Comprehensive Report on Tarlatamab (Imdelltra)

I. Introduction to Tarlatamab (Imdelltra)

A. Overview and Development

Tarlatamab, also known by its development code AMG-757 and marketed under the brand name Imdelltra, is an innovative antineoplastic agent engineered and developed by Amgen.[1] It represents a significant advancement in immunotherapy, specifically as a first-in-class agent targeting Delta-like ligand 3 (DLL3).[1] The development of Tarlatamab has been driven by the critical unmet medical need in treating aggressive hematological malignancies and solid tumors, particularly extensive-stage small cell lung cancer (ES-SCLC), a disease notorious for its rapid progression and limited effective treatment options following initial platinum-based chemotherapy.[5]

The designation of Tarlatamab as a "first-in-class" bispecific T-cell engager (BiTE) targeting DLL3 signifies a novel therapeutic strategy for SCLC.[1] This unique position underscores its potential to significantly alter the treatment landscape for this challenging cancer, provided its efficacy and safety are robustly confirmed in broader patient populations and potentially in earlier lines of therapy. SCLC has long been characterized by poor prognoses and a lack of durable responses to conventional treatments beyond the first line. The introduction of a therapy with a distinct mechanism of action, such as Tarlatamab, offers new hope for patients who have exhausted standard therapeutic avenues.

B. Chemical and Physical Properties

Tarlatamab is a biologic medication with the following identifiers and characteristics:

• DrugBank ID: DB17256 [1]
• CAS Number: 2307488-83-9 [1]
• Type: Biotech; specifically, it is a human monoclonal antibody engineered as a Bi-specific T-cell Engager (BiTE).[1]
• Molecular Formula: C4664​H7139​N1259​O1454​S34​ [1]
• Molar Mass: Approximately 105202.82 g·mol$^{-1}$ [1]
• Source: Human [1]

The substantial molar mass and biotechnological origin of Tarlatamab inherently dictate its mode of administration, which is intravenous. This is typical for large protein-based therapeutics that are not orally bioavailable due to degradation in the gastrointestinal tract and poor absorption. Furthermore, as with many biologic agents, there is a potential for immunogenicity, where the patient's immune system may recognize the drug as foreign and develop anti-drug antibodies (ADAs). The development of ADAs can influence the drug's pharmacokinetics, efficacy, and safety, necessitating careful monitoring and consideration in its clinical application. These characteristics are common to antibody-based therapies and shape aspects of dosing, patient monitoring, and manufacturing processes.

C. Drug Class and Therapeutic Category

• Drug Class: Tarlatamab is classified as an antineoplastic agent and, more specifically, a bispecific T-cell engager (BiTE) antibody.[1]
• ATC Code: L01FX33 (WHO) [1]
• Therapeutic Category: Immunotherapy.[3]

II. Mechanism of Action

A. Dual Targeting Strategy

Tarlatamab is a bispecific monoclonal antibody meticulously engineered to concurrently bind to two distinct molecular targets: Delta-like ligand 3 (DLL3) predominantly found on the surface of tumor cells, and the CD3 epsilon chain (CD3ε), a component of the T-cell receptor (TCR) complex on T-lymphocytes.[1] This dual-binding capability is the cornerstone of its therapeutic action.

B. Target Rationale: DLL3 and CD3

DLL3 (Delta-like ligand 3)

DLL3 is an atypical inhibitory Notch ligand. In healthy adult tissues, DLL3 is primarily localized within intracellular compartments, such as the Golgi apparatus, and exhibits minimal expression on the cell surface.[6] However, in a high percentage of SCLC cells (approximately 85-96%) and other neuroendocrine tumors, DLL3 is aberrantly translocated to and expressed on the cell surface.[4] This differential expression pattern—high on tumor cells and low on normal cells—makes DLL3 an attractive and relatively specific target for cancer immunotherapy, aiming to minimize off-tumor toxicities.[4] The DLL3 gene is known to be a direct transcriptional target of Achaete-Scute Family BHLH Transcription Factor 1 (ASCL1), a key transcription factor implicated in the proliferation of neuroendocrine cells and the pathogenesis of SCLC.[6]

CD3 (Cluster of Differentiation 3)

CD3 is a multi-protein complex expressed on the surface of all mature T-lymphocytes and is an integral part of the T-cell receptor (TCR).[1] The CD3 complex is essential for transducing activation signals following TCR engagement with its cognate antigen presented by major histocompatibility complex (MHC) molecules. By targeting CD3, Tarlatamab directly engages T-cells, a critical effector component of the adaptive immune system.

C. T-Cell Engagement and Activation

Tarlatamab functions by physically linking a T-cell to a DLL3-expressing tumor cell. One arm of the BiTE molecule binds to DLL3 on the cancer cell, while the other arm binds to CD3 on the T-cell.[5] This forced proximity creates an immunological synapse, leading to potent T-cell activation. This activation occurs independently of the T-cell's native TCR specificity and does not require peptide antigen presentation by MHC molecules on the tumor cell surface.[5] This mechanism effectively "redirects" the patient's own T-cells to recognize and eliminate tumor cells that they might otherwise ignore.

