New data from the DeLLphi300 clinical trial, a Phase 1 dose exploration and expansion study evaluating the safety and efficacy of investigational tarlatamab, a potential first-in-class half-life extended bispecific T-cell engager (HLE BiTE®) molecule targeting delta-like ligand 3 (DLL3), in small cell lung cancer (SCLC).

The drug is being developed by Amgen using the company’s BiTE® (bispecific T-cell engager) technology is a targeted immuno-oncology platform that is designed to engage patient’s own T-cells to any tumor-specific antigen, activating the cytotoxic potential of T cells to eliminate detectable cancer. The BiTE immuno-oncology platform has the potential to treat different tumor types through tumor-specific antigens.

Updated data from the ongoing Phase 1 study were presented at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer (WCLC) being held in Vienna, Austria.

“Small cell lung cancer is one of the most devastating and aggressive solid tumor cancers. The disease has lacked effective treatments with no therapies specifically approved to treat patients in the third-line setting,” said David M. Reese, M.D., executive vice president of Research and Development at Amgen.

“Our Phase 1 data for tarlatamab presented earlier today at WCLC continues to demonstrate exciting antitumor activity with remarkable response durability in heavily pre-treated patients. We are encouraged by the overall survival of 13.2 months.”

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Investigational drug
Tarlatamab is an investigational potential first-in-class half-life extended bispecific T-cell engager (BiTE) molecule that is uniquely designed to target delta-like ligand 3 (DLL3) in neuroendocrine cancers, such as small cell lung cancer (SCLC) and neuroendocrine prostate cancer – both of which have high unmet medical needs.[1][2][3]

DLL3 is highly upregulated on the cell surface of neuroendocrine tumors and rarely expressed on nonmalignant cells, making it a novel target for investigating a BiTE immuno-oncology molecule.[2][3][4]

An aggressive disease
Small cell lung cancer (SCLC) is a particularly aggressive form of the disease that accounts for about 10% to 15% of all lung cancers.[5] SCLC tends to spread faster than NSCLC, with nearly 70% of people with SCLC having metastatic disease at the time of diagnosis.[5]

The five-year survival rate for advanced SCLC remains low at 3% and unfortunately treatment options have not changed much in several decades.[6][7] Delta-like ligand 3 (DLL3) is an emerging treatment target that is expressed in greater than 80% of SCLC tumors with minimal expression in normal cells.[8]

The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.[9] Estimated new cases and deaths from lung cancer (SCLC and non-small cell lung cancer [NSCLC] combined) in the United States in 2022 includes 236,740 new cases and 130,180 deaths caused by the disease.[9]

Study design
In heavily pretreated patients with SCLC (n=106), a population with few treatment options beyond first-line, investigational tarlatamab demonstrated encouraging antitumor activity with notable response durability. Tarlatamab delivered a confirmed ORR of 23% (confirmed and unconfirmed responses), a median duration of response of 13.0 months and a median overall survival (OS) of 13.2 months.

Adverse events
Treatment-related adverse events (TRAEs) of any grade occurred in 97 patients (92%), and TRAEs grade ≥ 3 occurred in 33 patients (31%). Cytokine release syndrome (CRS) was primarily grade 1/2, mostly occurred in Cycle 1, rarely occurred in subsequent cycles and was generally manageable. Overall, treatment discontinuation due to treatment-related AEs was low (4%).

Based on these data, a potentially registrational Phase 2 study of tarlatamab in the third-line treatment of SCLC is currently enrolling patients. Additional studies investigating tarlatamab are underway, including DeLLphi-303, a Phase 1b study testing tarlatamab in combination with standard of care in first-line SCLC and a Phase 1b study in de novo or treatment-emergent neuroendocrine prostate cancer.

