CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 12, 2023
Expiration: April 11, 2024
Introduction
In this module, Hossein Borghaei, MS, DO, discuss emerging data on agents targeting delta-like ligand 3 (DLL3) for the treatment of small-cell lung cancer (SCLC). First, he reviews the rationale for DLL3 as a therapeutic target for SCLC and other neuroendocrine neoplasms. Then, he discusses recent phase I clinical trial results for the DLL3-targeted T-cell engagers tarlatamab and HPN328 in patients with SCLC, including commentary on the proposed mechanism of action.
Please note that the key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be downloaded here or by clicking any of the slide thumbnails in the module alongside the expert commentary.
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SCLC: Background
SCLC is a rare disease, making up only 13% to 15% of the 238,000 lung cancer cases annually diagnosed in the United States and approximately 1.5 million annually diagnosed globally.1-3 Unfortunately, it is very aggressive, and despite promising clues about the biological basis of the disease, not much progress has been made on treatment. However, our understanding of SCLC biology is improving, potentially leading to a new classification system that I hope will provide better treatment options for our patients. By and large, SCLC tumor cells are aggressive, rapidly proliferating, and tend to present with a bulky sort of central adenopathy. Most patients have evidence of metastatic disease at the time of initial presentation.
SCLC: Current Treatment and Prognosis
The majority of patients with SCLC already have reached extensive-stage disease at the time of diagnosis, but it should be noted that even patients diagnosed earlier have limited treatment options and relatively poor outcomes. For limited-stage SCLC, the standard treatment is radiation or surgery plus chemotherapy. Most of these cancers do recur, and these patients have only an approximately 30% survival rate at 5 years. Patients with the extensive-stage disease receive chemotherapy with the recent addition of immune checkpoint inhibitors. These new immunotherapies have provided significant improvements in survival compared with the previous standard of care, but there is still lots of room for improvement in long-term outcomes for these patients.
What Is DLL3?
DLL3 is an inhibitory ligand of the Notch signaling pathway, which is of great interest because of its role in cell proliferation and the potential malignant transformation of cells.4-6 This pathway also is believed to be heavily involved in epithelial mesenchymal transformation, which is particularly relevant to oncology. DLL3 expression also is believed to be related to ASCL1, a key neuroendocrine transcription factor. Different transcription factors in addition to ASCL1 can be used to subdivide SCLC into 3 or 4 categories, and recent research has been dedicated to understanding how they affect disease and potential treatment options.7
DLL3 Expression in Neuroendocrine Neoplasms
Although DLL3 is expressed at low levels in most normal tissue, it is found to be overexpressed in various neuroendocrine neoplasms, including approximately 85% of SCLC tumors.4,5 In addition, DLL3 normally is found only in the cytoplasm, but it is exposed on the surface of SCLC cells, making it a good therapeutic target.
DLL3 IHC Staining by Site of Origin
There is a simple immunohistochemistry (IHC) test for detection of DLL3 in various tissues, and this slide shows representative images of negative and positive results from different cancers.4 This test may be useful because many targeted treatments require some form of patient selection, although DLL3 expression has not yet been established as a biomarker for treatment response
Elevated Expression of DLL3 in SCLC and LCNEC
DLL3 messenger RNA is highly overexpressed in SCLC compared with normal tissue (left panel).8 Patient-derived xenograft models for SCLC or large-cell neuroendocrine cancer also show a higher level of DLL3 messenger RNA expression.
An H-score based on IHC staining of membranous DLL3 protein can be used to differentiate high‑expressing tumors from those with normal or low expression. There is a striking increase in membranous DLL3 expression in SCLC or large-cell neuroendocrine cancer compared with either normal lung tissue or non‑small‑cell lung cancer (right panel).
Tarlatamab: Mechanism of Action
Because the evidence suggests that DLL3 may be therapeutically relevant in SCLC, multiple potential strategies are investigating this particular target.9,10 As a cell surface marker, a straightforward way to target DLL3 is to use an antibody‑based treatment. Recently we have become familiar with bispecific T‑cell engagers, which are antibodies that target 2 different antigens. One such molecule being developed for SCLC is tarlatamab, which has one arm of the antibody that targets DLL3 expressed on the cancer cell surface and another arm that engages CD3 on a T‑cell. Binding of this bispecific antibody to DLL3 brings a T‑cell into proximity with the tumor cell, generating an immune synapse that activates the immune effector cells to initiate tumor cell lysis. Immune activation also stimulates proliferation of other T‑cells, which return to the tumor microenvironment to enhance tumor cell killing.
Originally, bispecific T-cell engagers were very short‑lived because of their small size, but newer half‑life‒extended products (such as tarlatamab) incorporate an additional fusion peptide to ensure that the drugs can stay in circulation a bit longer, improving their clinical utility.
DeLLphi-300: Tarlatamab in Patients With Relapsed/Refractory SCLC
The open-label phase I DeLLphi-300 trial looked at tarlatamab in patients with a history of relapsed/refractory SCLC who had progressed through ≥1 line of prior therapy (N = 107).11 Exclusion criteria included poor Eastern Cooperative Oncology Group performance status (>2) or symptomatic/untreated brain metastases. A dose range of 0.003-100 mg was tested in the dose-escalation phase (n = 73), with the 100-mg dose selected for further evaluation in the dose-expansion phase (n = 34). The primary objectives of the study were to evaluate the safety and tolerability of tarlatamab for SCLC and to determine the MTD or recommended phase II dose. Secondary endpoints included characterization of pharmacokinetics and antitumor activity of tarlatamab, in addition to duration of response, time to response, progression-free survival, and overall survival.
