Abstract 7164: Exposure-efficacy and exposure-safety relationships of tarlatamab to inform dose selection and benefit-risk assessment in patients with advanced small cell lung cancer (SCLC)

Abstract Introduction: Tarlatamab is a first in class, half-life extended bispecific T-cell engager (BiTE) immunotherapy targeting delta-like ligand 3 (DLL3) that has shown promising anti-tumor activity and survival outcomes with manageable safety profile in clinical studies of patients with previously treated SCLC (NCT03319940, NCT05060016) (Ahn et al, 2023; Paz-Ares et al, 2023). Here we characterized the exposure-efficacy and exposure-safety profiles associated with tarlatamab treatment in SCLC, including the effects of patient-specific covariates (brain or liver metastasis, smoking status, number of prior lines of therapy, prior PD-1/PD-L1 inhibitor therapy, sum of target lesion diameters, and presence of anti-drug antibody). Methods: The analysis dataset consisted of 412 subjects with SCLC from ongoing Phase 1 DeLLphi-300 study (dose range 0.003 mg to 100 mg Q2W and 200 mg Q3W) and Phase 2 DeLLphi-301 study (10 mg and 100 mg Q2W). Serum tarlatamab exposure averaged over the first cycle (28 days) was utilized as the predictor of response in the regression analysis. Efficacy endpoints included objective response rate, disease control rate, best tumor size response, progression-free survival and overall survival (OS). Safety endpoints included overall treatment related adverse event (TRAE), overall treatment emergent adverse event (TEAE), and TEAEs of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and associated neurologic events, and neutropenia. Only the grade ≥ 3 adverse events (AEs) were evaluated. Results: Significant exposure-response relationships were established for all key efficacy measures across the dose range investigated. Plateau in the exposure-efficacy relationship (maximal efficacy) was observed at the recommended dose of 10 mg Q2W. Exposures associated with lower doses were estimated to have lower efficacy. No clear trends for exposure-response relationships were identified for the evaluated AEs except for grade ≥ 3 neutropenia, where a shallow trend was observed for increased neutropenia rate with increasing tarlatamab exposures. Of all the evaluated covariate relationships, only higher baseline sum of target lesion diameters was statistically significantly correlated with worsening of OS. Conclusions: Overall results in this SCLC population suggest tarlatamab exposures associated with the recommended dose of 10 mg Q2W exhibited near maximal efficacy and a favorable benefit-risk profile. None of the evaluated patient-specific covariates resulted in clinically meaningful changes in efficacy or safety, and therefore do not warrant a dose adjustment. Citation Format: Po-Wei Chen, Mukul Minocha, Stephanie M. Kong, Erik S. Anderson, Amanda Parkes, Pablo Martinez, Brett E. Houk, Chih-Wei Lin. Exposure-efficacy and exposure-safety relationships of tarlatamab to inform dose selection and benefit-risk assessment in patients with advanced small cell lung cancer (SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7164.