CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: November 07, 2024
Expiration: May 06, 2025
Small-Cell Lung Cancer
SCLC is a relatively rare form of lung cancer that accounts for approximately 13% to 15% of all lung cancer cases in the United States and is often associated with significant tobacco use.1,2 The biology of SCLC is unique in that it is an aggressive disease that proliferates rapidly, resulting in metastatic disease in most patients at first presentation. It is also often initially responsive to therapies like chemotherapy and radiation; however, these responses are usually short-lived, resulting in overall poor outcomes.3 Therefore, there is an unmet need for more durably effective agents such as targeted therapies or immune-based therapies.
First-line and Second-line Therapy for ES-SCLC
Approximately two thirds of patients with SCLC have ES disease—a tumor that has spread past the boundaries of a single radiation field—when first diagnosed.4 The current recommendation for initial treatment of ES-SCLC is chemoimmunotherapy. Generally, platinum/etoposide is used in combination with an anti–PD-L1 antibody such as atezolizumab or durvalumab.4 For second-line treatment, there has been a need for improved therapy options, so clinical trials are often recommended for patients who relapse. However, there are several approved therapies that are commonly used in the second-line setting.
In cases where the disease is sufficiently sensitive to platinum to ensure a lengthy chemotherapy-free interval, retreatment with platinum/etoposide is an option.4 In other cases, lurbinectedin and topotecan may be considered. Lurbinectedin was studied in patients with disease relapse after 1 line of chemotherapy and was shown to have a 35% overall response rate (ORR) with higher ORR (45%) and a longer median OS rate (~1 year) for patients who relapsed ≥90 days after chemotherapy.5 Topotecan is a topoisomerase I inhibitor and for many years had been the only drug approved as a second-line treatment for ES-SCLC. In a trial of patients with relapsed disease ≥60 days after first-line therapy, the ORR was 24% with this agent.6 The ongoing LAGOON phase III trial (NCT05153239) is comparing lurbinectedin with or without irinotecan vs investigator’s choice of topotecan or irinotecan as second-line ES-SCLC treatments after 1 previous line of platinum-based chemotherapy with or without an anti–PD-1/PD-L1 antibody.
The most recently approved agent is tarlatamab, which is a bispecific T-cell engager that targets DLL3 and is discussed below.
What Is DLL3?
DLL3 is an inhibitory Notch ligand found on the surface of SCLC cells.7 The Notch signaling pathway is critical for neuroendocrine differentiation, cell proliferation, malignant transformation, and epithelial to mesenchymal transformation.8 DLL3 is a transcriptional target of ASCL1, which is a critical mediator of neuroendocrine development, and is highly expressed among neuroendocrine carcinomas.9
DLL3 Expression in Neuroendocrine Neoplasms
DLL3 expression is infrequent in normal tissue and is largely confined to the cytoplasm. However, neuroendocrine neoplasms (NENs), particularly NENs of high grade, overexpress DLL3 with expression commonly found on tumor cell surfaces.7 For instance, approximately 54% of large-cell neuroendocrine carcinomas (LCNENs) and approximately 85% of SCLC tumors have high DLL3 expression.7,8 Other NENs with DLL3 overexpression include Merkel cell skin cancer, neuroendocrine prostate cancer, and gastroenteropancreatic cancer.
DLL3 Immunohistochemistry Staining by Site of Origin
Seen here are immunohistochemistry stains of several carcinoid tissues to highlight the level of DLL3 expression seen across related NENs. A typical carcinoid is a low-grade NEN, or a neuroendocrine tumor that more rarely expresses DLL3. As NENs become more poorly differentiated and more aggressive, we see increased DLL3 expression that is frequently membranous. For example, atypical carcinoids have moderate expression; LCNENs have strong diffuse DLL3 expression; and >50% of SCLC cells are positive for DLL3.7
Elevated Expression of DLL3 in SCLC and LCNEC
The figure on the left shows high DLL3 mRNA expression measured using quantitative polymerase chain reaction (qPCR) in both tumor and patient-derived xenograft (PDX) SCLC and LCNEC tissue relative to normal lung tissues.10 Similarly, the figure on the right shows levels of membrane-specific DLL3. Here we see that no normal lung tissue or lung squamous cell carcinoma tested positive for surface DLL3 expression, whereas LCNEC and both treatment-naive and R/R SCLC had significant surface expression of DLL3.