A significant advantage of this BiTE-mediated T-cell activation is its potential to overcome common immune evasion strategies employed by tumors like SCLC. SCLC is often characterized by low immunogenicity and mechanisms to escape immune surveillance, including the downregulation or loss of MHC class I molecule expression, which is necessary for conventional antigen presentation to cytotoxic T-lymphocytes.[6] By directly linking T-cells to a tumor surface antigen (DLL3), Tarlatamab circumvents this limitation, potentially rendering it effective in tumors where traditional immunotherapies, such as checkpoint inhibitors alone, may have limited efficacy.

D. Induction of Tumor Cell Lysis

Upon activation, the engaged T-cells undergo polyclonal expansion and release a variety of cytotoxic molecules, including perforin and granzymes, as well as pro-inflammatory cytokines like interferon-gamma (IFN-γ).[10] These effector molecules are directed towards the targeted tumor cell, leading to its programmed cell death (apoptosis) and lysis.[5] Preclinical studies have corroborated this mechanism, demonstrating Tarlatamab's potent and specific cytotoxic activity against DLL3-expressing SCLC cell lines in vitro and significant tumor regression in murine xenograft models of SCLC.[12]

The high surface expression of DLL3 on tumor cells coupled with its minimal expression on normal tissues is fundamental to establishing a therapeutic window for Tarlatamab.[4] However, it is noteworthy that some level of DLL3 expression has been reported in certain normal tissues, including the brain, pituitary gland, and testis, albeit often intracellularly.[12] This raises the possibility of on-target, off-tumor toxicities if surface expression occurs or if the intracellular target becomes accessible under certain conditions. The observed neurological toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), associated with Tarlatamab treatment could be multifactorial, potentially related to systemic cytokine release affecting the central nervous system (CNS) or, more directly, to T-cell engagement with any DLL3 expressed on neural or endothelial cells within the CNS. Therefore, achieving a delicate balance between potent anti-tumor activity and manageable on-target, off-tumor effects remains a critical aspect of Tarlatamab's clinical use and ongoing development.

III. Pharmacokinetics

A. Binding Affinities (Dissociation Constants - KD​)

Tarlatamab exhibits differential binding affinities for its two targets. It binds with high affinity to human DLL3, with a reported dissociation constant (KD​) of 0.64 nM. Its affinity for non-human primate (NHP) DLL3 is similar, at 0.50 nM.[4] The affinity for human CD3 is lower, with a KD​ of 14.9 nM (12 nM for NHP CD3).[4] This hierarchy of binding affinities, with stronger binding to the tumor antigen (DLL3) than to the T-cell co-receptor (CD3), may be a deliberate design feature. Such a characteristic could promote initial anchoring of the BiTE molecule to the tumor cell surface before engaging and potently activating T-cells, potentially influencing the pharmacodynamics and localization of T-cell activity within the tumor microenvironment.

B. Absorption and Administration Route

Tarlatamab is administered via intravenous (IV) infusion.[1] As a large protein therapeutic, oral administration is not feasible due to degradation in the gastrointestinal tract and lack of absorption.

C. Distribution

The steady-state volume of distribution (Vss​) of Tarlatamab in non-human primates has been reported as 146 mL/kg.[14] Data on human Vss​ were not explicitly detailed in the provided information but are implicitly factored into the human pharmacokinetic models.

D. Metabolism

Consistent with other therapeutic proteins, Tarlatamab is expected to be metabolized into smaller peptides and individual amino acids through general, non-specific catabolic pathways distributed throughout the body.[10] Specific cytochrome P450 enzyme pathways are not anticipated to be major routes of elimination for monoclonal antibodies.

E. Elimination

• Half-life (t1/2​): Tarlatamab is characterized as a half-life extended (HLE) BiTE molecule.[4] In non-human primates, the mean terminal elimination half-life was approximately 234 hours (9.8 days).[14] In SCLC patients, the median terminal elimination half-life is reported to be 11.2 days.[10] This relatively long half-life is a significant pharmacokinetic feature. It supports the less frequent dosing schedule, typically every 2 weeks (Q2W), observed in clinical trials.[6] This is a notable improvement over earlier generations of BiTE molecules, which often possessed much shorter half-lives necessitating continuous intravenous infusion or more frequent administrations. The "HLE" designation indicates specific molecular engineering strategies, likely involving fusion to an Fc domain or other modifications, to prolong its systemic persistence.
• Clearance (CL): The mean clearance in NHPs was 0.487 mL/hour/kg.[14] In SCLC patients, the systemic clearance of Tarlatamab is approximately 0.65 L/day.[10]

The pharmacokinetic profile, particularly the extended half-life, facilitates a more convenient dosing regimen for patients, which can enhance compliance and overall quality of life during treatment. While pharmacokinetic data from NHPs provide initial estimations, the human pharmacokinetic parameters are paramount for clinical application and dose optimization. Interspecies differences are common, and factors such as target-mediated drug disposition (TMDD), the potential development of anti-drug antibodies, and individual patient characteristics (though not detailed as major clearance determinants here) can further influence the pharmacokinetic behavior of Tarlatamab in the clinical setting.

