B7-H3 ADCs Show Promise Across Lung, Prostate, and Gynecologic Cancers

Although the exact mechanism of B7-H3 targeting is not fully understood, this agent class has stirred excitement among investigators as B7-H3 offers a potentially viable treatment target with encouraging response rates in several tumor types, including lung, prostate, and gynecologic cancers, according to Nicholas Zorko, MD, PhD.

“B7-H3 is part of the PD-L1/2 family [which is] very familiar to most oncologists [due to] immune checkpoint inhibition, but it behaves in a bit of a different way,” Zorko said in an interview with OncLive®. “We know that it is highly expressed on most solid tumors, and even some hematologic malignancies, but the expression [level] is relatively low on most normal tissues. [B7-H3] offers a different way to target some of these tumors that we would normally not target with ipilimumab [Yervoy], nivolumab [Opdivo], or pembrolizumab [Keytruda].”

Zorko is an assistant professor of medicine in the Division of Hematology, Oncology and Transplantation at the University of Minnesota Medical School in Minneapolis.

Although no B7-H3–directed agents have received US Food and Drug Administration (FDA) approval to date, the therapeutic pathway has shown promise across multiple tumor types with several drugs progressing through the developmental pipeline, Zorko noted.

How could I-DXd add to the SCLC treatment landscape?

The B7-H3–targeted antibody-drug conjugate (ADC) ifinatamab deruxtecan (I-DXd) has displayed encouraging efficacy signals with a manageable safety profile in patients with extensive-stage small cell lung cancer (ES-SCLC). In April 2026, the FDA accepted and granted priority review to a biologics license application (BLA) seeking the approval of I-DXd for the treatment of adult patients with ES-SCLC who experienced disease progression on or after platinum-based chemotherapy.¹

The BLA was supported by data from the phase 2 IDeate-Lung01 trial (NCT05280470), with support from the phase 1/2 IDeate-PanTumor01 trial (NCT04145622). Data from the primary analysis of IDeate-Lung01 revealed that patients with ES-SCLC who received I-DXd at 12 mg/kg (n = 137) experienced a confirmed overall response rate (ORR) per blinded independent central review (BICR) of 48.2% (95% CI, 39.6%-56.9%).² The median duration of response (DOR) and time to response were 5.3 months (95% CI, 4.0-6.5) and 1.4 months (range, 1.0-8.1), respectively.

The median progression-free survival PFS per BICR was 4.9 months (95% CI, 4.2-5.5); the 3-, 6-, and 9-month PFS rates were 68.0% (95% CI, 59.4%-75.2%), 35.3% (95% CI, 27.3%-43.4%), and 19.3% (95% CI, 12.9%-26.5%), respectively. The median overall survival (OS) per BICR was 10.3 months (95% CI, 9.1-13.3); the 3-, 6-, and 9-month OS rates were 89.1% (95% CI, 82.5%-93.2%), 77.4% (95% CI, 69.4%-83.5%), and 59.1% (95% CI, 50.4%-66.8%), respectively.

In terms of safety, patients in the 12-mg/kg group experienced any-grade treatment-emergent adverse effects (TEAEs) at a rate of 98.5%; grade 3 or higher TEAEs and serious TEAEs occurred at respective rates of 62.0% and 39.4%, respectively.

The most common any-grade treatment-related adverse effects (TRAEs) included nausea (43.1%), anemia (34.3%), and neutropenia (34.3%). TRAEs associated with dose interruptions (1.5%), delays (25.5%), and reductions (15.3%) of I-DXd were all reported.

“B7-H3 appears to be a good target. The question is: What does it get paired with? We just don’t know. [We need to determine] what’s going to be tolerable based on where the on-target, off-tumor expression of B7-H3 is,” Zorko commented.

What is the potential of B7-H3 as a target in prostate cancer?

Another B7-H3 ADC, vobramitamab duocarmazine, is being examined in patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 2 TAMARACK trial (NCT05551117).³ The study enrolled patients with mCRPC who experienced disease progression following 1 prior line of chemotherapy for metastatic disease and no more than 2 prior lines of antihormonal therapy.

Findings from TAMARACK showed that patients who received vobramitamab duocarmazine at 2.7 mg/kg (n = 32) experienced a confirmed ORR of 40.6%, including a complete response rate of 3.1%. The median DOR was not evaluable (NE; range, 1.54-9.46). Among prostate-specific antigen (PSA)–evaluable patients (n = 71), the rate of decline of PSA levels of at least 50% (PSA50) was 52.1%. The median DOR in PSA50 responders was NE (range, 0.95-9.49).

In the 2.7-mg/kg safety population (n = 86), all patients had an any-grade TEAE, and 97.7% experienced an any-grade TRAE. TRAEs resulting in treatment discontinuation (38.4%), dose reductions (54.7%), and dose interruptions (59.3%) were also reported. The most common TEAEs that occurred in at least 10% of patients included asthenia (59.3%), pleural effusion (44.2%), and decreased appetite (39.5%).