Ongoing studies
Tarlatamab is being investigated in multiple studies, including DeLLphi-301, a potentially registrational Phase 2 study in relapsed/refractory SCLC; DeLLphi-303, a Phase 1b study testing tarlatamab in combination with standard of care therapies in first-line SCLC; DeLLphi-302, a Phase 1b combination study with AMG 404 in second-line or later SCLC; and DeLLpro-300, a Phase 1b study in de novo or treatment-emergent neuroendocrine prostate cancer.

Clinical trial
A Phase 2 Study of Tarlatamab in Patients With Small Cell Lung Cancer (SCLC) (DeLLphi-301) – NCT05060016
First-Line Tarlatamab in Combination With Carboplatin, Etoposide, and PD-L1 Inhibitor in Subjects With Extensive Stage Small Cell Lung Cancer (ES-SCLC) – NCT05361395
AMG 757 and AMG 404 in Subjects With Small Cell Lung Cancer (SCLC) – NCT04885998

[1] Giffin MJ, Cooke K, Lobenhofer EK, Estrada J, Zhan J, Deegen P, Thomas M, Murawsky CM, Werner J, Liu S, Lee F, Homann O, Friedrich M, Pearson JT, Raum T, Yang Y, Caenepeel S, Stevens J, Beltran PJ, Canon J, Coxon A, Bailis JM, Hughes PE. AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer. Clin Cancer Res. 2021 Mar 1;27(5):1526-1537. doi: 10.1158/1078-0432.CCR-20-2845. Epub 2020 Nov 17. PMID: 33203642.
[2] Puca L, Gavyert K, Sailer V, Conteduca V, Dardenne E, Sigouros M, Isse K, Kearney M, Vosoughi A, Fernandez L, Pan H, Motanagh S, Hess J, Donoghue AJ, Sboner A, Wang Y, Dittamore R, Rickman D, Nanus DM, Tagawa ST, Elemento O, Mosquera JM, Saunders L, Beltran H. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med. 2019 Mar 20;11(484):eaav0891. doi: 10.1126/scitranslmed.aav0891. PMID: 30894499; PMCID: PMC6525633.
[3] Rojo F, Corassa M, Mavroudis D, Öz AB, Biesma B, Brcic L, Pauwels P, Sailer V, Gosney J, Miljkovic D, Hader C, Wu M, Almarez T, Penault-Llorca F. International real-world study of DLL3 expression in patients with small cell lung cancer. Lung Cancer. 2020 Sep;147:237-243. doi: 10.1016/j.lungcan.2020.07.026. Epub 2020 Jul 27. PMID: 32745892.3.
[4] Leonetti A, Facchinetti F, Minari R, Cortellini A, Rolfo CD, Giovannetti E, Tiseo M. Notch pathway in small-cell lung cancer: from preclinical evidence to therapeutic challenges. Cell Oncol (Dordr). 2019 Jun;42(3):261-273. doi: 10.1007/s13402-019-00441-3. Epub 2019 Apr 9. PMID: 30968324.
[5] American Cancer Society. What Is Lung Cancer? 2021. Online. Last accessed on June 24, 2022. Accessed on June 24, 2022.
[6] American Cancer Society. Lung Cancer Survival Rates. 2021. Online. Last accessed on June 24, 2022.
[7] Koinis F, Kotsakis A, Georgoulias V. Small cell lung cancer (SCLC): no treatment advances in recent years. Transl Lung Cancer Res. 2016 Feb;5(1):39-50. doi: 10.3978/j.issn.2218-6751.2016.01.03. PMID: 26958492; PMCID: PMC4758968.
[8] Owen DH, Giffin MJ, Bailis JM, Smit MD, Carbone DP, He K. DLL3: an emerging target in small cell lung cancer. J Hematol Oncol. 2019 Jun 18;12(1):61. doi: 10.1186/s13045-019-0745-2. PMID: 31215500; PMCID: PMC6582566.
[9] Small Cell Lung Cancer Treatment (PDQ®). National Cancer Institute. Online. Last accessed on June 24, 2022

Featured image: Vienna, Austria. Photo courtesy: ©2022 Anton on Unsplash Used with permission.

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