IV. Clinical Development Program: The DeLLphi Trials

A. Overview of the DeLLphi Clinical Trial Program

Amgen has established a comprehensive clinical development program for Tarlatamab, known as the DeLLphi trials, primarily focusing on its efficacy and safety in SCLC, but also extending to other DLL3-expressing neuroendocrine neoplasms.[5] This program encompasses studies evaluating Tarlatamab as a monotherapy and in combination with other anti-cancer agents, across various lines of SCLC treatment, from relapsed/refractory settings to first-line therapy.[5] This strategic and robust clinical development plan, moving from late-line monotherapy to earlier lines and combination therapies, as well as exploring new DLL3-expressing tumor types, reflects considerable confidence in the therapeutic potential of Tarlatamab and the validity of DLL3 as a target.

B. Key Clinical Trials

The DeLLphi program and other significant studies investigating Tarlatamab are summarized in Table 1.

Table 1: Overview of Key Tarlatamab Clinical Trials

Trial ID (NCT Number)	Phase	Official Title (or concise description)	Patient Population	Key Objectives/Endpoints	Intervention(s)	Current Status (as per latest info)	Key Findings (Briefly)
DeLLphi-300 (NCT03319940)	1 (First-in-Human)	A Study of Tarlatamab (AMG 757) in Patients With Relapsed/Refractory Small Cell Lung Cancer (SCLC)	Relapsed/refractory SCLC	Safety, tolerability, PK, MTD/RP2D, preliminary antitumor activity	Tarlatamab IV (dose escalation/expansion, incl. 10 mg Q2W)	Completed, extended follow-up reported	Established RP2D (10 mg Q2W), durable responses, promising OS, intracranial activity observed 6
DeLLphi-301 (NCT05060016)	2	A Phase 2 Study of Tarlatamab in Patients With Small Cell Lung Cancer (SCLC) (DeLLphi-301)	ES-SCLC with progression on/after platinum-based chemotherapy (typically ≥2 prior lines for study entry, FDA approval for ≥1 prior line)	Primary: ORR by BICR. Secondary: DOR, DCR, PFS, OS, safety, PK, PROs	Tarlatamab IV (1 mg step-up, then 10 mg Q2W or 100 mg Q2W; 10 mg selected)	Completed, supported regulatory approvals	ORR 40% (10 mg), mDOR 9.7 mo, mOS 14.3-15.2 mo; manageable safety 1
DeLLphi-304 (NCT05740566)	3	A Study Comparing Tarlatamab With Standard of Care Chemotherapy in Relapsed Small Cell Lung Cancer (DeLLphi-304)	Relapsed SCLC after 1 platinum-based first-line regimen (~700 pts)	Primary: OS. Secondary: PFS, ORR, DOR, PROs, safety	Tarlatamab IV vs. SOC chemo (lurbinectedin, topotecan, or amrubicin)	Ongoing, met primary endpoint (OS) per interim analysis	Tarlatamab showed statistically significant and clinically meaningful OS improvement vs. SOC 2
DeLLphi-303	1b	Study of Tarlatamab in Combination with Standard of Care Therapies in First-Line ES-SCLC	First-line ES-SCLC	Safety, tolerability, preliminary efficacy of combinations	Tarlatamab IV + SOC	Ongoing	Data pending 5
DeLLphi-310 (NCT06898957)	1b	Study of Tarlatamab in Combination for SCLC	SCLC (second-line therapy or greater)	Safety, tolerability, preliminary efficacy of combinations	Tarlatamab IV + other agent(s)	Planned (April 2025 start)	Data pending 3
NCT06745323	2	A Study of Tarlatamab in Patients With Small Cell Lung Cancer	SCLC (second-line therapy or greater)	Efficacy, safety	Tarlatamab IV	Recruiting (Switzerland)	Data pending 3
NCT06788938 (NCI-2025-00344)	2	Tarlatamab for the Treatment of Metastatic or Unresectable Stage III or IV Neuroendocrine Neoplasms and Other Solid Tumors	Stage III/IV NENs (various types, e.g., GEP-NEN, LCNEC) and other DLL3+ solid tumors, progressed on prior therapy	Primary: ORR. Secondary: DOR, PFS, OS, safety	Tarlatamab IV	Recruiting	Data pending 13
NCT06937905	3	Tarlatamab vs Standard of Care Chemotherapy in Patients With Pre-treated Advanced, Pulmonary or Gastroenteropancreatic Poorly Differentiated Neuroendocrine Carcinomas (NECs)	Advanced, pre-treated pulmonary or GEP poorly differentiated NECs	Efficacy, safety	Tarlatamab IV vs. SOC chemo	Not Yet Recruiting	Data pending 8

Abbreviations: BICR=Blinded Independent Central Review; DCR=Disease Control Rate; DOR=Duration of Response; ES-SCLC=Extensive-Stage Small Cell Lung Cancer; GEP-NEN=Gastroenteropancreatic Neuroendocrine Neoplasm; IV=Intravenous; LCNEC=Large Cell Neuroendocrine Carcinoma; MTD=Maximum Tolerated Dose; NEC=Neuroendocrine Carcinoma; NEN=Neuroendocrine Neoplasm; ORR=Objective Response Rate; OS=Overall Survival; PFS=Progression-Free Survival; PK=Pharmacokinetics; PROs=Patient-Reported Outcomes; Q2W=Every 2 Weeks; RP2D=Recommended Phase 2 Dose; SOC=Standard of Care.

