Tarlatamab: New Star on the Horizon for Small-Cell Lung Cancer?

Small-cell lung cancer (SCLC) comprises approximately 14% of all lung cancer diagnoses and is exceptionally lethal. Approximately two thirds of patients with SCLC present with extra-thoracic metastases, and the median overall survival of patients with extensive stage disease remains only slightly over 1 year.^1,2 Although addition of PD-L1 inhibitory antibodies to the first-line treatment for patients with SCLC was an important advance,^1,2 the limited survival benefit emphasizes the urgent need for additional strategies to better treat this disease.

THE TAKEAWAY

• In the article that accompanies this editorial, Paz-Ares et al¹⁰ present the tolerability and initial efficacy data for the bispecific T-cell engager, tarlatamab, in 107 patients with metastatic small-cell lung cancer (SCLC). In addition to introducing a novel therapeutic agent and strategy, the study offers encouraging durable responses in a subgroup of patients with heavily pretreated SCLC.

An important contributor to the lack of immune checkpoint blockade efficacy in most patients with SCLC may be tumor-intrinsic suppression of Major Histocompatibility Complex class I (MHC-I), required for antigen presentation to cytolytic CD8+ T cells.³ While many investigators are focusing on epigenetic strategies to restore antigen presentation in SCLC, an alternative strategy is to bypass canonical antigen presentation machinery entirely through the use of a bispecific T-cell engager (BiTE)—an antibody-derived hybrid molecular construct that binds tightly to a surface determinant on the cancer cell, and another on the T cell, enforcing interaction and triggering T-cell activation and target cell lysis. Tarlatamab is a BiTE targeting the Notch ligand DLL3 on SCLC cells and the CD3 complex on T cells (Fig 1). Tarlatamab activates T cells when incubated in vitro with DLL3-positive SCLC cells, resulting in SCLC lysis.⁴ Tarlatamab also produces impressive tumor regression in vivo in a disseminating orthotopic model of SCLC.⁵ Tarlatamab is the first DLL3-targeted immune therapy to be evaluated in a clinical trial.

FIG 1.

Tarlatamab: A bispecific T-cell engager targeting cancer cells.

Regulation of Notch signaling orchestrates many developmental processes, including the derivation of pulmonary neuroendocrine cells.⁶ DLL3 is a transmembrane inhibitor of Notch signaling, which, in healthy adult tissues, is confined to intracellular compartments including the Golgi apparatus. The DLL3 gene is a direct target of ASCL1, a transcription factor that induces neuroendocrine cell proliferation, which is critically implicated in the development of SCLC.⁷ In ASCL1-expressing SCLC, DLL3 is markedly upregulated and aberrantly trafficked to the cell surface, defining an attractive candidate for tumor-selective targeting.⁸ Relative to other cell surface proteins that have been exploited as cancer targets, expression of DLL3 on SCLC is notably of low prevalence, on the order of 10,000 molecules per cell.^8,9 However, the unique tumor specificity of its cell surface exposure has prompted the development of a variety of DLL3-targeting agents.

In the article that accompanies this editorial, Paz-Ares et al¹⁰ report the safety and preliminary efficacy of tarlatamab in an international phase I dose-escalation study that included 107 patients with recurrent metastatic SCLC. Although the observed response rate of 23.4% is similar to that of many standard cytotoxics used for patients with recurrent SCLC, the median duration of response of 12.3 months, with 44% of these responding patients having ongoing responses at data cutoff, is exceptional, showing substantial promise for this experimental drug. Most patients with durable tumor responses had received the higher dosages of the study drug: 10, 30, or 100 mg once every 2 weeks. The median overall survival of 13.2 months (95% CI, 10.5 to not reached) is also encouraging in this context.

Cytokine release syndrome (CRS) was the most serious recurrent adverse event (AE) observed, occurring predominantly after the first dose. Eight patients received tocilizumab for CRS, with others typically receiving combinations of steroids, antipyretics, and fluids. All CRS-related toxicities were reversible, and none resulted in discontinuation of tarlatamab although 12 patients (11.2%) experienced grade ≥3 neurologic AEs. The pathophysiology and mechanisms underlying symptoms of CRS are not fully understood. Both immune effector cell–associated neurotoxicity syndrome and CRS have been associated with potent responses to immune-modulating therapies; high levels of circulating cytokines appear to trigger endothelial cell activation and blood-brain barrier disruption, resulting in an inflammatory cascade that can inflict diffuse cerebral edema.^11,12 Informed management algorithms for CRS management would be of substantial utility for future investigation of tarlatamab and other emerging next-generation immunotherapies.

The trial had several limitations. Almost all patients had good performance status (0-1), and none had brain metastases; application in the more diverse population of typical patients with metastatic SCLC remains to be defined. The study includes a very limited analysis of potential predictive biomarkers, restricted to immunohistochemical staining for DLL3 in a subset of patients with available archival tumor biopsies. A robust effort to quantitate baseline (pretreatment, proximal to therapy) target expression on tumor would be of benefit in defining patients most likely to benefit from tarlatamab. Obtaining core biopsies admittedly may not be safe or feasible in all patients. One alternative, allowing pretreatment and on-treatment dynamic assessment, might be analysis of circulating tumor cells which are typically abundant in patients with SCLC.¹³ Another approach, avoiding the inherent sampling biases of immunohistochemistry and reflecting in vivo accessibility of the target in tumors, would be quantitative anti-DLL3 positron emission tomography scanning using a radioimmunoconjugate. The feasibility of this approach has been demonstrated in multiple patient-derived xenograft models, and clinical assessment is ongoing (ClinicalTrials.gov identifier: NCT04199741).^14,15

Tarlatamab is one of several DLL3-targeted therapeutic agents that have been or are being investigated in human clinical trials. The first of these was the antibody-drug conjugate (ADC) rovalpituzumab tesirine (Rova-T), an anti-DLL3 antibody linked to the toxin pyrrolobenzodiazepine.^8,16 Rova-T produced clinical responses in patients with SCLC, but significant toxicities including body cavity effusions precluded repetitive dosing, and the median overall survival for patients with recurrent SCLC was <6 months.¹⁷ Development of an anti-DLL3 ADC with a better tolerated therapeutic payload remains a viable strategy.

BI 764532 is an anti-DLL3/anti-CD3 BiTE, conceptually similar to tarlatamab. BI 764532 has demonstrated activity in a human T-cell–engrafted mouse model, including complete tumor regressions.¹⁸ A phase I study is ongoing in patients with SCLC and other neuroendocrine tumors expressing DLL3.¹⁹ HPN328 is a third anti-DLL3 T-cell engager, referred to as a trispecific T-cell activating construct. HPN328 contains three binding domains: anti-DLL3, anti-CD3, and antialbumin, promoting long half-life in circulation. An ongoing phase I/IIa study of HPN328 in patients with metastatic SCLC and other neuroendocrine cancers associated with DLL3 expression has shown preliminary evidence of efficacy, with no grade 3 CRS events observed in the first 16 patients.²⁰

Taken together, preclinical and clinical data are pointing to DLL3 as an exciting new target for treatment of patients with SCLC. The initial safety and efficacy data of tarlatamab are an important milestone, further validating both DLL3 as a target and MHC-I bypass as an immunotherapeutic strategy for SCLC. The durable responses observed in this study should offer hope to patients with SCLC and other aggressive neuroendocrine cancers.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Collection and assembly of data: Salomon Tendler

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Tarlatamab: New Star on the Horizon for Small-Cell Lung Cancer?

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