DeLLphi-300: Baseline Characteristics
This patient population with SCLC was heavily pretreated (median of 2 prior treatments), and approximately 30% had received ≥3 prior treatments.11 One half of the patients had received prior immunotherapy, and—as is common for this disease—many unfortunately had evidence of either liver or brain metastases.
DeLLphi-300: Response
The overall response rate was 23%, and approximately 36% of all patients had a ≥30% reduction in target lesions.11 The waterfall plot is color coded according to the various tarlatamab dose levels. Responses can be seen at multiple levels, but there seems to be a greater response as the dose increases, at least based on the patients who participated in this particular study.
DeLLphi-300: Response
This figure shows the duration of response (median: 12.3 months; 95% CI: 6.6-14.9) in those patients with confirmed response (n = 25), also highlighting that many of these responses happened quite early (median time to response: 1.81 months; interquartile range: 1.68-1.91).11 These results establish tarlatamab as a very interesting drug, although additional data obviously are needed to confirm this response.
DeLLphi-300: Survival
The median progression‑free survival was 3.7 months (95% CI: 2.1-5.4), and the median overall survival was 13.2 months (95% CI: 10.5 to not reached).11
DeLLphi-300: Treatment-Related AEs
No cancer therapy is without potential toxicities, and tarlatamab is no different. Any‑grade serious AEs were seen in 51% of patients, and these were grade ≥3 in 28% of patients.11
Because tarlatamab interacts with the immune system, CRS was a concern and did occur in 52% of patients, but most cases were grade 1-2 and considered to be very manageable. Fever was another common phenomenon and was seen in 37% of all patients, but only 2% had grade 3.
Digging deeper, one half of patients had some sort of neurologic event (50%). These neurologic events were mostly grade 1 dysgeusia and headaches, with the most common grade ≥3 event being confusion in 5 patients (1 with grade 4). Any-cause neutropenia was seen in 16% of patients; 9% of cases were grade ≥3, and only 4% were grade 4. No cases of febrile neutropenia were considered to be treatment related. Thus, there certainly are AEs that require close attention when patients are receiving tarlatamab.
HPN328: Mechanism of Action
HPN328 is another DLL3-targeted T-cell‒engaging agent that currently is in clinical trials. Similar to tarlatamab, one arm of the agent binds CD3 on T-cells, and another binds DLL3 expressed on tumor cells.12 An additional antialbumin-binding domain is incorporated to help the drug stay in circulation a bit longer. Like tarlatamab, this drug works by bringing the T‑cell into proximity with the tumor cell, initiating tumor cell lysis.
Phase I Study of HPN328 in Patients With Relapsed/Refractory SCLC or Other NENs
HPN328 currently is being evaluated in a phase I dose-escalation and dose-expansion study, which still is enrolling.12 The patient population (N = 18 at this interim analysis) includes those with relapsed/refractory SCLC or other neuroendocrine neoplasms. The primary objectives are to evaluate safety and tolerability and pharmacokinetics and to determine the MTD or recommended phase II dose. Secondary endpoints include assessments of antitumor activity and immunogenicity.
Phase I HPN328: Characteristics and Time on Treatment
Thus far, 61% of patients enrolled had SCLC, 11% had neuroendocrine prostate cancer, and 28% had other neuroendocrine neoplasms.12 Again, this is a heavily pretreated patient population, with 44% having received ≥3 prior therapies and 78% having received prior immunotherapy. The swimmer plot combines treatment duration with the percentage of target lesion shrinkage (red numbers) for patients with tumor response. These results suggest that this may be a very active drug, and I hope there will be further confirmation soon.
Phase I HPN328: Target Lesion Response
Although this study has reported data from very few patients thus far (N = 18), it is good to see patients who are having at least partial responses.12 In total, 39% of all patients showed any decrease in target lesion size, and 27% of those with SCLC had a >30% decrease. These are encouraging data, but it is too early to know the true response rate.
Phase I HPN328: Safety
Regarding safety, 22% of patients had grade 1-2 CRS events, but there were no grade ≥3 events, and no ICANS was reported.12 However, there were many other AEs—such as dysgeusia, fatigue, and hypotension—that must be watched closely. With this drug, any-grade neutropenia was seen in 17% of patients (11% with grade ≥3), which seems to be something to keep in mind with this class as it is developed further.
Ongoing Trials of DLL3-Targeting Agents in SCLC
Numerous ongoing phase I and II studies are looking at DLL3‑targeting agents in patients with SCLC. These include tarlatamab and HPN328, as previously discussed, as well as the bispecific antibody BI764532, which has not yet reported data. Of note, most of these trials do not require tumor expression of DLL3 for enrollment. A phase III trial of tarlatamab also is expected to begin enrolling in 2023. I hope these studies will be positive, which would provide many additional needed treatment options for this patient population.
Conclusions and Key Takeaways
DLL3 is an active area of investigation in SCLC. Having participated in some of these studies, I personally think DLL3-targeted T-cell engagers are very attractive drugs. Overall, these drugs have shown great promise, which is why many additional studies are underway to fully establish their safety and efficacy.
The risk of CRS toxicity is real and will require careful monitoring and management of any events. More thorough characterization of the entire safety profile also will be needed before these drugs become available for clinical use so all potential AEs can be managed appropriately and patients can be fully informed.
Another interesting way to potentially develop these drugs is to consider patient selection based on DLL3 expression. Although there is not yet enough information to suggest the utility of DLL3 expression for patient selection with these agents, it is an area that I hope will see additional exploration.
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