The progression from the first-in-human DeLLphi-300 study, which established initial safety and the recommended Phase 2 dose, to the pivotal Phase 2 DeLLphi-301 trial that supported accelerated approvals, and subsequently to the large, randomized Phase 3 DeLLphi-304 confirmatory trial, illustrates a typical yet rapid development pathway for a highly promising oncology drug. Furthermore, the expansion into first-line SCLC (DeLLphi-303) and other DLL3-expressing neuroendocrine tumors (NCT06788938, NCT06937905) signifies a strategic effort to maximize Tarlatamab's therapeutic potential.

An important aspect of this clinical development program is the increasing emphasis on patient-reported outcomes (PROs). PROs were evaluated in DeLLphi-301 and are a key secondary endpoint in the Phase 3 DeLLphi-304 trial.[11] This focus reflects a growing recognition by regulatory authorities and drug developers of the importance of capturing the patient's perspective on treatment benefit and tolerability, particularly in diseases like SCLC which are associated with a significant symptom burden and impact on quality of life. For a therapy like Tarlatamab, which has notable potential toxicities such as CRS and ICANS, demonstrating a manageable impact on daily functioning and overall well-being is crucial for its comprehensive value assessment.

V. Efficacy in Extensive-Stage Small Cell Lung Cancer (ES-SCLC)

The clinical efficacy of Tarlatamab in ES-SCLC has been evaluated through a series of studies, primarily the DeLLphi trials.

A. DeLLphi-300 (Phase 1) Study Findings (NCT03319940)

The DeLLphi-300 study was the first-in-human trial of Tarlatamab, enrolling patients with relapsed/refractory SCLC who had received multiple prior lines of therapy.[6] Initial reports from this dose-escalation and expansion study indicated promising antitumor activity. Confirmed responses were observed in 23% of patients, with a median duration of response (DOR) exceeding 12 months and a median overall survival (OS) of 13.2 months.[11]

Extended follow-up data from the DeLLphi-300 trial, focusing on cohorts receiving Tarlatamab doses of ≥10 mg (N=152) with a median follow-up of 12.1 months, showed an overall objective response rate (ORR) of 25.0%, a median DOR of 11.2 months (95% CI, 6.6 to 22.3), and a median OS of 17.5 months (95% CI, 11.4 to not estimable [NE]).[19]

For the cohort of 17 patients who received the 10 mg Q2W dose (the dose selected for further development), the extended follow-up revealed an ORR of 35.3%, a median DOR of 14.9 months (95% CI, 3.0 to NE), and a median OS of 20.3 months (95% CI, 5.1 to NE). Notably, 29.4% of these patients experienced sustained disease control, defined as time on treatment of ≥52 weeks.[19]

A particularly significant finding from the DeLLphi-300 extended follow-up was the observation of intracranial activity. Using modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, CNS tumor shrinkage of ≥30% was observed in 62.5% (10 out of 16) of patients who had baseline CNS lesions ≥10 mm. This included responses in patients long after previous brain radiotherapy.[19] This is a crucial observation, as brain metastases are frequent in SCLC and typically confer a poor prognosis. The ability of a systemic agent like Tarlatamab to induce responses within the CNS, potentially by crossing the blood-brain barrier or by activating T-cells that can then infiltrate and act within the CNS, could address a substantial challenge in SCLC management. This finding warrants further investigation in larger, dedicated cohorts.

B. DeLLphi-301 (Phase 2) Study Findings (NCT05060016)

The DeLLphi-301 trial was an open-label, multicenter, multi-cohort Phase 2 study that formed the primary basis for Tarlatamab's accelerated regulatory approvals.[1] The efficacy population for the FDA approval comprised 99 patients with ES-SCLC whose disease had progressed on or after platinum-based chemotherapy.[26] These patients were heavily pre-treated, with a median of two prior lines of therapy (range, 1-6).[28] Baseline characteristics for the 10 mg cohort (N=100 in the PRO analysis) showed that most patients were male (72%), from Europe (56%), had metastatic disease (98%), and an ECOG performance status of 1 (74%).[30] Patients with treated and stable brain metastases were permitted entry.[22] The intervention consisted of an initial 1 mg step-up dose of Tarlatamab on Cycle 1 Day 1, followed by 10 mg on Cycle 1 Day 8 and Day 15, and then 10 mg Q2W thereafter.[7]

The primary endpoint was ORR as assessed by Blinded Independent Central Review (BICR) per RECIST 1.1 criteria.[7] Key efficacy results for the 10 mg Q2W dose group (N=99-100) from the primary analysis and subsequent updates (e.g., WCLC 2024) are as follows:

• ORR: 40% (95% CI: 31, 51 or 29-52).[1]
• Complete Response (CR): Initially 1-2% [27]; updated to 3% at WCLC 2024.[22]
• Partial Response (PR): Initially 38-39% [27]; updated to 37% at WCLC 2024.[22]
• Median DOR: 9.7 months (range 2.7, 20.7+) or not estimable (95% CI 5.9-NE), with 55-59% of responses lasting at least 6 months.[1]
• Disease Control Rate (DCR): 70%.[29]
• Median PFS: Primary analysis reported 4.9 months (95% CI 2.9-6.7).[18] Extended follow-up (median 13.6 months) presented at WCLC 2024 showed a median PFS of 4.3 months (95% CI 2.9-5.6).[22]
• 6-month PFS rate (WCLC 2024): 39.2%.[22]
• 12-month PFS rate (WCLC 2024): 24.0%.[22]
• Median OS: Primary analysis reported 14.3 months (95% CI 10.8-NE).[2] Extended follow-up (median 20.7 months) presented at WCLC 2024 showed a median OS of 15.2 months.[22]
• 9-month OS rate (primary analysis): 68%.[21]
• 18-month OS rate (Kaplan-Meier estimated, WCLC 2024): 46%.[22]
• Tumor Shrinkage (WCLC 2024): Occurred in 72% of patients.[22]
• Sustained Disease Control (≥52 weeks, WCLC 2024): 26%.[22]

Subgroup analysis based on platinum sensitivity status in 69 evaluable patients showed an ORR of 52% (95% CI 32, 71) in 27 patients with platinum-resistant SCLC (defined as progression <90 days after the last platinum dose) and 31% (95% CI 18, 47) in 42 patients with platinum-sensitive SCLC (progression ≥90 days after the last platinum dose).[1] This suggests activity in both platinum-sensitive and, notably, the more difficult-to-treat platinum-resistant population.

Patient-reported outcomes (PROs) from DeLLphi-301 were also favorable, with high completion rates for questionnaires like the EORTC-QLQ-C30 and LC13.[24] Patients reported a trend towards improvement in global health status and stabilization in physical functioning. There was a reduced symptom burden for dyspnea, particularly in later cycles, and stabilization for chest pain and cough. Median time to deterioration for cough and dyspnea exceeded 6 months. Overall, from the patient's perspective, Tarlatamab was generally well-tolerated, with the majority reporting minimal bother from side effects post-baseline.[24]

The consistent efficacy demonstrated in Phase 1 (DeLLphi-300) and Phase 2 (DeLLphi-301) trials, especially the durable responses (mDOR of 9.7-14.9 months) and encouraging median OS (14.3-20.3 months) in such a heavily pre-treated ES-SCLC population, is particularly noteworthy.[1] SCLC is characterized by rapid relapse after initial therapy, and subsequent treatments historically offer limited survival benefits, often with median OS in the range of 6-9 months.[19] Tarlatamab's performance in these settings represents a substantial improvement and provides a strong rationale for its accelerated approvals and ongoing Phase 3 investigations.

C. DeLLphi-304 (Phase 3) Study Findings (NCT05740566)

DeLLphi-304 is a large, randomized, open-label, global Phase 3 trial designed to confirm the clinical benefit of Tarlatamab. It enrolled approximately 700 patients with relapsed SCLC after one prior platinum-based first-line chemotherapy regimen.[2] Patients were randomized 1:1 to receive either Tarlatamab monotherapy or investigator's choice of standard-of-care (SOC) chemotherapy, which included topotecan, lurbinectedin (in specific regions like the US, Canada, Australia), or amrubicin (in Japan).[2] The primary endpoint of this trial is OS.[2]

In April 2025, Amgen announced topline results from a preplanned interim analysis of the DeLLphi-304 trial.[2] The trial met its primary endpoint, with Tarlatamab demonstrating a statistically significant and clinically meaningful improvement in OS compared to SOC chemotherapy.[2] The safety profile of Tarlatamab in DeLLphi-304 was reported to be consistent with its known profile from previous studies. Detailed results from this pivotal trial are anticipated to be presented at an upcoming major medical congress.[2]

The positive OS outcome from DeLLphi-304 is a critical milestone. Demonstrating a survival advantage over active comparators in a randomized Phase 3 setting is the gold standard in oncology and is essential for converting accelerated/conditional approvals to full approvals. This finding solidifies Tarlatamab's role in the treatment of second-line ES-SCLC and is expected to establish it as a new standard of care, offering a more effective option than existing chemotherapies for this patient population.

Table 2: Summary of Key Efficacy Results from Pivotal ES-SCLC Trials

Efficacy Endpoint	DeLLphi-301 (10mg Q2W, N=99-100)	DeLLphi-304 (Tarlatamab arm)
ORR (%)	40% (95% CI: 31, 51) 1	Data pending full presentation
Median DOR (months)	9.7 (range 2.7, 20.7+) 1	Data pending full presentation
Median PFS (months)	4.3 - 4.9 (95% CI ~2.9-6.7) 21	Data pending full presentation
Median OS (months)	14.3 - 15.2 (95% CI ~10.8-NE) 21	Statistically significant & clinically meaningful improvement vs SOC 2

Data for DeLLphi-301 represent primary analysis or later updates as specified. DeLLphi-304 data are based on topline press release; full details awaited.

VI. Safety and Tolerability Profile

The safety profile of Tarlatamab has been characterized through the DeLLphi clinical trial program. While demonstrating promising efficacy, Tarlatamab is associated with notable toxicities characteristic of T-cell engaging therapies, requiring careful management.

