IDeate-Lung02: A Phase 3, Randomized, Open-Label Study of Ifinatamab Deruxtecan (I-Dxd) Vs Treatment of Physician’s Choice (TPC) in Relapsed Small Cell Lung Cancer (SCLC).

TPS8126 Background: SCLC is an aggressive malignancy, and patients (pts) with extensive stage (ES)-SCLC have a relatively short median overall survival (OS), with limited treatment options beyond first-line (1L) therapy. B7 homolog 3 (B7-H3 [CD276]) is a transmembrane protein expressed in many solid tumors but with low/no expression in normal tissue. In SCLC, B7-H3 is highly expressed and associated with poor prognosis and lack of response to standard therapy. I-DXd is a B7-H3-directed antibody–drug conjugate comprising an anti-B7-H3 mAb linked to a topoisomerase I inhibitor payload (DXd) via a stable cleavable linker, designed to enhance selective tumor cell death and reduce systemic exposure. I-DXd demonstrated durable efficacy (objective response rate [ORR] 52.4%; median duration of response [DoR] 5.9 mo; median OS 12.2 mo) irrespective of B7-H3 status, with a manageable safety profile in 21 ES-SCLC pts with a median of 2 prior lines of therapy in a Phase 1/2 trial (NCT04145622). I-DXd is being investigated in an ongoing Phase 2 trial in pretreated ES-SCLC, IDeate-Lung01 (NCT05280470). We describe a Phase 3 trial comparing the efficacy and safety of I-DXd vs TPC in relapsed SCLC. Methods: IDeate-Lung02 (NCT06203210) is a global, multicenter, randomized, open-label, Phase 3 trial in adult pts with relapsed SCLC who have received 1 prior line of platinum-based therapy and have an ECOG PS of ≤1; pts with asymptomatic brain metastases are eligible. Pts are randomized 1:1 to receive I-DXd 12 mg/kg iv every 3 wks (n = 234) or TPC (n = 234; topotecan, amrubicin, or lurbinectedin). Randomization is stratified by chemotherapy-free interval after 1L therapy (< 90 vs ≥90 days); TPC (topotecan vs amrubicin vs lurbinectedin); prior treatment with PD-(L)1 (yes vs no); and presence/history of asymptomatic brain metastases (yes vs no). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 wks for 48 wks, then every 12 wks. Dual primary efficacy endpoints are ORR per RECIST v1.1 by blinded independent central review (BICR) and OS. Secondary efficacy endpoints are ORR per investigator; progression-free survival, DoR, disease control rate and time to response by BICR and investigator; and patient-reported outcomes. Safety endpoints include incidence of treatment-emergent adverse events (TEAEs), deaths, serious TEAEs, and TEAEs leading to dose modification or discontinuation. Immunogenicity of I-DXd and relationship between B7-H3 expression and clinical outcome are also secondary objectives. ORR will be analyzed using a Cochran-Mantel-Haenszel test at a 2-sided 1% alpha level, and OS will be analyzed using a log-rank test at a 2-sided 4% significance level, under a 2-look group sequential design. Clinical trial information: NCT06203210 .