The antibody-drug conjugate ifinatamab deruxtecan (I-DXd) is showing clinically meaningful responses in patients with extensive-stage small cell lung cancer (ES-SCLC) who have been heavily pretreated, according to an interim analysis from the Phase 2 IDeate-Lung01 study presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer. The study suggests a potential new treatment option for a cancer with historically poor outcomes.
Targeting B7-H3 in SCLC
Small cell lung cancer (SCLC) is an aggressive malignancy, and patients with extensive-stage disease face limited treatment options and poor prognoses. B7 homolog 3 (B7-H3), also known as CD276, is a protein highly expressed in many solid tumors, including SCLC, but is minimally present in normal tissues. Its consistent expression across all molecular subtypes of SCLC and association with poor prognosis make it an attractive therapeutic target.
IDeate-Lung01 Study Design and Results
The Phase 2 IDeate-Lung01 trial evaluated two doses of I-DXd (8 mg/kg and 12 mg/kg IV every 3 weeks) in patients with ES-SCLC who had received one to three prior lines of systemic treatment, including platinum-based chemotherapy. The primary endpoint was objective response rate (ORR) as assessed by blinded independent central review. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), time to response (TTR), and safety profile. Patients with asymptomatic brain metastases were eligible for the study.
As of the data cutoff on April 25, 2024, 88 patients had received at least one dose of I-DXd (46 patients at 8 mg/kg and 42 patients at 12 mg/kg), with median follow-up times of 14.6 and 15.3 months, respectively. The confirmed ORR was 54.8% in the 12-mg/kg cohort and 26.1% in the 8-mg/kg cohort. The median DOR was 7.9 months in the 8-mg/kg cohort and 4.2 months in the 12-mg/kg cohort. A rapid response (TTR: 1.4 months) was observed at both doses.
Intracranial Response and Safety
In a subgroup analysis of 16 patients with brain target lesions at baseline, the intracranial response rate was 66.7% in the 8-mg/kg cohort (n=6) and 50.0% in the 12-mg/kg cohort (n=10). Treatment-emergent adverse events (TEAEs) were more frequent in the 12-mg/kg cohort, primarily gastrointestinal, hematologic, or fatigue-related. The incidence of adjudicated interstitial lung disease was similar between the two cohorts.
Expert Commentary
"I-DXd at both doses showed clinically meaningful efficacy in heavily pretreated patients with ES-SCLC, with the 12-mg/kg dose demonstrating approximately twice the confirmed ORR of the 8-mg/kg dose," said Dr. C.M. Rudin of Memorial Sloan Kettering Cancer Center. He noted that the safety profile was generally consistent across the two doses, although TEAEs were more frequent at the higher dose.
Next Steps
The 12-mg/kg dose has been selected as the optimal dose for monotherapy in SCLC and will be further evaluated in the extension part of IDeate-Lung01 and in the Phase 3 IDeate-Lung02 study. These studies will further define the role of I-DXd in the treatment landscape for ES-SCLC.