“B7-H3 is very highly expressed in the vast majority of prostate cancers, but we [see] very low expression of PD-L1/2, so there’s something different about it,” Zorko said. “It does not have the same tissue distribution, even within tumors, compared with some of our other immune checkpoints.”

Moreover, during the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium, investigators presented data from the phase 2 ARTEMIS-003 trial (NCT06001255), which is evaluating the B7-H3 ADC risvutatug rezetecan in patients with mCRPC.⁴ The study enrolled patients who had experienced disease progression following at least 1 prior line of standard therapy.

At a median follow-up of 8.72 months (range, 0.1-16.7), the 9-month radiographic PFS rate in the total population (n = 47) was 55.7% (95% CI, 34.3%-72.5%). Among patients with target lesions at baseline (n = 30), the confirmed ORR was 36.7% (95% CI, 19.9%-56.1%) and the median DOR was not reached (NR; 95% CI, 7.0-NR). The confirmed PSA50 response rate among evaluable patients (n = 48) was 33.3% (95% CI, 20.4%-48.4%).

What have early data shown with B7-H3–targeted agents in gynecologic malignancies?

The novel B7-H3–targeted ADC SYS6043 is being examined for the treatment of patients with advanced or metastatic solid tumors, including gynecologic cancers, in a phase 1/2 Chinese study (ChiCTR2400094683).⁵ Findings from the trial presented during the 2026 Society of Gynecologic Oncology Annual Meeting showed that the agent displayed early antitumor activity with a manageable safety profile in heavily pretreated patients with ovarian, endometrial, or cervical cancer.

Efficacy-evaluable patients with ovarian cancer (n = 70) experienced an ORR of 45.7% (95% CI, 33.7%-58.1%) and a disease control rate of 88.6% (95% CI, 78.7%-94.9%). Notably, responses were observed in patients with B7-H3–positive (n = 56) and –negative (n = 11) disease, with respective ORRs of 48.2% (95% CI, 34.7%-62.0%) and 36.4% (95% CI, 10.9%-69.2%). At a median follow-up of 5.2 months, the median DOR and PFS were 6.9 months (95% CI, 3.0-not available [NA]) and 8.3 months (95% CI, 5.6-NA), respectively.

SYS6043 also displayed efficacy in other gynecologic malignancies; the ORRs among patients with endometrial (n = 21) and cervical (n = 39) cancer were 33.3% (95% CI, 14.6%-57.0%) and 35.9% (95% CI, 21.1%-52.8%), respectively. The median PFS values were 8.0 months (95% CI, 2.9-NA) and 5.8 months (95% CI, 4.4-NA), respectively.

In the ovarian cancer cohort, all patients experienced any-grade TEAEs, and 41.4% had grade 3 or higher TEAEs. TEAEs leading to death (2.9%), dose interruption (34.3%), or dose reduction (7.1%) were reported. No instances of death or treatment discontinuation due to TRAEs occurred; dose interruptions or reductions due to TRAEs occurred at rates of 28.6% and 7.1%, respectively.

“This is an exciting space, and there is a lot of interest [in B7-H3],” Zorko said. “There are also a couple of B7-H3 CAR T-cell [agents in development] as well. There are a lot of different methods that [investigators] are [using to] go after B7-H3, and it’s reassuring to see that it’s a good target.”

References

1. Ifinatamab deruxtecan granted priority review in the U.S. for adult patients with previously treated extensive-stage small cell lung cancer who experienced disease progression on or after platinum-based chemotherapy. News release. Daiichi Sankyo. April 13, 2026. Accessed May 28, 2026. https://daiichisankyo.us/web/dsi/press-releases/-/article/ifinatamab-deruxtecan-granted-priority-review-in-the-us-for-adult-patients-with-previously-treated-extensive-stage-small-cell-lung-cancer-who-experienced-disease-progression-on-or-after-platinum-based-chemotherapy
2. Rudin CM, Johnson ML, Paz-Ares L, et al. Ifinatamab deruxtecan in patients with extensive-stage small cell lung cancer: primary analysis of the phase II IDeate-Lung01 trial. J Clin Oncol. 2026;44(4):261-273. doi:10.1200/JCO-25-02142
3. de Bono JS, Helissey C, Fizazi K, et al. TAMARACK: randomized phase II trial of the B7-H3 targeting antibody drug conjugate (ADC) vobramitamab duocarmazine (vobra duo) in metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2024;35(suppl 2):S996-S997. doi:10.1016/j.annonc.2024.08.1735
4. Bian X, Shen P, Bi J, et al. ARTEMIS-003: a phase 2 study of HS-20093 (GSK5764227) in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2026;44(suppl 7):150. doi:10.1200/JCO.2026.44.7_suppl.150
5. Zuo J, Li G, Zheng T, et al. SYS6043, a B7-H3 targeting antibody-drug conjugate in patients with advanced gynecologic cancers: a phase 1/2, first-in-human study. Presented at: 2026 Society of Gynecologic Oncology Annual Meeting; April 10-13, 2026; San Juan, Puerto Rico.