October 18, 2023

Brittany Lovely
Megan Hollasch

Expression of DLL3, an inhibitor ligand of the Notch pathway associated with tumorigenesis, has emerged as a target of interest for drug development.

Martin Wermke, MD

Expression of DLL3, an inhibitor ligand of the Notch pathway associated with tumorigenesis, has emerged as a target of interest for drug development.

Its involvement in the Notch pathway has been observed in small cell lung cancer (SCLC) and other high-grade neuroendocrine tumors, with recent data also showing expression in melanoma, small cell bladder cancer, metastatic castration-resistant prostate cancer, glioblastoma multiforme, and neuroendocrine lung tumors.^1,2

“SCLC and other neuroendocrine carcinomas [NECs] are an area of great unmet clinical need,” Martin Wermke, MD, said in an interview with OncologyLive. “We have an established first-line treatment, which induces remissions; however, these remissions are usually shortlived and [if] patients relapse, [they] receive another chemotherapy with a lower response rate [and shorter] duration of response [DOR], and quickly run out of therapeutic options. It was discovered that NECs express DLL3 on their surface. This molecule is virtually absent from any other adult human tissue, so it’s an [ideal] target for immunotherapeutics.”

Targeted therapies in development leveraging DLL3 include antibody-drug conjugates (ADCs), CAR T-cell therapies, and bispecific T-cell engagers (BiTEs); however, recent trials have shown that T-cell engagers are currently the most promising.^1,2 DLL3 is expressed on the surface of up to 85% of SCLC tumors and its expression varies across other tumor types as well sparking interest in the development of DLL3-targeting agents for patients with SCLC.³

Wermke, who is head of the Early Clinical Trial Unit of the National Center for Tumor Diseases Dresden at the University Hospital Carl Gustav Carus in Germany, added, “[Because] DLL3 is expressed on the surface of the tumor cells but not on the surface of healthy tissue, you have the chance to redirect the T cells exactly where you want them to act. It’s relatively stably expressed, so this is not a problem of downregulation [where] you lose the antigen [as] the tumor evolves. It’s a stable target for different lines of treatment and that also differentiates it from other targets in SCLC.”

Early Data Emerges For the Novel Agent BI 764532

At the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Wermke presented data from a phase 1 study (NCT04429087) evaluating the T-cell engager BI 764532. The findings demonstrated a clinically acceptable safety profile and early efficacy when the agent was administered at doses of 90 μg/kg or greater in patients with DLL3-positive SCLC or NECs, groups that historically do not have many efficacious treatment options.⁴

At doses of 90 μg/kg or more, BI 764532 elicited a partial response (PR) rate of 25% in the overall population (n = 71), 26% in the SCLC group (n = 39), 19% in those with extrapulmonary NECs (n = 27), and 60% in patients with large cell NECs (n = 5). Wermke noted that although the median DOR had not been reached, responses appeared to be durable, with a disease control rate of 52% for all patients given 90 μg/kg or more.

Furthermore, drug discontinuation due to treatment-related adverse effects (TRAEs) was low. Dose-limiting toxicities (DLTs) occurred
in 5 of 107 patients treated on the study at all dose levels but were reversible and patients recovered. The toxicities included grade 3/4 cytokine release syndrome (CRS) occurring in 2 patients, as well as grade 3 confused state, grade 2 infusion-related reaction, and a grade 3 nervous system disorder occurring in 1 patient each.

“BI 764532 is a molecule that binds to DLL3 on the tumor cells and to CD3 on the T cells, thereby redirecting T cells to the tumor, inducing an immune cytologic cell death to the tumor cell. The next steps are for dose optimization,” Wermke said. “We will try to find a schedule [that] is convenient for smaller hospitals and private practice oncology [clinics] and will try to move this compound to earlier lines of treatment, combining it with first-line chemotherapy [as well as] standard maintenance regimens, and finding novel combinations with other
immunotherapeutics.”

