Tarlatamab, a First-in-Class DLL3-Targeted Bispecific T-Cell Engager, in Recurrent Small-Cell Lung Cancer: An Open-Label, Phase I Study

Abstract

Purpose: Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb-mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC.

Patients and methods: This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics.

Results: By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; n = 73) and expansion (100 mg; n = 34) cohorts. Median prior lines of anticancer therapy were 2 (range, 1-6); 49.5% received antiprogrammed death-1/programmed death ligand-1 therapy. Any-grade treatment-related adverse events occurred in 97 patients (90.7%) and grade b % 3 in 33 patients (30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common treatment-related adverse event, occurring in 56 patients (52%) including grade 3 in one patient (1%). Maximum tolerated dose was not reached. Objective response rate was 23.4% (95% CI, 15.7 to 32.5) including two complete and 23 partial responses. The median duration of response was 12.3 months (95% CI, 6.6 to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to 5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively. Exploratory analysis suggests that selecting for increased DLL3 expression can result in increased clinical benefit.

Conclusion: In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing.

Trial registration: ClinicalTrials.gov NCT03319940.

FIG 1.

Response to tarlatamab. (A) Best percent change from baseline in tumor burden (defined by the sum of the longest diameters of all target lesions) in 94 patients whose data cutoff date is at least 9 weeks after the first dose date and for whom postbaseline tumor data were available. ^aSD, patients had an initial response but did not have confirmation of response on the subsequent scan and ^bPR, patients had an initial PR and still have potential for future confirmative scans. One confirmed patient in the 100 mg expansion cohort had missing sum of diameters for lesion measurement and was not included in the plot. ^cStep dosing (ie, 1 mg run-in dose) was used in these cohorts. (B) TTR, the duration of treatment, and patient status as of the data cutoff date according to dose of tarlatamab for all patients with confirmed response (n = 25). CR, complete response; NE, not evaluable; PR, partial response; SD, stable disease; TTR, time to response.

FIG 2.

Efficacy of tarlatamab in patients with SCLC. (A) Kaplan-Meier curve of PFS for patients whose data cutoff date is at least 9 weeks after the first dose date (N = 107). (B) Kaplan-Meier curve of OS for patients whose data cutoff date is at least 9 weeks after the first dose date (N = 107). OS, overall survival; PFS, progression-free survival; SCLC, small-cell lung cancer.

FIG 3.

ROC curve of objective response enrichment by DLL3 expression. ROC curve reflecting true-positive rate and false-positive rate of enrichment of objective response when FIH patients (1-100 mg cohorts) are retrospectively examined for selection using DLL3 expression assessed with the Ventana SP347 assay. ROC analysis included 77 patients enrolled in the 1-100 mg cohorts for whom pretreatment DLL3 expression readouts were available. DLL3, delta-like ligand 3; FIH, first-in-human; ROC, receiver operating characteristic.