Background Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with poor prognosis. While treatment with platinum and etoposide chemotherapy and a programmed death-ligand 1 (PD-L1) inhibitor has modest benefit for a subset of patients, most patients develop resistance and relapse. Tarlatamab (AMG 757) is a bispecific T-cell engager (BiTE^®) immune therapy that is designed to bind CD3 on T cells and the tumor surface antigen delta-like ligand 3 (DLL3) on SCLC cells, resulting in T cell-mediated lysis of SCLC cells. In a phase 1 study in SCLC patients who had previously received platinum-based therapy, tarlatamab had a manageable safety profile with encouraging antitumor activity.¹ Here, we evaluated the effects of chemo-immune therapy on tarlatamab activity in SCLC preclinical models.

Methods We generated chemotherapy-resistant SCLC cell lines and compared DLL3 expression and tarlatamab-mediated cytotoxicity to that in chemotherapy-naïve cells. We assessed the impact of platinum and etoposide treatment on T cell viability and proliferation, and evaluated tarlatamab monotherapy and the combination with platinum, etoposide and/or an anti-PD-L1 inhibitor in SCLC cells in vitro. In vivo, we tested the pharmacodynamic activity and anti-tumor efficacy of the combination of tarlatamab with chemotherapy in a SCLC xenograft model.

Results Although chemotherapy treatment showed the potential to modulate DLL3 expression levels, tarlatamab-mediated cytotoxicity was similar in chemotherapy-naïve and chemotherapy-resistant SCLC cell lines. Etoposide caused a dose-dependent decrease in T cell viability, whereas only high dose levels of platinum agents affected T cells. Viable T cells showed similar proliferation in response to tarlatamab treatment. Tarlatamab-mediated cytotoxicity was increased in combination with platinum, etoposide, or both agents. Tarlatamab treatment increased PD-L1 expression, and the combination of tarlatamab and anti-PD-L1 treatment also led to enhanced T cell-dependent cytotoxicity in SCLC cells in vitro. In vivo, the combination of chemotherapy and tarlatamab enhanced T cell infiltration and anti-tumor response and led to significant regression of SCLC xenograft tumors when compared to either chemotherapy or tarlatamab monotherapy.

Conclusions Our preclinical studies showed similar tarlatamab activity in chemotherapy-naïve and chemotherapy-resistant SCLC cells, supporting the potential benefit of tarlatamab for patients with relapsed SCLC. The increased cytotoxic activity observed with the combination of tarlatamab and chemotherapy and/or anti-PD-L1 treatment suggests that tarlatamab may be used together with standard of care therapy to increase response rate or durability. These data support the continued clinical evaluation of tarlatamab in patients with SCLC, including in combination with chemo-immune therapy in the first-line setting.

References

1. Paz-Ares L, Champiat S, Lai WV, et al. J Clin Oncol. 2023;41:2893–2903.