The Tarlatamab Takeover: Targeting DLL3 in Extensive Stage Small Cell Lung Cancer

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, accounting for roughly 15% of all cases. For decades, the disease saw no successful trials or new approvals, leaving platinum–etoposide chemotherapy as the standard of care—an approach plagued by poor outcomes and rapid resistance.

SCLC presents a paradoxical biological profile, which contributes to the challenge of developing efficacious therapies. Although SCLC carries a very high DNA damage and mutation burden, it behaves as an "immune desert" with very few T cells in the tumor microenvironment. Historically, this meant no actionable oncogenic drivers and no targeted therapies.

However, there have been key advancements over the past decade, representing a new frontier in the SCLC treatment landscape. The addition of immune checkpoint inhibitors in the first line represented the first significant shift to chemo-immunotherapy. Adding a PD-L1 inhibitor such as durvalumab (Imfinzi; AstraZeneca) or atezolizumab (Tecentriq; Roche) to a platinum-based chemotherapy and etoposide backbone improved overall survival (OS) compared with chemotherapy alone and became the latest standard for treatment of extensive-stage SCLC (ES-SCLC). This was followed by the introduction of lurbinectedin (Zepzelca; Jazz Pharmaceuticals), which received initial approval in the second line setting and is presently used as maintenance setting alongside atezolizumab. It represents one of the first nonplatinum agents to gain a defined role in SCLC—another step forward in SCLC treatment evolution.

Introducing T-Cell Engagers to SCLC Treatment

Tarlatamab (Imdelltra; Amgen) represents a significant advancement in SCLC care as the first approved therapy capable of targeting tumor-associated surface antigens, breaking a decades-long drought in which the disease lacked any targetable molecular vulnerability. It is a T-cell engager (TCE) designed to target DLL3, an inhibitory Notch ligand that is highly expressed on SCLC and other high‑grade neuroendocrine carcinomas but minimally expressed in most normal tissues. Often, DLL3 is most highly expressed in immune‑cold SCLC subtypes. Tarlatamab exploits this by functioning as a bispecific antibody that simultaneously binds DLL3 on tumor cells and CD3 on T cells, physically bridging the 2 and forcing an immune interaction.

“DLL3 is most highly expressed in those SCLC tumors that are immune-cold—and I really can't emphasize enough that small cell lung cancer is an immune desert,” said Carl M. Gay, MD, PhD, associate professor in the department of thoracic/head and neck medical oncology at University of Texas MD Anderson Cancer Center. “Over 80% of SCLC cases have essentially a complete absence of T cells, and frankly, many immune cells altogether—certainly the ones that are helpful—as well as low expression of immune checkpoints. They don't need them. There are no T cells there to exhaust.”

Tarlatamab was investigated in the phase 3 DeLLphi-304 trial (NCT05740566) for treatment of patients with relapsed SCLC following first-line chemotherapy or chemo-immunotherapy who had preserved performance status. They were randomized to receive either tarlatamab or investigator's choice chemotherapy, which included agents such as topotecan and lurbinectedin.

The trial met its primary end point, demonstrating a significant OS benefit with tarlatamab—a more than 5-month improvement in median OS, with the tarlatamab arm reaching approximately 13.6 months. Progression-free survival (PFS) showed only a modest numerical improvement of roughly 0.5 months, but the PFS curve exhibited a meaningful tail, reflecting a subset of patients who derive durable, long-lasting benefit. The survival advantage was consistent across key subgroups, including patients who had or had not received prior PD-L1 therapy, across chemotherapy-free interval categories, and in patients with or without brain.

From a safety standpoint, the overall rate of treatment-emergent adverse events was similar between arms, though the toxicity profiles differed in character. Tarlatamab was associated with cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and dysgeusia reflecting on-target, off-tumor effects, while chemotherapy carried the expected risks of myelosuppression and nausea. Grade 5 events and permanent discontinuations were low in both arms.

Treatment Approaches for SCLC

In ES-SCLC, tarlatamab is preferred in the second line over traditional chemotherapy following treatment with first-line chemo-immunotherapy and maintenance with a PD-L1 inhibitor alone or in combination with lurbinectedin. Underlying this sequencing is a core principle emphasized throughout the talk: the best drugs should be deployed earlier, because roughly half of patients are lost at each line of therapy due to attrition.

Efforts are now underway to move tarlatamab into earlier lines of therapy. The DeLLphi-303 trial (NCT05361395), a phase 1/2 study, explored adding tarlatamab during the maintenance phase alongside durvalumab or atezolizumab following standard frontline chemo-immunotherapy. While primarily designed to assess the safety and tolerability of this early combination, the efficacy signals were striking.

The estimated median OS exceeded 2 years, substantially better than the roughly 12 to 13 months seen historically with chemo-imunotherapy alone and even the 16 to 17 months associated with newer maintenance approaches. These results must be interpreted cautiously given the early-phase design, small sample size, and lack of randomization against a modern control, but they are encouraging.