“Focusing on the potentially efficacious dose levels above 90 μg/kg, the response rate was 25%, and these responses [did] not seem to be restricted to any of the subentities included. It’s not just [patients with] SCLC, extrapulmonary NECs, [or] large cell NECs for lung [who responded to treatment]—it’s all 3 of them. The responses seem to be durable, too. At the time of the data cutoff, 14 out of 18 responses were
ongoing and we have patients responding for 1 year or more.”

CAR T-cell Therapy and ADC Therapy Fall Short Targeting DLL3

Although the T-cell engager BI 764532 showed promise targeting DLL3, the ADC rovalpituzumab tesirine, which initially exhibited encouraging data, failed to provide a benefit over placebo as maintenance therapy, leading to its discontinuation by manufacturer AbbVie in 2019.⁵ Additionally, a phase 1 trial (NCT03392064) evaluating the CAR T-cell therapy AMG 119 has been suspended and there are no patients actively enrolled, but the trial potentially may resume.⁶

Tarlatamab Shows Promise in Phase 1 Data

However, the half-life BiTE tarlatamab (formerly AMG 757) demonstrated encouraging results regarding response durability and safety in patients with relapsed/refractory SCLC.⁷ In the phase 1 DeLLphi-300 study (NCT03319940), patients included in the interim efficacy analysis (n = 107) experienced a confirmed objective response rate of 23% (95% CI, 15.7%- 32.5%) with best confirmed responses including complete response (2%), PR (22%), stable disease (28%), progressive disease (8%), or could not be evaluated/no assessment (40%). The DOR was 12.3 months (95% CI, 6.6-14.9) and 51.4% of patients experienced disease control (95% CI, 41.5%-61.2%).

The maximum-tolerated dose (MTD) of tarlatamab was not reached in the trial and the highest dose of the agent evaluated was 100 mg with 0.003, 0.01, 0.03, 0.1, 0.3, 1.0, 3.0, 10.0, and 30.0 mg also examined. DLTs occurred in 6 patients and chills, pyrexia, and neutropenia were experienced by 1 patient each, all of whom were treated with 100 mg of tarlatamab. Pneumonitis occurred in a patient who was last treated at the 0.3-mg dose. Increased alanine aminotransferase and CRS occurred
in 1 patient each treated at 1 mg, and encephalopathy occurred in 1 patient treated at the 10-mg dose level.

Grade 3 or higher TRAEs occurred in 30.0% of patients. CRS was a toxicity of interest and was the most common TRAE, occurring in 52% of patients at any grade and in 1 patient at grade 3. Neurologic events related to treatment occurred in 50% of patients at any grade and neutropenia related to treatment occurred in 16% of patients at any grade. Additional common TRAEs included pyrexia (37%), dysgeusia (22%), fatigue (22%), and nausea (20%).

T-Cell Engagers Remain Agents of Interest

Furthermore, the trispecific T-cell engager HPN328, which was granted orphan drug designation in March 2022 by the FDA,⁸ is under evaluation as monotherapy or in combination with atezolizumab (Tecentriq) in a phase 1/2 trial (NCT04471727) that is currently enrolling patients with advanced cancers expressing DLL3.⁹

Interim data presented on the agent at the 2022 ASCO Annual Meeting revealed that 39% of patients (n = 7/18) treated with HPN328 monotherapy experienced a reduction in the sum of their target lesion diameter. This included 5 patients with SCLC, 1 with neuroendocrine
prostate cancer, and 1 with thymic atypical carcinoid. One patient with SCLC also achieved a confirmed PR.¹⁰

The MTD of HPN328 was not reached and no DLTs occurred in the trial. Grade 3 TRAEs occurred in 6% of patients and grade 1 or 2 CRS occurred in 22% of patients. Additionally, no patients discontinued the study treatment due to AEs.

“It’s an exciting time for an immuno-oncologist, seeing all these great compounds and making progress for our patients. It’s rewarding to see patients who [we] would otherwise lose in a matter of months living on [the BiTE BI 764532] drug for more than 1 year; that’s something that makes you feel great if you’re able to do that,” Wermke said.