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B7 H3 ADCs in SCLC
The Promise of B7-H3 ADCs in Small-Cell Lung Cancer

Released: July 21, 2025

Expiration: January 20, 2026

Lauren A. Byers
Lauren A. Byers, MD
Christine L. Hann
Christine L. Hann, MD, PhD
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Key Takeaways
  • B7-H3 is a promising therapeutic target expressed on the cell surface of the majority of small-cell lung cancer cells.
  • Antibody-drug conjugates targeting B7-H3 have shown high response rates in early-phase trials.
  • The antibody–drug conjugate ifinatamab deruxtecan is now in phase III development for extensive-stage small-cell lung cancer.

Small cell lung cancer (SCLC) remains challenging to manage, with limited therapeutic options and treatment durability. Despite the recent incorporation of immune checkpoint inhibitors into first-line therapy, overall survival gains for extensive-stage (ES) SCLC have remained modest, underscoring the urgent need for novel therapeutic targets and treatment modalities. B7-H3 is one of those promising therapeutic targets.

The Rationale for Targeting B7-H3

Lauren A. Byers, MD:
B7-H3 is a transmembrane, immune-regulatory protein. Its expression is limited in normal tissues but is frequently upregulated in a broad range of solid tumors, including the majority of SCLC cases. Of note, high B7-H3 expression correlates with poor prognosis in SCLC, making it both a biologically and clinically relevant target in SCLC. The high level of B7-H3 expression on SCLC tumor cells makes it an attractive target for antibody–drug conjugates (ADCs). ADCs consist of a monoclonal antibody against a tumor antigen linked to a cytotoxic payload. These “smart bombs” deliver chemotherapy directly to tumor cells, enhancing efficacy while minimizing systemic toxicity.

Ifinatamab Deruxtecan

Christine L. Hann, MD, PhD:
Ifinatamab deruxtecan (I-DXd) is the most clinically advanced B7-H3–targeting ADC. This ADC is comprised of a monoclonal antibody against B7-H3, a cleavable linker, and the topoisomerase I inhibitor deruxtecan as the payload.

The phase I IDeate-PanTumor01 trial enrolled 22 patients with relapsed SCLC, the majority of whom were heavily pretreated and received varying doses of I-DXd. Among the 21 patients who received I-DXd at ≥6.4 mg/kg, there was an impressive confirmed objective response rate (ORR) of 52.4%, a notable result in this refractory population. Adverse events (AEs) with I-DXd were largely gastrointestinal (eg, nausea), fatigue, and hematologic.

The phase II IDeate-Lung01 trial was designed to further optimize the dose of I-DXd with an expansion cohort to follow. In the dose-finding stage, patients were randomized to receive either 8 mg/kg or 12 mg/kg of I-DXd every 3 weeks. The confirmed ORR at the 12 mg/kg dose (n = 42) was 54.8% vs 26.1% at 8 mg/kg (n = 46). Of note, intracranial responses were observed in 37.8% of patients with baseline brain metastases—a particularly relevant finding given the high incidence of central nervous system involvement in SCLC. Although hematologic toxicities such as anemia and neutropenia were more common at the higher dose, they were generally manageable. Interstitial lung disease (ILD)/pneumonitis, a serious AE associated with some ADCs, was observed in 9 of 88 patients, highlighting the importance of vigilance for this potential AE.

IDeate-Lung02 (NCT06203210) is a randomized, open-label phase III trial comparing I-DXd with physician’s choice chemotherapy as second-line therapy for ES-SCLC after platinum-based therapy. The trial’s coprimary endpoints are ORR and overall survival. In addition, the phase Ib/II IDeate-Lung03 frontline study is investigating I-DXd in combination with atezolizumab, either as maintenance therapy or as a substitution for traditional chemotherapy in combination with platinum agents and immunotherapy. If positive, these trials are poised to shift ADCs into earlier lines of therapy, possibly even replacing conventional chemotherapy in the future.

Additional B7-H3–Targeting ADCs

Christine L. Hann, MD, PhD:
Several other B7-H3–targeting ADCs with promising activity in SCLC are in early development.

  • YL201, a B7-H3–targeting ADC with a novel topoisomerase I inhibitor payload yielded an ORR of 63.9% in a phase I dose escalation and expansion study that enrolled 79 patients with ES-SCLC, many of whom had brain metastases. Intracranial responses were observed in 3 of 10 evaluable patients. Of note, the safety profile was favorable, with treatment-related grade ≥3 ILD occurring in <2% of all patients with any tumor type.
  • HS-20093 (GSK'277) is another B7-H3–targeting ADC with a proprietary topoisomerase I inhibitor payload that resulted in an ORR of 61.3% at a dose of 8 mg/kg (n = 31) and 50.0% at 10 mg/kg (n = 22). Similar to other B7-H3–targeting ADCs, hematologic and gastrointestinal toxicities were common.
  • MHB088C is also a B7-H3–targeting ADC, but it contains a “super” topoisomerase I inhibitor payload and is reported to be 5-10 times more potent than deruxtecan with a short half-life. In a recently reported phase II study, the ORR was 57.5% at a dose of 2.0 mg/kg every 2 weeks (n = 33). Again, the AEs were primarily hematologic and gastrointestinal. There was 1 case of grade 2 ILD among 93 patients enrolled in the study.

Conclusion

Lauren A. Byers, MD:
B7-H3 represents a highly promising therapeutic target in ES-SCLC. I-DXd demonstrated high response rates in heavily pretreated patients and is now in phase III development. Other B7-H3–targeting ADCs report comparable efficacy in early-phase studies. We look forward to validation of these preliminary yet promising results along with ongoing examination of the safety profiles of these agents in larger randomized phase III trials.

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