A. Boxed Warnings (FDA)

The U.S. Food and Drug Administration (FDA) prescribing information for Imdelltra includes Boxed Warnings for two significant toxicities [1]:

• Cytokine Release Syndrome (CRS): Serious or life-threatening CRS can occur. The labeling mandates initiation of treatment with a step-up dosing schedule to mitigate the incidence and severity of CRS. Management involves withholding or permanently discontinuing Tarlatamab based on the severity of the event.
• Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Serious or life-threatening neurologic toxicities, including ICANS, can occur. Patients require close monitoring for signs and symptoms, and prompt treatment if they arise. Similar to CRS, management may involve withholding or permanently discontinuing Tarlatamab based on severity.

B. Common Adverse Reactions

Based on pooled data from clinical trials, particularly DeLLphi-301 (10 mg dose), the most common adverse reactions (typically occurring in >20% of patients) include [1]:

• Cytokine Release Syndrome (CRS): Approximately 51-55% (predominantly Grade 1 or 2)
• Fatigue: Approximately 51%
• Pyrexia (Fever): Approximately 36%
• Dysgeusia (Taste alteration): Approximately 30-36%
• Decreased Appetite: Approximately 29-34%
• Musculoskeletal Pain: Approximately 30%
• Constipation: Approximately 27.5-30%
• Anemia: Approximately 25-27%
• Nausea: Approximately 22% Other very common adverse reactions reported, for instance by the MHRA, include asthenia, hyponatremia, and dyspnea.[15]

C. Neurologic Toxicity (including ICANS)

Neurologic toxicity is a significant concern with Tarlatamab. In the pooled safety population, neurologic toxicities (including ICANS) occurred in 47% of patients, with 10% experiencing Grade 3 events.[5] The most frequently reported neurologic toxicities were headache (14%), peripheral neuropathy (7%), dizziness (7%), insomnia (6%), muscular weakness (3.7%), delirium (2.1%), syncope (1.6%), and general neurotoxicity (1.1%).[5] ICANS specifically occurred in 7-9% of patients, with recurrent ICANS observed in 1.6% of patients.[5]

D. Serious Adverse Reactions (SARs)

Serious adverse reactions were reported in 58-59% of patients receiving the 10 mg dose of Tarlatamab in the DeLLphi-301 trial.[5] SARs occurring in greater than 3% of patients included CRS (24%), pneumonia (6%), pyrexia (3.7%), and hyponatremia (3.6%).[5]

E. Fatal Adverse Reactions

Fatal adverse reactions occurred in 2.7-3% of patients in the DeLLphi-301 (10 mg) cohort.[5] These were attributed to causes such as pneumonia (0.5%), aspiration (0.5%), pulmonary embolism (0.5%), respiratory acidosis (0.5%), and respiratory failure (0.5%).[5]

F. Grade 3 or 4 Laboratory Abnormalities

Clinically significant Grade 3 or 4 laboratory abnormalities (with an incidence of ≥5%) observed with Tarlatamab treatment include [1]:

• Decreased lymphocytes: ~57%
• Decreased sodium: ~16%
• Increased uric acid: ~10%
• Decreased total neutrophils: ~6%
• Decreased hemoglobin: ~5%
• Increased activated partial thromboplastin time (aPTT): ~5%
• Decreased potassium: ~5% Increased aspartate aminotransferase (AST) has also been noted.[5]

G. Other Warnings and Precautions

Additional warnings and precautions associated with Tarlatamab include cytopenias, infections, hepatotoxicity, hypersensitivity reactions, and potential for embryo-fetal toxicity.[17]

H. Management of Key Toxicities

The management of CRS and ICANS is critical for the safe administration of Tarlatamab. This involves the implementation of a step-up dosing schedule during the first cycle of treatment and close patient monitoring, particularly during initial infusions.17 Hospitalization for the administration of the initial doses is typically recommended, with advice for patients to remain in proximity to a healthcare facility capable of managing such reactions for a period afterward.17

Encouragingly, data from the DeLLphi-300 Part F substudy suggested that for selected patients, a reduced outpatient monitoring period (6-8 hours) following Cycle 1 doses yielded similar safety outcomes, including hospitalization rates and CRS incidence/resolution time, compared to the standard 48-hour inpatient monitoring.37 This finding indicates that with increasing experience and careful patient selection, the monitoring burden might be safely reduced, which would improve patient convenience and lessen healthcare resource utilization.

The overall safety profile, characterized by the potential for CRS and ICANS, is consistent with the known class effects of T-cell engaging immunotherapies. These toxicities arise from the potent activation of T-cells and the subsequent release of cytokines. The development and refinement of specific management guidelines, including prophylactic measures, step-up dosing, and clear protocols for intervention, are paramount for the successful clinical integration of Tarlatamab. While patient-reported outcomes from DeLLphi-301 suggest a manageable impact on quality of life for many patients who tolerate the treatment [24], the high incidence of serious adverse events and significant laboratory abnormalities underscores that Tarlatamab is a potent therapy. Its administration requires experienced clinicians and appropriate healthcare settings. The benefit-risk assessment, particularly in the palliative context of relapsed ES-SCLC, must carefully balance the demonstrated efficacy gains against these potential toxicities.

