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DLL3 in SCLC
DLL3: Bringing Bispecific Therapy to SCLC

Released: May 11, 2023

Ticiana Leal
Ticiana Leal, MD
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Key Takeaways
  • SCLC is a highly aggressive malignancy with a significant unmet need for patients with progressive disease.
  • DLL3 is a rational therapeutic target based on its frequent cell-surface expression in SCLC tumor cells.
  • Tarlatamab, a bispecific T-cell engager targeting DLL3 on cancer cells and CD3 on T-cells, has shown safety and efficacy in a phase I trial in patients with relapsed/refractory SCLC.

Small-cell lung cancer (SCLC) comprises 13% of newly diagnosed cases of lung cancer worldwide—and lung cancer, including SCLC, remains the leading cause of cancer deaths. SCLC is a highly aggressive disease marked by rapidly growing tumors and early metastatic spread.

Despite advances with the approval of chemoimmunotherapy for first-line treatment of SCLC, there remains significant unmet clinical need for patients with SCLC who have disease progression, with median progression-free survival of approximately 5 months and median overall survival of approximately 12.8 months. Recent advances in second-line therapies include lurbinectedin, a selective inhibitor of oncogenic transcription, which received accelerated approval based on a single-arm phase II basket trial showing an overall response rate of 35%. Currently, there is no approved third-line therapy for patients with SCLC. Therefore, new therapies and personalized approaches for patients with SCLC are under investigation.

Based on genomic analysis of SCLC samples in preclinical models, it has been determined that Notch is a tumor suppressor and master regulator of neuroendocrine differentiation in SCLC, providing a link between Notch and the neuroendocrine phenotype in SCLC.

DLL3 is an inhibitory ligand of the Notch signaling pathway that plays an important role in developmental cell fate decisions and has been implicated in oncogenesis. It is localized to intracellular membranes and is a downstream transcriptional target of ASCL1, a lineage-specific oncogenic driver of SCLC. In contrast to its expression in normal adult tissue, DLL3 is expressed at the cell surface in SCLC in 83% to 88% of cases. It therefore has been a rational therapeutic target. Furthermore, as proof of concept, a DLL3-targeted antibody‒drug conjugate reduced survival of tumor-initiating cells and led to responses in preclinical studies.

In a phase I clinical trial, rovalpituzumab tesirine, a first-in-class antibody‒drug conjugate directed against DLL3, demonstrated promising antitumor activity with a manageable safety profile in patients previously treated with 1 or more prior therapies, including platinum-based chemotherapy. However, the phase III MERU and TAHOE trials failed to show efficacy and safety superiority of rovalpituzumab tesirine compared with standard-of-care therapy in first-line maintenance and second-line treatment of SCLC. Concerns regarding the toxicity of the tesirine payload likely also contributed to its discontinuation.

New efforts in investigating DLL3 as a therapeutic target were warranted given the efficacy signal observed in patients with SCLC thus far. Tarlatamab, a half-life‒extended bispecific T-cell engager molecule, binds both DLL3 on cancer cells and CD3 on T-cells, leading to T-cell‒mediated tumor lysis. Tarlatamab led to tumor regression in preclinical studies and is the first DLL3-targeted immune therapy to be evaluated clinically in SCLC.

In the phase I DeLLphi-300 study, tarlatamab demonstrated encouraging responses in patients with relapsed/refractory SCLC. Most patients had received 2 or more lines of therapy, 25% were platinum refractory, and 50% had prior PD-1/PD-L1 inhibitor therapy. The maximum tolerated dose was not reached, and 100 mg was selected for the expansion dose. Cytokine-release syndrome was the most common treatment-related adverse event, occurring in 52% of patients, including grade 3 in 1 patient (1%). The overall response rate was 23.4%. Median duration of response was 12.3 months. Median progression-free survival and overall survival were 3.7 months and 13.2 months, respectively. In an exploratory analysis, increased DLL3 expression trended with higher magnitude of clinical benefit. Further follow-up is needed given the modest follow-up reported (8.7 months). Additional questions remain regarding the feasibility of outpatient administration without need for inpatient observation and whether DLL3 can be used as a biomarker for patient selection.

These results have led to enthusiasm in the field and have paved the way to ongoing trials of tarlatamab as monotherapy in SCLC and other neuroendocrine cancers. These include the phase II DeLLphi-301study in patients with SCLC after 2 or more lines of therapy, a phase Ib study in neuroendocrine prostate cancer, and a phase I study of first-line tarlatamab in combination with carboplatin, etoposide, and a PD-L1 inhibitor in extensive-stage SCLC.

Learn More
To learn more about the rationale and clinical development of therapies targeting DLL3 for patients with SCLC, read a text module and download the associated slideset from Hossein Borghaei, DO, MS.

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