DLL3 T-Cell Engager Mechanism of Action
The aim of developing new T-cell engager agents is to force interaction between T-cells and tumor cells using 2 linked antibodies. In the case of DLL3 T-cell engagers, the agents have an antibody subunit targeting DLL3, which is expressed on the tumor cell surface, along with a second antibody subunit targeting CD3, expressed on the T-cell surface.11 This combination essentially forces an interaction between the tumor cells and the T-cells.
In SCLC in particular, T-cell interactions with tumor cells are rare without this type of intervention because T-cells are largely excluded from the tumor microenvironment. DLL3 T-cell engaging antibodies drive T-cells to what is otherwise an immune desert, and subsequently lead to proliferation of those T-cells and eventually T-cell–dependent tumor cell death.11,12
DLL3 T-Cell Engagers in Development
The nuances in design of the various DLL3 T-cell engagers that have reached clinical trials are beyond the scope of this module, but we briefly highlight some of their unique features here.
The general design of all of these DLL3 T-cell engagers is the same, including both a DLL3-targeting region and a CD3-targeting region. However, there are some nuanced differences in their structures. MK-6070, formerly HPN328, is a trispecific molecule that, in addition to the DLL3- and CD3-binding domains, has an antialbumin domain that is intended to extend the agent’s half-life.13,14 R07616789 on the right is also trispecific and has a CD137-binding domain that is intended to engage this costimulatory target.14 Theoretically, this not only binds to T-cells and brings them to the microenvironment, but also helps ensure T-cell activation.
DeLLphi-301: Tarlatamab in Relapsed ES-SCLC
The most mature of the data that we have for DLL3-targeting T-cell engagers is from tarlatamab, which was granted accelerated FDA approval in May 2024, based on the open-label phase II DeLLphi-301 study, which enrolled patients with R/R ES-SCLC.15 Eligible patients for this trial had ≥2 prior lines of therapy, including ≥1 line of platinum-based therapy, as well as an Eastern Cooperative Oncology Group performance status of 0-1 (N = 222). Patients with treated, stable asymptomatic brain metastases were allowed on this trial.
The dose-evaluation stage included a step-up dosing strategy where patients initially received a 1-mg dose on Day 1 followed by a step-up to either 10 or 100 mg on Days 8 and 15 and every 2 weeks thereafter (N = 88 each). The 10-mg dose was selected for dose expansion (N = 12) and was continued with a reduced inpatient monitoring strategy (N = 34). The primary endpoint was ORR evaluated per Response Evaluation Criteria in Solid Tumours version 1.1 by blinded independent central review. Secondary endpoints were DoR, disease control rate (DCR), progression-free survival, OS, safety, and serum concentration.
DeLLphi-301: Response
This figure illustrates the responses seen in 91 patients with R/R ES-SCLC treated with the 10-mg dose.15 At least 1 patient with a partial response had no detectable DLL3 expression, and there were numerous responses that did not have DLL3 evaluable.
The ORR was 40% for the patients treated with the 10-mg dose (N = 100) and 32% for those treated with the 100-mg dose (N = 88). From here we focus on the 10-mg dose, which has since been approved by the FDA. The DCR was 70% the patients treated with the 10-mg dose. Of note, the DoR was impressive for previously treated ES-SCLC patients, with 25% of patients having responses lasting ≥9 months. These patients usually have a limited life expectancy of <6 months.16
DeLLphi-301: Sustained Disease Control
In this figure, we can see that patients responded relatively early, and frequently remained in response during follow-up.17 In this cohort, several patients have been followed for well over a year. Overall, 72% of the patients have had some degree of tumor shrinkage and 26% have had disease control lasting for ≥1 year.
DeLLphi-301: Onset and Duration of Response
This figure illustrates the DoR and treatment status for the 40 patients with complete or partial responses.17 In the context of R/R ES-SCLC, the median DoR of 9.7 months demonstrates a fairly sizable improvement in disease control using tarlatamab compared with historical controls. We also see that at the time of this report, many patients were still on treatment and often experiencing an ongoing response.
DeLLphi-301: Survival
The median OS of 15.2 months is worth emphasizing here.17 Despite the fact that these are relapsed patients, the survival data compares favorably with first-line survival data for platinum-based chemotherapy in combination with atezolizumab (IMpower133 trial) or durvalumab (CASPIAN trial) and other approved regimens.18 This impressive DoR and median OS with tarlatamab in the previously treated disease setting is what we expect to see with immune-based responses, which have the potential to be more durable than other second-line treatments.
