Tarlatamab-dlle: A Beginning for Bispecific Therapies in Small Cell Lung Cancer

Précis

Second-line and later treatment options for small cell lung cancer are limited. Tarlatamab offers a new approach to small cell lung cancer therapy, demonstrating long-lasting responses and tolerable adverse effects in pretreated patients.

Introduction

Image credit: Dr_Microbe | stock.adobe.com

Small cell lung cancer (SCLC) is a highly proliferative malignancy and the most aggressive type of lung cancer, accounting for 15% of bronchogenic carcinomas worldwide.^1,2 Although the overall incidence of and mortality rate for SCLC have decreased over the last several decades, the 5-year survival rate continues to be poor, at less than 10%.² SCLC is known to be responsive to chemotherapy and radiotherapy,¹ but more recent developments indicate that it is also responsive to immunotherapy, although less so than other types of cancer.¹ Patients with SCLC treated with platinum-based therapy in the first-line setting may be retreated with platinum-based therapy if the platinum-free interval has been more than 6 months¹; those with SCLC who are platinum resistant may be treated with agents such as lurbinectedin (Zepzelca; Jazz Pharmaceuticals, Inc), which has demonstrated a response rate of 35.2% or greater depending on the chemotherapy-free interval but a short duration of response (DOR; median, 5.3 months).³ Because the historical standard of care for SCLC (ie, chemoimmunotherapy) produces high initial response rates that are short-lived—particularly for extensive-stage SCLC—there remains an unmet need for more effective treatment options with durable responses, particularly once initial therapy has failed.³

In May 2024, the FDA granted accelerated approval to tarlatamab-dlle (Imdelltra; Amgen Inc) for the treatment of adult patients with extensive-stage SCLC with disease progression on or after at least 1 platinum-based chemotherapy. The approval was based on the agent demonstrating long-lasting responses in pretreated patients and made tarlatamab the first bispecific T-cell engager therapy for SCLC.⁴

Mechanism of Action

Delta-like protein 3 (DLL3) is an attractive therapeutic target because it is overexpressed in SCLC cells in 85% to 94% of patients with SCLC and minimally expressed in normal cells, and it acts as an inhibitor of the Notch signaling pathway,^5,6 which is a neuroendocrine differentiation regulator in SCLC that causes cell proliferation when aberrantly activated.^5,6 Tarlatamab is a bispecific T-cell engager that binds to DLL3 on the surface of cancer cells and to CD3 on the surface of T cells, leading to T cell–mediated lysis of DLL3-expressing cells.^5-8 DLL3 testing via immunohistochemistry is not required for the use of tarlatamab in extensive-stage SCLC.⁵

Dosage and Administration

Tarlatamab requires a step-up dosing schedule for the first cycle to reduce the incidence and severity of cytokine release syndrome (CRS), one of the major adverse effects (AEs) of this medication.⁵ Table 1 shows the dosing schedule, recommended monitoring, and concomitant medications. The cycle repeats every 28 days, with tarlatamab 10 mg administered on day 1 and day 15, except for cycle 1.⁵

Tarlatamab is administered over 1 hour. Dexamethasone 8 mg is recommended prior to tarlatamab for cycle 1 day 1 and day 8 doses only, and 1 L of normal saline over 4 to 5 hours is recommended post infusion for days 1, 8, and 15 of the first cycle.⁵

CRS, cytokine release syndrome; ICANS, immune effector cell–associated neurotoxicity syndrome; IV, intravenous; NA, not applicable; NS, normal saline.

^aTarlatamab treatment cycles are typically 28 days.

^bPatients who experienced grade ≥ 2 CRS, ICANS, or neurological toxicity during prior tarlatamab infusion require extended monitoring in a health care setting.

Clinical Data

Tarlatamab was first evaluated in the phase 1 DeLLphi-300 trial (NCT03319940) and demonstrated durable antitumor activity and a manageable safety profile.⁸ These findings led to the subsequent phase 2, open-label, international DeLLphi-301 trial (NCT05060016), on which the FDA based its approval of tarlatamab.⁴

The primary end point of the DeLLphi-301 trial was confirmed objective response (complete or partial response). Patients were eligible if they were 18 years or older and had histologically confirmed SCLC and an ECOG performance status of 0 or 1, and had received at least 2 prior lines of therapy. Patients with asymptomatic, treated, stable brain metastases were also included in the trial.⁹

