively. There were 7 DLTs recorded with 3 occuring in the 1.5 mg/kg group of the 21-day cycle dose group.

The most common any-grade TEAEs in the 21-day cycle dose group vs the 28-day cycle dose group included fatigue (26.8% vs 33.3%), peripheral sensory neuropathy (24.4% vs 24.4%), diarrhea (22.0% vs 11.1%), nausea (7.3% vs 20.0%), neutropenia (17.1% vs 2.2%), and anemia (9.8% vs 13.3%).

Although there were no treatment-related deaths in either dose groups in part A of the study, findings reported from the part C dose expansion revealed that after the data-cutoff, 2 treatment-related deaths occurred. Both patients received the 1.5 mg/kg dose in a 21-day cycle; 1 patient with adenoid cystic carcinoma experienced grade 5 febrile neutropenia and 1 patient with gallbladder carcinoma experienced grade 5 hyperglycemia as well as grade 4 neutropenia and the study noted the patient had type 2 diabetes mellitus and severe obesity.¹

Further, 12.2% of patients expereinced grade 3 or higher neutropenia when given doses in a 21-day cycle. Therefore, all patients have been transitioned to the 28-day cycle dosing.

Although early efficacy data were not presented on SGN-B7H4V at ESMO, Perez explained that “compelling preliminary clinical [activity] was seen because we saw responses in every single tumor type included on part A of the trial. Particularly, we saw responses in patients with TNBC, endometrial cancer, ovarian cancer, and ER-positive breast cancer; these responses were durable with some patients that have been on study now for more than a year and as most [patients] stay on the study, the responses will continue to deepen with time. There are patients with complete responses on the trial, which is very encouraging for this heavily pretreated population.”

References

1. Perez CA, Henry JT, Lakhani N, et al. First-in-human study of SGN-B7H4V, a B7-H4-directed vedotin ADC, in patients with advanced solid tumors: preliminary results of a phase I study (SGNB7H4V-001). Ann Oncol. 2023;34(suppl 2):S464-S465. doi:10.1016/j.annonc.2023.09.1846
2. Wu J, Zhang J, Li H, et al. First-in-human/phase I trial of HS-20089, a B7-H4 ADC, in patients with advanced solid tumors. Ann Oncol. 2023;34(suppl 2):S336. doi:10.1016/j.annonc.2023.09.558