Table 3: Common Adverse Reactions (≥20%) and Grade 3/4 Laboratory Abnormalities (≥5%) from DeLLphi-301 (Tarlatamab 10mg dose)

Adverse Reaction / Lab Abnormality	Frequency (%)	Snippet Examples
Common Adverse Reactions (≥20%)
Cytokine Release Syndrome (CRS)	51-55	1
Fatigue	51	1
Pyrexia	36	1
Dysgeusia	30-36	1
Decreased Appetite	29-34	1
Musculoskeletal Pain	30	1
Constipation	27.5-30	1
Anemia	25-27	1
Nausea	22	1
Grade 3/4 Laboratory Abnormalities (≥5%)
Decreased Lymphocytes	57	1
Decreased Sodium	16	1
Increased Uric Acid	10	1
Decreased Total Neutrophils	6	1
Decreased Hemoglobin	5	1
Increased Activated Partial Thromboplastin Time (aPTT)	5	1
Decreased Potassium	5	1

VII. Dosage and Administration

A. Recommended Dosing Regimen

Tarlatamab (Imdelltra) is administered as an intravenous (IV) infusion, typically over a period of 1 hour.[1] The dosing regimen incorporates a step-up schedule in the first cycle to mitigate the risk and severity of CRS and other acute infusion-related reactions. The recommended dosing is as follows [1]:

• Cycle 1, Day 1: An initial step-up dose of 1 mg.
• Cycle 1, Day 8: A second step-up dose of 10 mg.
• Cycle 1, Day 15: The first full therapeutic dose of 10 mg.
• Subsequent Cycles (Cycle 2 onwards): 10 mg administered every 2 weeks (Q2W).

Treatment with Tarlatamab is continued until disease progression or the development of unacceptable toxicity.[1] The elaborate step-up dosing strategy and intensive initial monitoring directly address the significant risk of acute, severe toxicities like CRS and ICANS, which are most pronounced during the initial phases of T-cell activation. This gradual escalation allows the patient's immune system to acclimate to the T-cell stimulation, potentially reducing the intensity of cytokine release.

B. Preparation and Administration Instructions

Tarlatamab must be prepared and administered by qualified healthcare professionals in an appropriate healthcare setting that has the necessary medical support to manage severe reactions, including CRS and ICANS.[17] The drug is administered using an infusion pump at a constant flow rate to ensure controlled delivery.[25]

C. Monitoring Requirements

Due to the potential for serious adverse reactions, particularly CRS and ICANS, a structured monitoring protocol is essential during Tarlatamab therapy [17]:

• Cycle 1, Day 1 (1 mg dose) and Day 8 (10 mg dose): Patients should be monitored from the start of the infusion for 22 to 24 hours in an appropriate healthcare setting. It is also recommended that patients remain within a 1-hour travel distance of an appropriate healthcare facility, accompanied by a caregiver, for a total of 48 hours from the start of these initial infusions.
• Cycle 2 (Day 1 and 15, 10 mg doses): Post-infusion observation is typically reduced to 6-8 hours.
• Cycles 3 and 4 (Day 1 and 15, 10 mg doses): Post-infusion observation is further reduced to 3-4 hours.
• Cycles 5 and subsequent infusions (10 mg doses): Post-infusion observation is typically 2 hours.

If a patient experiences Grade ≥2 CRS, ICANS, or other significant neurological toxicity during prior treatments or cycles, the monitoring duration should be extended as clinically indicated.25

In addition to monitoring for acute reactions, routine laboratory monitoring is required:

• Complete blood counts (CBC) should be monitored prior to initiating Tarlatamab, before each subsequent dose, and as clinically indicated to assess for cytopenias.[17]
• Liver enzymes (e.g., ALT, AST) and bilirubin should be monitored prior to treatment, before each dose, and as clinically indicated to detect hepatotoxicity.[17]

The decreasing intensity of post-infusion monitoring in later cycles suggests that the acute risk of severe reactions diminishes after the initial T-cell activation phase. This is likely due to evolving T-cell dynamics, potential desensitization, or the establishment of a more stable immunological state. This graduated monitoring approach has important practical implications, potentially improving patient convenience and optimizing healthcare resource allocation for long-term Tarlatamab therapy. The findings from the DeLLphi-300 Part F substudy, which explored the feasibility of reduced outpatient monitoring, further support this trend towards de-escalating monitoring burden with accumulated experience and careful patient selection.[37]

VIII. Regulatory Status and Approvals

Tarlatamab has achieved significant regulatory milestones, reflecting its promising clinical profile in a challenging disease area.