DeLLphi-301 was conducted in 3 parts: Part 1 was a dose-comparison assessment of 176 patients who had been randomly assigned 1:1 to receive tarlatamab 10 mg or 100 mg. Investigators performed an interim analysis after 30 patients in each group were evaluable for objective response or had been followed for 13 weeks, whichever came first. After analyzing the data, a dose-selection committee recommended the target dose of 10 mg for parts 2 and 3 of the trial. In part 2, additional patients were enrolled (n = 12) at the 10-mg dose so that 100 patients (parts 1 and 2 combined) were reached. Part 3 was a safety substudy after part 2 enrollment completion that evaluated the reduced duration of inpatient monitoring (from 48 to 24 hours) following administration of the first 2 doses of tarlatamab.⁹

Patients enrolled in the study were predominantly former smokers, had a median age of 62.0 to 65.5 years, and had received a median of 2 prior lines of treatment. Twenty-three patients in the 10-mg tarlatamab group (parts 1 and 2) and 32 patients in the 100-mg tarlatamab group (part 1) had brain metastases. Median follow-up among those evaluated for antitumor activity and survival was 10.6 months in the 10-mg group and 10.3 months in the tarlatamab 100-mg group.⁹

The objective response rate (ORR) was 40% (97.5% CI, 29%-52%) in the 10-mg group and 32% (97.5% CI, 21%-44%) in the 100-mg group.⁹ Among patients with an objective response, the DOR—a secondary end point of the trial—was at least 6 months in 59% of patients, with objective responses ongoing at the time of data cutoff in 55% of responders in the 10-mg group and 57% of responders in the 100-mg group.9 Median progression-free survival was 4.9 months (95% CI, 2.9-6.7) and 3.9 months (95% CI, 2.6-4.4) in the 10-mg and 100-mg groups, respectively.⁹

Additionally, investigators performed safety and efficacy analyses by the presence or absence of baseline brain metastases. The overall systemic ORR was 45.3% and 32.6% in patients with and without brain metastases, respectively. In the 10-mg tarlatamab group, the ORR was 54.5% in those with brain metastases and 36.4% in those without and any grade of immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 14% and 6% of patients with and without brain metastases, respectively; grade 3 or greater ICANS occurred only in patients in the 100-mg group and did not lead to tarlatamab discontinuation in any patient with brain metastases.¹⁰

Adverse Events

The most common AE during the treatment period of the DeLLphi-301 trial was CRS, which occurred in 51% and 61% of patients in the 10-mg and 100-mg tarlatamab groups, respectively,^5,9 primarily at grade 1/2 (50% and 53%).⁹ Grade 3 CRS occurred in 1% and 6% of patients in the 10-mg and 100-mg groups, respectively, and required vasopressin.^8,9 The median onset of CRS (all grades) was 13.1 hours (range, 7.8-27.4), with a median duration of 4 days (IQR, 2-6).⁹ The most common symptoms among patients with CRS were fever, hypotension, and hypoxia.⁹ Most patients with CRS were treated with fluids, acetaminophen, and glucocorticoids, with additional interventions such as supplemental oxygen, vasopressor support, and tocilizumab used as necessary for grade 3 CRS.^5,9 Two patients in the trial’s part 3 reduced-monitoring cohort (from which a significant portion of the recommendations for supportive care for CRS was derived⁵) received tocilizumab for grade 3 CRS.⁹

Neurologic toxicity including ICANS occurred in 47% of patients.⁹ Nine percent of patients experienced any grade of ICANS,⁵ and no patients in the 10-mg group (parts 1 and 2) experienced grade 3 or higher.⁹ Recurrent ICANS occurred in 1.6% of patients treated with tarlatamab.⁹

During the DeLLphi-301 trial, most cases of ICANS occurred during cycle 19; however, pooled safety population data from tarlatamab’s prescribing information show that most patients experienced ICANS after the cycle 2 day 1 dose,⁵ which has also been this author’s experience thus far. The median time to onset of ICANS from the first dose of tarlatamab in the pooled safety population was 29.5 days, with a median time to resolution of 33 days.⁵

AE, adverse effect.

^aBesides cytokine release syndrome.

