Phase 1 study of AMG 119, a chimeric antigen receptor (CAR) T cell therapy targeting DLL3, in patients with relapsed/refractory small cell lung cancer (SCLC).

Abstract

TPS8576 Background: SCLC is an aggressive neuroendocrine tumor, with initial sensitivity to chemotherapy and radiotherapy often followed by chemoresistant disease progression. Notch signaling is a key regulator of neuroendocrine differentiation in SCLC, and delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors. DLL3 is expressed in most SCLC tumors but minimally expressed in normal tissues, suggesting that it may be a promising target for cancer immunotherapy. AMG 119 is an adoptive cellular therapy that consists of a patient’s autologous T cells that have been genetically modified ex vivo to express a transmembrane CAR that targets DLL3 and redirects cytotoxic T cell specificity to DLL3-positive cells. AMG 119 CAR T cells show potent killing of SCLC cells expressing DLL3 in vitro and inhibit tumor growth in an SCLC xenograft model in vivo. Methods: This phase 1 study will evaluate the safety and tolerability of AMG 119 administered as a single infusion in adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. The primary objectives are to evaluate safety and tolerability and determine the maximum tolerated cell dose (MTCD) or recommended phase 2 cell dose (RP2CD). Secondary objectives are to evaluate preliminary evidence of antitumor activity, expansion and persistence of AMG 119, and trafficking of AMG 119 to the tumor in post-treatment biopsy. Key inclusion criteria include histologically confirmed SCLC with radiographically documented disease progression or recurrence after at least 1 platinum-based regimen, ECOG performance status 0–1, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. In the cell dose exploration phase, 3–4 patients will receive a single IV infusion of AMG 119 at each cell dose. Cell dose escalation/de-escalation decisions will be guided by a modified toxicity probability interval design. The dose expansion phase will seek to confirm the MTCD or RP2CD and obtain further safety and efficacy data. Clinical trial information: NCT03392064.

Drugs in development for small cell lung cancer

“…A phase I trial of AMG 757 in patients with relapsed SCLC is underway. AMG 119 employs an alternate strategy whereby autologous T cells are genetically modified ex vivo to express transmembrane chimeric antigen receptor targeting DLL3 (44). Preclinical data show high potency and specificity for tumor cells expressing DLL3; this agent is also in phase I investigation in patients with relapsed SCLC.…”

Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study

“…AMG 757, a bispecific T-cell engager antibody against DLL3 and CD3, and AMG 119, an adoptive cellular therapy designed to target DLL3expressing cells, are both under evaluation in phase 1 studies in patients with SCLC. 20,21 DLL3 is also typically expressed in castration-resistant neuroendocrine prostate cancer, 22 gastrointestinal neuroendocrine carcinomas, 23 and small cell bladder cancer, 24 and thus, may be a useful target in a number of cancers.…”

Multi-omics profiling of primary small cell carcinoma of the esophagus reveals RB1 disruption and additional molecular subtypes

“…Our profiling also introduced insight for future preclinical research for PSCCE. Highly and specifically expressed genes might be therapeutic targets, including E2F family 50 and DLL3 51 . Notch pathway reactivation may suppress essential neuroendocrine programs of PSCCE, leading to tumor regression 52 .…”