Managing Toxicities With TCEs

Several strategies are employed to reduce the toxicity burden of tarlatamab, particularly the risk of CRS. Step-up dosing is the cornerstone of this approach: patients receive 1 mg on day 1, followed by 10 mg on days 8 and 15, and then 10 mg every 2 weeks thereafter. This gradual escalation is designed to blunt the intensity of first-dose CRS. The first 2 doses carry the highest risk and require in-hospital or observation-level monitoring for approximately 24 hours, and patients must remain within 1 hour of a hospital for 48 hours following each of these early doses. The resource burden decreases with subsequent doses, which are typically administered in the outpatient setting with shorter observation periods.

Premedication and hydration further reduce toxicity risk. Dexamethasone is given ahead of infusion to dampen the cytokine surge, and one liter of normal saline is administered as pre- or peri-infusion hydration. Together, these measures have meaningfully reduced both the frequency and severity of CRS in real-world practice. Dose delays must also be managed carefully: if a gap between doses becomes too prolonged, patients may need to repeat the step-up sequence to mitigate the reemergent CRS risk. The specific thresholds that trigger this reescalation are defined in the prescribing information and institutional protocols, but once a patient tolerates the 10-mg dose uneventfully again, they generally return to the standard every 2-week schedule.

CRS

Grade 1 CRS, characterized by fever alone in a hemodynamically stable patient, is managed with supportive care including antipyretics and oral or intravenous fluids. Steroids such as dexamethasone may be considered if symptoms persist or begin to escalate, and tarlatamab is typically held until resolution before being resumed under close monitoring.

Grade 2 CRS warrants a more aggressive response including hospitalization if the patient is not already inpatient, IV fluids, supplemental oxygen, and dexamethasone, for which the threshold to initiate is relatively low. Tocilizumab (Actemra; Genentech, Inc) is kept readily available at many centers and is administered if there is not rapid improvement with fluids and steroids alone. Tarlatamab is withheld until full resolution but is not permanently discontinued for grade 2 CRS—patients resume at the next scheduled dose.

Grade 3 and 4 CRS require intensive care unit (ICU)-level support, including vasopressors, high-flow oxygen, or ventilatory support as needed, along with high-dose steroids and tocilizumab. In refractory cases, additional cytokine blockade with agents such as anakinra may be considered. Grade 4 CRS typically results in permanent discontinuation of tarlatamab.

ICANS

Pharmacists should monitor for evidence of ICANS regularly with ICE scoring and remain alert to new confusion, worsening lethargy, language changes, or seizure-like activity. An important practical nuance is the need to distinguish true ICANS from other causes of neurological change, including sedating medications, polypharmacy, metabolic derangements, infection, or stroke, as these require fundamentally different management.

Management is graded in parallel with severity. Grade 1 ICANS is managed with supportive care and frequent neurological checks, with tarlatamab typically withheld temporarily. At grade 2 and above, dexamethasone should be initiated promptly, a neurology consult obtained, and MRI brain performed to evaluate for cerebral edema or alternative etiologies.

Many centers initiate antiepileptic drugs early in the setting of ICANS, and some do so prophylactically, though practice varies and there is ongoing reconsideration of how aggressively this is pursued. More severe cases may require ICU-level care, airway protection, and escalating steroid doses. Unlike CRS, tocilizumab plays a less central role in ICANS management—the approach is predominantly steroid-driven with close neurological support.

The Pharmacist’s Role

Pharmacists play a central role across the full arc of tarlatamab treatment. In the pretreatment phase, they assess comorbidities and prior toxicities to help select the safest regimen, review concomitant medications for interactions and CNS-affecting drugs that could confound ICANS assessment, and provide education to patients and caregivers on CRS symptoms, neurological changes to watch for, and when and where to seek help.

During treatment, pharmacists ensure that necessary medications are available and support the logistical demands of step-up dosing, inpatient versus outpatient scheduling, and monitoring requirements. On the operational and reimbursement side, pharmacists help design and implement workflows around the 2-midnight rule and observation status, allowing hospital-level monitoring to be billed as outpatient care and reducing insurance denials. They also play a key role in insurance appeals, particularly for off-label use in neuroendocrine carcinoma cases.

“Really implementing tarlamamab and BiTE therapies is a challenge, and it takes not just the pharmacist or the oncologist, but a multifaceted all the stakeholders need to be involved and on the same page,” said Shelby L. Quinn, PharmD, BCOP, oncology clinical pharmacy coordinator at Atrium Health Levine Cancer Institute in Charlotte, North Carolina. “It requires a ton of coordination and education..."

The emergence of tarlatamab marks a turning point in the treatment of SCLC—a disease that resisted therapeutic progress for decades. Pharmacists, oncologists, and the broader care team must be equipped not only to administer these agents safely, but to anticipate and manage their unique toxicity profiles with confidence. The infrastructure built around tarlatamab will serve as a foundation for the next generation of T-cell engagers and bispecific antibodies likely to follow in SCLC and beyond.

REFERENCES

Gay C, Quinn S. The 3 P’s of pharmacist focused ES-SCLC care with DLL3 targeting T-cell engagers: Plans, protocols, and patient education. Presented at: 2026 HOPA Annual Meeting. March 26-28, 2026. New Orleans, LA.