Background
DLL3
Agent | Mechanism of action | Statusb/trial identifier | Indications | Sponsor |
---|---|---|---|---|
ADCs | ||||
Rovalpituzumab tesirine | ADC targeting DLL3 | Completed NCT02674568 (phase 2) NCT01901653 (phase 1/2) NCT02874664 (phase 1) NCT03061812 (phase 3) NCT03086239 (phase 1) | Relapsed/refractory/recurrent/extensive-stage/advanced/metastatic SCLC/delta-like protein 3–expressing advanced solid tumors | AbbVie/Stemcentrx |
Terminated or withdrawn NCT02819999 (phase 1) NCT03026166 (phase 1/2) NCT03033511 (phase 3) NCT03334487 (phase 3) NCT02709889 (phase 1/2) | ||||
SC-002 | ADC targeting DLL3 | Terminated NCT02500914 (phase 1) | Relapsed SCLC or large cell NEC | Stemcentrx |
CAR therapies | ||||
DLL3-CAR-NK cells | Anti-DLL3–transduced NK cells | Recruiting NCT05507593 (phase 1) | Relapsed/refractory extensive-stage SCLC | Tianjin Medical University Cancer Institute and Hospital |
AMG 119 | Anti-DLL3–transduced autologous T cells | Suspended NCT03392064 (phase 1) | Relapsed/refractory SCLC | Amgen Inc |
T-cell engagers | ||||
Tarlatamab | Half-life–extended DLL3 x CD3 bispecific T-cell engager | Recruiting NCT03319940 (phase 1; DeLLphi-300) NCT05060016 (phase 2; DeLLphi-301) Active, not recruiting NCT04885998 (phase 1; DeLLphi-302) Not yet recruiting NCT05740566 (phase 3; Dellphi-304) | Relapsed/refractory SCLC | Amgen Inc |
Recruiting NCT05361395 (phase 1; DeLLphi-303) | First-line treatment for extensive-stage SCLC | |||
BI 764532 | DLL3/CD3 T-cell–engaging bispecific antibody | Recruiting NCT04429087 (phase 1) | Refractory, DLL3-expressing SCLC and other neuroendocrine neoplasms | Boehringer Ingelheim |
HPN328 | Tri-specific recombinant protein construct | Recruiting NCT04471727 (phase 1/2) | Relapsed/refractory, advanced DLL3-expressing malignancies | Harpoon Therapeutics |
RO7616789 | DLL3 x CD3/CD137 multispecific antibody | Recruiting NCT05619744 (phase 1) | Relapsed extensive-stage SCLC or high-grade NEC of any other origin | Hoffmann-La Roche |
PT217 | Anti-DLL3 x anti-CD47 bispecific antibody | Not yet recruiting NCT05652686 (phase 1) | Advanced or metastatic relapsed/refractory SCLC, large cell NEC, neuroendocrine prostate cancer, and gastroenteropancreatic neuroendocrine tumors | Phanes Therapeutics |
QLS31904 | Anti-DLL3 x anti-CD3 bispecific antibody | Recruiting NCT05461287 (phase 1) | Patients with advanced solid tumors, including SCLC, who progress on or are intolerant to standard of care, or have no effective standard therapeutic regimen | Qilu Pharmaceutical |
DLL3-targeting ADCs
Mechanism of action
Rova-T
Preclinical experience
Clinical experience
Safety profile
Efficacy profile
Preclinical data | SCLC clinical program statusa | Clinical safety | Clinical efficacy | |
---|---|---|---|---|
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 | 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 | 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 |