DeLLphi-301: OS by Disease Control With Frontline Platinum-Based Chemotherapy
This figure shows the OS outcomes for patients who were progression free for <90 days compared with those who were progression free for ≥90 days following platinum-based chemotherapy.17 The takeaway from these data is that there is not much difference between the 2 populations, so tarlatamab appears to be similarly beneficial in patients with ES-SCLC who have long or short chemotherapy-free intervals post-platinum. This is in contrast to many available therapies for relapsed SCLC that favor patients with longer platinum-free intervals.
DeLLphi-301: CRS and ICANS
One important thing to note is tarlatamab and other T-cell engagers have some unique toxicities with which thoracic oncologists and general oncologists who focus on solid tumors may not have experience. These toxicities include both CRS, a systemic inflammatory response, and immune effector cell‒associated neurotoxicity syndrome (ICANS), which is a neurologic syndrome that happens in response to an inflammatory cascade.
This figure shows that CRS is common after the Day 1 low-dose and the Day 8 stepped-up dose administration of tarlatamab. These doses resulted in 40% and 28% of patients, respectively, with some evidence of CRS.15 However, CRS of grade ≥3 was rare (≤1%). And after these first 2 doses, the occurrence of any degree of CRS greatly decreases (≤6%). The occurrence of ICANS, which also is seen with CAR T-cell therapies, was rare and primarily with early onset (<6 months) with no grade ≥3 events reported.17
Phase I Study of BI 764532 (DLL3/CD3 Bispecific Antibody) in DLL3-Positive Tumors
BI 764532 (proposed international nonproprietary name of obrixtamig) is another DLL3 and CD3 bispecific T-cell engaging agent that is being assessed in ES-SCLC. The first-in-human phase I study of this agent involved several different doses as well as dosing schedules.19,20 This trial enrolled patients who had advanced SCLC, extrapulmonary neuroendocrine carcinoma (epNEC) or pulmonary LCNEC, and had ≥1 prior line of therapy or were ineligible for standard therapies (N = 168). A key characteristic of this trial, unlike the DeLLphi-301 trial, is that it required ≥1% DLL3 expression in archival or in-study biopsies.
Phase I Study of BI 764532: Overall Efficacy
Among all response-evaluable patients, across all histologies and all dosing strategies with BI 764532, the ORR was 18%.20
Phase I Study of BI 764532: Efficacy by Tumor Type
Here we can see efficacy data for the patients who received BI 764532 doses ≥90 μg/kg (n = 135) and with the data separated by the different histologic subtypes of disease.20 For advanced SCLC (n = 65), the ORR was 17%. There was also an additional 26% of patients with stable disease, leading to a DCR of 43%. Comparable data were seen in the patient populations with epNEC (n = 60) and LCNEC of the lung (n = 10). The latter was a smaller subset with impressive response rates and a DCR of 90%. Of note, pulmonary LCNEC is similarly aggressive as SCLC and a disease with its own unmet needs.
Phase I Study of BI 764532: DoR
Numerous patients had responses to BI 764532 that lasted in excess of a year and that are ongoing trending toward 2 years at the time of this report.20 This study of BI 764532 has shown further evidence of the potential for durability of responses to T-cell engager therapies, unlike the transient responses we have seen historically with chemotherapeutic agents.
Phase I Study of BI 764532: Safety Summary
CRS was the most frequently observed treatment-related adverse event (TRAE) reported in this trial, with a rate of 57%.20 And as with tarlatamab, CRS with BI 764532 was often grade 1/2 and generally occurred during the earlier doses. There were also several cases of grade ≥3 CRS and grade ≥3 ICANS, one of which was grade 5, and a grade 5 confusional state. In addition, there were 4 dose reductions and 6 discontinuations because of TRAEs.
First-in-Human Phase I/II Trial of MK-6070 in Patients With SCLC and Other Neuroendocrine Cancers
Next, we discuss the phase I/II trial of MK-6070 (formerly HPN328), which also included patients with various histologies, such as R/R SCLC with ≥1 prior line of therapy including platinum-based chemotherapy, R/R neuroendocrine prostate cancer, and other high-grade NENs that demonstrated DLL3 expression (N = 97).21 Several dosing strategies and schedules of MK-6070 were tested with primary endpoints of safety, tolerability, determining the recommended phase II dose and maximum tolerated dose, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity.
