DLL3-Targeting BiTE Therapy in SCLC: A Pharmacist’s Guide to Evidence and Integration

Why Target DLL3 in SCLC?

DLL3 is an inhibitory Notch ligand abnormally expressed on the surface of SCLC cells in 85% to 94% of patients, but it is rarely found on healthy tissues.^3-5 This makes it an interesting tumor-associated antigen for targeted therapy. It is important to note that DLL3 is especially prevalent in immunologically “cold” tumors—those that are poorly responsive to checkpoint inhibitors—offering a biologic mechanism to convert these tumors into an inflammatory, immunogenic microenvironment.^6,7

Mechanism and Structure of DLL3-Targeting BiTEs Currently in Development

Tarlatamab is the most clinically advanced DLL3-targeting BiTE. It is a single-chain bispecific fusion protein that simultaneously binds DLL3 on tumor cells and CD3 on T cells, triggering T-cell recruitment, activation, and cytotoxic synapse formation. This ultimately leads to amplification of the immune response via cytokine release and tumor cell apoptosis.³

Other BiTEs in development include BI 764532, a full-length IgG-based BiTE targeting DLL3 and CD3, and HPN328, a trispecific antibody structure that includes an anti-albumin domain to extend half-life. These agents vary structurally in ways that may influence administration, half-life, and toxicity profiles, factors that pharmacists will need to evaluate carefully when managing therapy.

As these therapies approach broader availability, proactive pharmacist engagement in clinical workflows, patient education, and adverse-event management will be key to their successful integration.

Safety and Pharmacovigilance Considerations with BiTEs

Shelby L. Quinn presented her frontline experiences in managing tarlatamab-related adverse events (AEs) at her institution in her presentation, “Safety and Dosing Considerations With Novel DLL3-Targeting BiTE Therapy.” In particular, she highlighted the pharmacist’s role in the drug’s implementation and offered tips for effectively managing AEs and mitigating barriers to implementation.⁸

The Role of the Hematology/Oncology Pharmacist in Implementing Tarlatamab

When it comes to the pharmacist’s role in implementing this novel therapy, education is key, Dr Quinn noted.

“As for the pharmacist’s role in this, it’s pretty significant,” Dr Quinn shared in an interview. “Not only are we providing education to patients, but we also are providing education to other healthcare professionals. For example, if you have a dedicated inpatient solid tumor team that’s going to be managing these patients, this might be the first BiTE therapy they’re seeing, and they may not be familiar with how to manage these side effects or these therapies.”

In addition, she noted that in practices where providers may treat multiple oncology disease states, they may not be as familiar with tarlatamab and how to optimize this therapy in patients.

Managing Adverse Events: Focus on CRS and ICANS

Pharmacists also play an essential role in adverse-event management, and knowledge gained from the use of BITE therapy in hematology can be applied in SCLC.

“It's been a learning curve,” said Dr Quinn. “But BiTE therapies aren’t new. They’ve been in the hematology setting for quite some time, and these practitioners have been able to really hone their skills in managing some of these side effects seen with BiTE therapies. Your institution may have existing protocols describing management approaches should these side effects occur.”

The most serious adverse events associated with tarlatamab are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS, an AE that can have potentially life-threatening complications, typically arises during doses 1 and 2.⁹ For this reason, patients receiving the drug must undergo inpatient monitoring for up to 24 hours on cycle 1 day 1 and cycle 1 day 8; in addition, it is recommended that patients remain within 1 hour of an appropriate healthcare center for the first 48 hours after the start of each cycle.¹⁰ To reduce the risk for and severity of CRS, step-up dosing and concomitant medications such as dexamethasone and saline are used.

Although it occurs less frequently than CRS, ICANS can happen at any point after receiving tarlatamab, making patient and caregiver education critical so this adverse event can be detected in the outpatient setting. “My advice to other pharmacists is really honing in on that, because we may not identify ICANS during an infusion or office visit. Patients and caregivers need to know what to look for so we can identify and treat these adverse events early,” Dr Quinn suggested.

Both CRS and ICANS necessitate inpatient management, with treatment based on the grade of the adverse event. Medications used to manage these AEs include tocilizumab, dexamethasone, siltuximab, and anakinra.¹¹ Tarlatamab is withheld until AE resolution and can be restarted except in patients with recurrent grade 3 CRS/ICANS or grade 4 CRS/ICANS, which necessitate permanent tarlatamab discontinuation.¹⁰ For grade 3 ICANS with no improvement to grade ≤1 within 7 days or that reoccurs within 7 days of reinitiation, tarlatamab should also be permanently discontinued.¹⁰

Addressing Barriers to Access and Equity in Care

Tarlatamab has shown promising overall survival benefit,^3,12-14 yet barriers to care can prevent some patients from receiving this treatment, in particular, patients traveling from rural areas. With the required 24-hour inpatient monitoring period and remaining within 1 hour of a treatment center for 48 hours after certain infusions, access to care can be complicated for rural patients.

“We want to make sure that we don’t have disparities in care for these patients,” said Dr Quinn. “And so it may take an extra step to find suitable housing for those first 2 admissions for patients and caregivers to be close enough to meet those requirements for that 48-hour rule, to be within 1 hour of the healthcare setting.”

At Dr Quinn’s institution, multidisciplinary support teams—including social workers and patient assistance and financial toxicity coordinators—collaborate to address access to care, while pharmacists ensure that the therapy and its supportive care are in place. The goal of this coordinated approach is to ensure that treatment is available, accessible, and equitable.

