Table 2 Overview of DLL3-targeting development programs

DLL3-targeting T-cell engagers

Tarlatamab

In PDX studies, tarlatamab caused significant tumor regression (83%–98%) and a significant reduction in tumor volume [59]

In a disseminating orthotopic model of SCLC, tarlatamab-induced significant tumor growth inhibition at a low mg/kg weekly dose [59]

In exploratory toxicology studies in NHPs, tarlatamab induced a transient increase in heart rate, a transient minor decrease in lymphocyte frequency, and a mild infiltration of lymphocytes and eosinophils into the pituitary [60]

Administered to > 100 patients in an ongoing FIH phase 1 study as second-line (and beyond) treatment for SCLC

Phase 1 combination studies with anti–PD-1 and anti–PD-L1 (with or without platinum-etoposide) in ES-SCLC are ongoing

Phase 2 study in SCLC is ongoing

Phase 3 study comparing tarlatamab with SOC chemotherapy for patients with relapsed SCLC will begin patient recruitment shortly

Phase 1 (NCT03319940) results:

 TRAEs in 90.7%; grade ≥ 3 in 30.8%

 CRS (52.3%), pyrexia (37.4%), dysgeusia (22.4%), fatigue (21.5%), and nausea (19.6%) were the most commonly observed TRAEs

  Most CRS events occurred in the first treatment cycle and were managed with supportive care, corticosteroids, and tocilizumab when necessary

 Other adverse events of special interest (based on Amgen’s MedDRA query narrow safety reporting definitions) included neurological events and neutropenia

  Treatment-related neurologic events, 49.5% (grade ≥ 3, 6.5%); treatment-related neutropenia, 15.9% (grade ≥ 3, 9.3%)

Results from the phase 1 study:

 Confirmed ORR of 23.4% (including two [1.9%] complete responses and 23 [21.5%] partial responses)

 Disease control rate of 51.4%

 Median duration of response of 12.3 months

 Median PFS of 3.7 months and median OS of 13.2 months

HPN328

HPN328-mediated T-cell–dependent cellular cytotoxicity against the DLL3-positive, NCI-H82 cell lines and against DLL3-expressing cynomolgus cells [57, 62]

HPN328 inhibited the growth of NCI-H82 xenografts

HPN328 was well-tolerated in NHPs at 1 mg/kg and 10 mg/kg and had a half-life of 2.8–3.3 days [61, 62]

Administered to 18 patients so far in a phase 1 study [72]

Maximum tolerated dose not yet reached; dose escalation ongoing

Dysgeusia, fatigue, and hypotension seen in seven patients (39%) each [72]

CRS transient and manageable, with 22% of patients experiencing grade 1–2 CRS; no grade ≥ 3 CRS reported [72]

Three of eleven (27%) patients with SCLC had > 30% decreases in sum of target lesion diameters, including one confirmed partial response [72]

Four of six (67%) patients treated at ≥ 1.215 mg/week had a decrease in sum of target lesion diameters [72]

BI 764532

BI 764532 induced T-cell lysis of several DLL3-expressing SCLC cell lines in a dose-dependent manner [55]

BI 764532 induced T-cell infiltration into tumors, tumor regression, and tumor growth inhibition in a CD3 + T-cell humanized mouse model with an SHP-77 xenograft [55]

Phase 1, dose-escalation study in patients with SCLC, large cell neuroendocrine carcinoma, neuroendocrine carcinoma, or small cell carcinomas is ongoing [110]

Results not yet published

Results not yet published

QLS31904

QLS31904 inhibited tumor growth in triple-immunodeficient mice implanted with SHP-77 and human T cells [112]

Well-tolerated in NHPs at five weekly doses of 10 mg/kg [112]

Patient recruitment for a phase 1 study ongoing

Unknown

Unknown

Antibody-drug conjugates

Rovalpituzumab tesirine (Rova-T)

In PDX models, mice treated with Rova-T demonstrated complete and durable responses against chemotherapy-resistant and recurrent tumors in contrast to mice treated with cisplatin and etoposide [17]

In NHPs, Rova-T treatment was associated with reversible myelosuppression, mild kidney degeneration, and skin thickening and hyperpigmentation [17]

Administered to > 1000 patients across more than 10 studies, including two phase 3 studies

Clinical development discontinued due to a lack of survival benefit in phase 3 studies

Results across multiple studies:

 Thrombocytopenia, pleural effusions, photosensitivity reactions, and anemia were the most frequently encountered TRAEs

 Toxicity attributed to the cytotoxic warhead—PBD

 Adverse events managed by dose reductions, treatment interruptions, treatment discontinuations, and symptom-specific management

Response rates of 12%–18% in the initial phase 1 and 2 studies [31, 33]

Randomized phase 3 studies failed to show a benefit with Rova-T:

 Phase 3 TAHOE: Median OS: Rova-T (6.3 months) vs topotecan (8.6 months); ORR: Rova-T (15%) vs topotecan (21%) [6]

 Phase 3 MERU: OS: Rova-T (8.8 months) vs topotecan (9.9 months); ORR: Rova-T (9%) vs topotecan (4%) [35]

SC-002

Unknown/not published

Administered to 35 patients with relapsed/refractory SCLC in an FIH study [113]

Study terminated with no further development planned

Commonly occurring TEAEs were dyspnea (43%), pleural effusions (43%), and decreased appetite (34%) [113]

Five patients (14%) achieved a partial response [113]

No patient achieved a complete response

Fourteen (40%) patients experienced stable disease

Eleven patients had progressive disease

CAR therapies

AMG 119

Exhibited cytotoxic activity against DLL3-expressing cells and SCLC cell lines at low effector-target ratios [73]

Induced complete tumor regression in female NOD SCID mice with SHP-77 xenografts [73]

Five patients treated in an FIH study [74]

Reported TRAEs included pneumonitis, seizure, supraventricular tachycardia, and anemia [74]

One of five patients (20%) achieved a confirmed partial response, two patients (40%) achieved stable disease, one patient had progressive disease, and one patient’s response was unevaluable [74]

DLL3-CAR- NK-92 cells

DLL3-CAR-NK-92 cells induced tumor regression in a metastatic SCLC model and a subcutaneous tumor model [76]

DLL3-CAR-NK-92 cell infiltration observed in subcutaneous tumor sites [76]

Recruiting patients with relapsed/refractory ES-SCLC for a phase 1 trial

Unknown

Unknown