Phase I/II Trial of MK-6070: Response
Patients with advanced SCLC generally did benefit from MK-6070 when treated with a 1-mg priming dose, followed by 12-mg or 24-mg target doses (N = 28).21 This population had an ORR of 39% and a DCR of 71%, and when measuring specifically extracranial responses, ORR and DCR were 50% and 75%, respectively. Later, we discuss how brain metastases and intracranial vs extracranial responses may factor into the use of these agents.
Phase I/II Trial of MK-6070: DoR
This figure shows the DoR with MK-6070 in this trial, with several patients continuing treatment and some ongoing for more than 1 year.21 The ability of new agents like MK-6070 to produce such durable responses in previously treated ES-SCLC is quite exciting and, again, not something frequently seen with previous agents.
Phase I/II Trial of MK-6070: Safety
The toxicities associated with MK-6070 are similar to those seen with other DLL3 T-cell engagers. Any-grade CRS was the most common TRAE reported (63%), but grade ≥3 CRS was rare (3%).21 Some cytopenias were associated with this agent, such as neutropenia (14%) and thrombocytopenia (12%). Other relatively common adverse effects reported with MK-6070 are more familiar to healthcare professionals who focus on solid tumor oncology, such as nausea (23%), fatigue (21%), and diarrhea (19%).
Analysis of CNS Activity
Trials with DLL3 T-cell engagers include special considerations for central nervous system (CNS) activity. Many to date have excluded patients who had active or symptomatic brain metastases but have generally allowed patients with previously treated or asymptomatic CNS disease. This has allowed for retrospective analyses for evidence of activity in the CNS in patients who received DLL3-targeted T-cell engager therapy.
DeLLphi-301: Intracranial Antitumor Activity
In the DeLLphi-301 trial, 17 patients had baseline CNS lesions that were ≥10 mm and were treated with either 10-mg or 100-mg doses of tarlatamab.22 Among this small group of patients, 59% had ≥30% CNS tumor shrinkage and 94% of them had intracranial disease control with only 3 experiencing CNS progression.
Phase I/II Trial of MK-6070: CNS Antitumor Activity
Similar data are seen from the MK-6070 trial, which enrolled 28 patients with a history of brain metastases.23 Nine of these patients had eventual CNS progression. Of note, 5 of 20 patients who had brain metastases at baseline experienced complete response in the brain (25%) and no new CNS disease developed among 24 patients without a history of brain metastases.
So, there are early hints of activity in the central nervous system for DLL3-targeted T-cell engager therapies. Whether this effect is because of T-cells that have been amplified in the periphery and are circulating and seeking out DLL3-expressing tumor cells is currently not known.
Select Trials of DLL3-Targeting T-Cell Engagers in SCLC
There are numerous ongoing and future trials that are incorporating various DLL3-targeting T-cell engagers. DeLLphi-305 and 306 trials are incorporating tarlatamab into earlier lines of therapy, such as immediately following chemoimmunotherapy for ES-SCLC as part of a maintenance strategy or immediately following chemoradiation for limited-stage SCLC. There are also ongoing studies for BI 764532 as a frontline therapy in combination with chemoimmunotherapy and for R/R ES-SCLC in combination with chemotherapy. There are also studies evaluating the safety and early-phase efficacy of QLS31904 and RO7616789.
DLL3-Targeted T-Cell Engagers in SCLC: Conclusions
DLL3 is highly expressed at the surface of SCLC tumor cells as well as other NENs, particularly those with high-grade histology. At least 3 bispecific and trispecific T-cell engager agents have demonstrated antitumor activity in SCLC and other DLL3-positive disease entities such as epNEC, neuroendocrine prostate cancer, and pulmonary LCNEC. Now, tarlatamab is the first FDA-approved DLL3-targeting T-cell engager indicated for adults with ES-SCLC and disease progression on or after platinum-based chemotherapy. In the future, we may see the approval of additional DLL3-targeted T-cell engager therapies with differing properties.
It is worth noting the unique toxicities that come with this class of drugs and similar therapies that will undoubtedly follow. CRS and ICANS have been observed with all of the tested DLL3-targeting T-cell engaging therapies to date. These toxicities have generally been low-grade in the study populations where patients had very good baseline performance status. As these agents enter standard clinical practice, we as healthcare providers need to be aware of and prepared to manage both CRS and ICANS.
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