“A multidisciplinary approach is really the key to be successful in giving this therapy,” stated Dr Quinn.

The 2 Midnight Rule: Reimbursement and Practical Implications

Observing Medicare’s 2-Midnight rule can help address reimbursement challenges. Patients observed for fewer than 2 midnights qualify for outpatient reimbursement of medications, which is typically more cost-effective.

In Dr Quinn’s institution, tarlatamab’s administration strategy of giving the drug in the outpatient setting and then admitting patients under observation helps to align with this rule. “In that 24-hour period, if patients experience ICANS, we can treat it quickly and efficiently,” noted Dr Quinn.

However, “if a patient remains beyond that 2-Midnight rule, it flips from an observation to hospital admission, and then you are no longer getting outpatient reimbursement,” she added. “Thus, it will likely be more expensive for your healthcare system and the patient.

Key Takeaways for Hematology/Oncology Pharmacists

1. Prioritize education: Ensure all those involved in treatment—patients, caregivers, nurses, and providers—are educated about BiTE therapy management, especially in settings unfamiliar with using BiTE therapy in solid tumors.
2. Address disparities in care: Use a multidisciplinary approach to mitigate barriers related to housing, cost, and logistics. Aim to provide equitable access regardless of a patient’s geographic or financial situation.
3. Develop and follow institutional protocols: Be familiar with—and advocate for—clear institutional guidelines for managing toxicities like CRS and ICANS. These protocols are critical for timely, effective intervention, especially during off-hours.

Looking Ahead

As BiTE therapies continue expanding beyond hematology into the treatment of patients with solid tumors, pharmacists remain essential to their successful adoption. Dr Quinn’s insights offer a valuable blueprint for institutions looking to integrate these therapies effectively, equitably, and safely.

“I’m meeting with providers now about trials for BiTE therapies, and implementing those is a lot of work, especially for the inpatient team during the initial doses and monitoring,” she said. “So, I think it’s going to be very interesting. It’s exciting, and great for patients,” she concluded.

Editor’s Note: This article summarizes segments in the presentation “DLL3-Targeting BiTE Therapy in SCLC: A Pharmacist’s Guide to Evidence and Integration” by Amanda Cass, PharmD, BCPS, BCOP, Clinical Pharmacist Specialist, Vanderbilt-Ingram Cancer Center, Nashville, TN, and Shelby Quinn, PharmD, BCOP, Oncology Clinical Pharmacy Coordinator, Thoracic/Head & Neck Oncology, Atrium Health Levine Cancer, Charlotte, NC, given at the 21st Hematology/Oncology Pharmacy Association Annual Conference (April 9-12, 2025; Portland, OR). This continuing education presentation was supported by an educational grant from Amgen.

References

1. Horn L, Mansfield AS, Szczesna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379:2220-2229.
2. Reck M, et al. European Society for Medical Oncology Congress 2019 (ESMO 2019). Abstract 2374.
3. Paz-Ares L, Champiat S, Lai WV, et al. Tarlatamab, a first-in-class DLL3-targeted bispecific t-cell engager, in recurrent small-cell lung cancer: an open-label, phase I study. J Clin Oncol. 2023;41:2893-2903.
4. National Comprehensive Cancer Network. Small Cell Lung Cancer. Version 4.2025. Accessed June 22, 2025. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf
5. Giffin MJ, Cooke K, Lobenhofer EK, et al. AMG 757, a half-life extended, DLL3-targeted bispecific t-cell engager, shows high potency and sensitivity in preclinical models of small-cell lung cancer. Clin Cancer Res. 2021;27:1526-1537.
6. Rudin CM, Reck M, Johnson ML, et al. Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer. J Hematol Oncol. 2023;16:66.
7. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39:346-360.e7.
8. Cass AS, Hafez, N, Quinn SL. DLL3-targeting BiTE therapy in SCLC: a pharmacist’s guide to evidence and integration. Presented at the Hematology/Oncology Pharmacy Association 21st Annual Conference; April 9, 2025; Portland, OR.
9. Sands JM, Champiat S, Hummel HD, et al. Practical management of adverse events in patients receiving tarlatamab, a delta-like ligand 3–targeted bispecific T-cell engager immunotherapy, for previously treated small cell lung cancer. Cancer. 2025;131:e35738.
10. Imdelltra (tarlatamab-dlle) for injection, for intravenous use [prescribing information]. Amgen; May 2024. www.pi.amgen.com/united_states/Imdelltra/Imdelltra_fpi.pdf
11. Crombie JL, Graff T, Falchi L, et al. Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy. Blood. 2024;143:1565-1575.
12. Dowlati A, Hummel HD, Champiat S, et al. Sustained clinical benefit and intracranial activity of tarlatamab in previously treated small cell lung cancer: DeLLphi-300 trial update. J Clin Oncol. 2024;42:3392-3399.
13. Sands J, Cho BC, Ahn MJ, et al. Tarlatamab sustained clinical benefit and safety in previously treated SCLC: DeLLphi-301 phase 2 extended follow-up. Abstract OA10.03. Presented at the IASLC World Conference on Lung Cancer; September 9, 2024; San Diego, CA.
14. Dingemans AMC, Ahn MJ, Blackhall FH, et al. DeLLphi-301: tarlatamab phase 2 trial in small cell lung cancer (SCLC)—efficacy and safety analyzed by presence of brain metastasis. J Clin Oncol. 2024;42(16 suppl):Abstract 8015.