Sustained Clinical Benefit and Intracranial Activity of Tarlatamab in Previously Treated Small Cell Lung Cancer: DeLLphi-300 Trial Update

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3, has shown durable anticancer activity and manageable safety in previously treated small cell lung cancer (SCLC) in DeLLphi-300 phase I and DeLLphi-301 phase II trials. Here, we report extended follow-up of DeLLphi-300 (median follow-up, 12.1 months [range, 0.2-34.3]) in fully enrolled cohorts treated with tarlatamab ≥10 mg dose administered once every two weeks, once every three weeks, or once on day 1 and once on day 8 of a 21-day cycle (N = 152). Overall, the objective response rate (ORR) was 25.0%; the median duration of response (mDOR) was 11.2 months (95% CI, 6.6 to 22.3), and the median overall survival (mOS) was 17.5 months (95% CI, 11.4 to not estimable [NE]). Among 17 patients receiving 10 mg tarlatamab once every two weeks, the ORR was 35.3%, the mDOR was 14.9 months (95% CI, 3.0 to NE), the mOS was 20.3 months (95% CI, 5.1 to NE), and 29.4% had sustained disease control with time on treatment ≥52 weeks. No new safety signals were identified. In modified Response Assessment in Neuro-Oncology Brain Metastases analyses, CNS tumor shrinkage of ≥30% was observed in 62.5% of patients (10 of 16) who had a baseline CNS lesion of ≥10 mm, including in a subset of patients with tumor shrinkage long after previous brain radiotherapy. In DeLLphi-300 extended follow-up, tarlatamab demonstrated unprecedented survival and potential findings of intracranial activity in previously treated SCLC.

Trial registration: ClinicalTrials.gov NCT03319940.

FIG 1.

Extended follow-up efficacy outcomes after tarlatamab treatment. (A) Swimmer plot of responders (n = 38) as assessed by the investigator. (B) Kaplan-Meier estimate of duration of response. (C) Kaplan-Meier estimate of PFS in the overall population. (D) Kaplan-Meier estimate of OS in the overall population. Alternative dosing includes: 1 mg→25 mg→100 mg in cycle 1 followed by 100 mg once every 2 weeks in cycle 2 and beyond, 1 mg→100 mg→200 mg in cycle 1 followed by 200 mg once every 3 weeks in cycle 2 and beyond, and 1 mg→100 mg in cycle 1 followed by 100 mg on day 1 and day 8 of a 21-day cycle in cycle 2 and beyond. ^aSee the Data Supplement, Table S1, for further dosing details. DOR, duration of response; eIV, extended intravenous; NE, not estimable; OS, overall survival; PFS, progression-free survival; PR, partial response.

FIG 2.

Intracranial activity of tarlatamab assessed per mRANO-BM by blinded independent central review in 16 patients with a baseline CNS lesion ≥10 mm. (A) Waterfall plot showing the best percentage change from baseline in the sum of diameters of CNS lesion(s) in patients receiving five different tarlatamab regimens, sorted by interval from previous brain RT to cycle 1 day 1 (C1D1) of tarlatamab. Two patients, noted with an asterisk, had brain RT after disease progression; the best CNS tumor shrinkage occurred before this subsequent brain RT. (B) Time from last brain RT and duration of tarlatamab treatment. The last previous brain RT is denoted by a diamond, with blue designating previous SBRT or SRS and yellow designating previous WBRT. A postbaseline response assessment per modified RECIST 1.1 was not available for one patient. ^aSee the Data Supplement, Table S1, for further dosing details. BOR: best overall response; C1D1, cycle 1 day 1 of tarlatamab treatment; eIV, extended intravenous; mRANO-BM, modified Response Assessment in Neuro-Oncology Brain Metastases; NA, not available; PD, progressive disease; PR, partial response; RT, radiotherapy; SBRT, stereotactic body radiation therapy; SD, stable disease; SLD, sum of the longest diameters of lesions; SRS, stereotactic radiosurgery; WBRT, whole-brain radiation therapy.