Table 2⁵ shows other significant AEs of tarlatamab that occurred in patients with extensive-stage SCLC in the DeLLphi-300 and DeLLphi-301 trials. Laboratory abnormalities that worsened from baseline in patients from both trials included hyponatremia, hypokalemia, decreased lymphocytes, decreased neutrophils, and increased liver enzymes.⁵ Table 3 highlights the AE differences between the 10-mg dose and the 100-mg dose of tarlatamab in the DeLLphi-301 trial⁹; of note, neutropenia or febrile neutropenia did not lead to treatment discontinuation in any patient.⁹

Tarlatamab's Place in Therapy

The National Comprehensive Cancer Network (NCCN) guidelines recommend tarlatamab as a second-line treatment option for platinum-sensitive extensive-stage SCLC (ie, an alternative to retreatment with platinum-based chemotherapy). It is also one of the preferred second-line options for patients with platinum-resistant extensive-stage SCLC. The NCCN guidelines note that these recommendations are based on the promising durability of response and acceptable safety profile of tarlatamab.¹¹

The FDA approved tarlatamab for patients with extensive-stage SCLC with disease progression on or after at least 1 platinum-based therapy, but the DeLLphi-301 trial enrolled patients with at least 2 prior lines of treatment. This raises the question: Who is the ideal patient for tarlatamab? The DeLLphi-301 trial included patients with a fairly robust performance status who were not chemotherapy naive. In clinical practice, providers need to take into account whether the patient, at the time of progression, is fit enough to handle tarlatamab. Additionally, patients who have received radiation, particularly whole-brain radiation, could be at risk for neurotoxicity depending on the time interval between the end of radiation and the start of tarlatamab. As we see more data on tarlatamab, perhaps some of our initial questions will be answered.

CRS, cytokine release syndrome; ICANS, immune effector cell–associated neurotoxicity syndrome.

^aThis cohort is most similar to the real-world patient population receiving tarlatamab because during part 3 of the trial, investigators evaluated the reduced duration of inpatient monitoring (from 48 to 24 h) following administration of the first 2 doses of tarlatamab.

Clinical Considerations

Several bispecific therapies are utilized in hematology, with some variation in how to premedicate to mitigate the risk of and manage CRS or ICANS. For tarlatamab, due to the risk of CRS and neurologic toxicity, including ICANS, the package insert recommends monitoring patients in an appropriate health care facility for 22 to 24 hours after the first 2 doses.⁵ It is up to the institution what is the best course of action to do this safely. Moreover, clinicians may want to consider additional premedications (eg, acetaminophen, diphenhydramine, famotidine) plus dexamethasone to prevent or lessen the severity of CRS or ICANS, which have been successful with other bispecific specific therapies in other types of cancer.¹² Data are limited on the real-world toxicities of tarlatamab, but more will become available as additional patients are treated with the agent.

Tarlatamab has a significant risk of lymphopenia, and in solid tumor malignancies, antimicrobial prophylaxis is not typically used up front.5,9 We will need more clinical data to know whether antiviral prophylaxis and Pneumocystis jirovecii pneumonia prophylaxis are necessary when lymphopenia occurs. Other hematologic abnormalities have been seen with this medication,^5,9 but additional supportive measures are at the provider’s discretion because they are not mentioned in the package insert.

Logistical Considerations

Because of the risk of CRS and ICANS with tarlatamab, it is up to the institution whether outpatient administration of tarlatamab for the first 2 doses is adequate.⁵ Some institutions are equipped with clinics that cater to patients on bispecific therapies and with staff who are adequately educated on the signs and symptoms of CRS and ICANS and on the proper procedures to follow when CRS or ICANS occurs. Other institutions may prefer inpatient administration of the first dose of tarlatamab and outpatient administration for dose 2 with inpatient observation. Patient safety as well as costs and revenue must be factored into these decisions. Another consideration is that some patients travel to be treated at a cancer center or high-acuity hospital but live in an area where the local hospital is not equipped to handle CRS or ICANS; therefore, it would be helpful to give these patients information on tarlatamab to provide to their local emergency department should an emergency arise.

Conclusions

Tarlatamab has a place in therapy as a second-line agent for SCLC, with a novel mechanism of action not previously seen in this disease state.¹¹ Future research on tarlatamab could include longer-term overall survival data and possible prospective trials for patients with small cell neuroendocrine cancers of the prostate because these cancers act similarly to SCLC. Findings from a phase 1b trial presented at the 2024 American Society of Clinical Oncology Annual Meeting on tarlatamab monotherapy in patients with metastatic de novo or treatment-emergent neuroendocrine prostate cancer showed a median progression-free survival of 1.9 months.¹³ Additionally, HPN328, a trispecific half-life–extended DLL3-targeting T-cell engager, demonstrated clinical activity and tolerability in patients with SCLC and other neuroendocrine cancers.¹⁴ The National Cancer Institute notes that regardless of the stage, the prognosis for patients with SCLC is “unsatisfactory” despite improvements in diagnosis and therapy over the past few decades.¹ Tarlatamab offers a new approach for treating this aggressive cancer and will hopefully shed light on the overall immunogenicity of SCLCs to allow more targeted agents to be developed.

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