A. U.S. Food and Drug Administration (FDA)

• Approval: The FDA granted accelerated approval to Tarlatamab-dlle (Imdelltra) on May 16, 2024.[1]
• Indication: It is indicated for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has progressed on or after platinum-based chemotherapy.[1]
• Basis for Approval: The accelerated approval was based on the compelling overall response rate (ORR) and duration of response (DOR) data from the Phase 2 DeLLphi-301 study (NCT05060016).[1] Continued approval for this indication is contingent upon verification and description of clinical benefit in confirmatory trials, such as the DeLLphi-304 study.[1]
• Special Designations: Tarlatamab received several special designations from the FDA, underscoring its potential to address a serious unmet medical need:
• Priority Review.[2]
• Breakthrough Therapy Designation.[26]
• Orphan Drug Designation.[26]
• It is also considered a First-in-Class medication by the FDA.[1]
• The FDA review was conducted under Project Orbis, an initiative facilitating concurrent submission and review of oncology drugs among international regulatory partners, and utilized the Real-Time Oncology Review (RTOR) pilot program.[26]

B. UK Medicines and Healthcare products Regulatory Agency (MHRA)

• Approval: The MHRA granted Conditional Marketing Authorisation to Imdylltra (tarlatamab) on December 31, 2024.[15]
• Indication: It is indicated for the treatment of adult patients with ES-SCLC with disease progression on or after at least two prior lines of therapy, including platinum-based chemotherapy.[15] The wording "at least two prior lines" for the MHRA indication differs slightly from the FDA's "on or after platinum-based chemotherapy," though for ES-SCLC, progression after platinum-based therapy often implies at least one prior line, and the DeLLphi-301 trial predominantly enrolled patients with ≥2 prior lines.
• Basis for Approval: The conditional approval was based on the results from the Phase 2 DeLLphi-301 study.[15]
• This is a conditional approval, meaning that further evidence on the medicinal product is awaited to confirm the benefit-risk balance. Tarlatamab is subject to additional monitoring in the UK.[15]
• The MHRA approval was also granted under the framework of Project Orbis.[40]

C. European Medicines Agency (EMA) and Other Regions

• EMA: As of May 2025, explicit marketing authorization from the EMA was not found in the provided information. However, clinical trials, including the pivotal DeLLphi-301 study (under EUCT number 2024-511837-37-00), are ongoing or have significant enrollment within the EU/EEA, with an estimated end date of October 2025 for DeLLphi-301 in this region.[23] Regulatory submissions to the EMA are anticipated or may be under review.
• Health Canada (via CDA-AMC pCODR): A review by the Canadian Agency for Drugs and Technologies in Health (CADTH) pan-Canadian Oncology Drug Review (pCODR) Expert Review Committee (pERC) acknowledged that Tarlatamab may provide an additional treatment option with durable responses in a heavily pretreated ES-SCLC population based on DeLLphi-301. However, due to the single-arm nature of the trial and limitations of indirect treatment comparisons, uncertainty remained regarding the magnitude of OS and PFS benefit compared to other treatments. Consequently, pERC recommended that Tarlatamab be funded on the condition of a significant price reduction.[42]

The consistent granting of special regulatory designations by agencies like the FDA and MHRA highlights the significant unmet medical need in relapsed ES-SCLC and the promising nature of Tarlatamab's early clinical data. These designations are typically reserved for therapies that demonstrate the potential for substantial improvement over existing treatments for serious conditions. The involvement of Project Orbis further signifies international recognition of Tarlatamab's importance and facilitates collaborative review efforts.

The accelerated and conditional nature of the current approvals, primarily based on Phase 2 data focusing on ORR and DOR, places considerable emphasis on the outcomes of the confirmatory Phase 3 DeLLphi-304 trial. The positive topline OS results announced for DeLLphi-304, showing superiority over SOC chemotherapy, are a critical step towards converting these initial approvals into full marketing authorizations and firmly establishing Tarlatamab's role in the ES-SCLC treatment algorithm.[2]

Table 4: Regulatory Approval Summary for Tarlatamab

Regulatory Agency	Brand Name	Indication	Approval Date	Type of Approval	Key Special Designations
U.S. Food and Drug Administration (FDA)	Imdelltra	Adult patients with ES-SCLC with disease progression on or after platinum-based chemotherapy	May 16, 2024	Accelerated Approval	Priority Review, Breakthrough Therapy, Orphan Drug, First-in-Class 1
UK Medicines and Healthcare products Regulatory Agency (MHRA)	Imdylltra	Adult patients with ES-SCLC with disease progression on or after at least two prior lines of therapy, including platinum-based chemotherapy	Dec 31, 2024	Conditional Marketing Authorisation	Project Orbis participant 15
European Medicines Agency (EMA)	Imdelltra (anticipated)	ES-SCLC (anticipated)	Pending	Pending	Clinical trials ongoing in EU 23

IX. Investigational Uses and Ongoing Research

Beyond its approved indication in relapsed/refractory ES-SCLC, Tarlatamab is being actively investigated for other DLL3-expressing malignancies and in different therapeutic settings.

A. Neuroendocrine Neoplasms (NENs) / Carcinomas (NECs)

Given that DLL3 is expressed on various neuroendocrine tumors in addition to SCLC, this is a logical area of expansion for Tarlatamab.[12]

• The NCT06788938 study, a Phase 2 trial (also known as NCI-2025-00344), is currently evaluating Tarlatamab in patients with Stage III or IV neuroendocrine neoplasms. This includes various subtypes such as low and intermediate-grade neuroendocrine carcinoma (carcinoid and atypical carcinoid), gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), large cell neuroendocrine carcinoma (LCNEC), and SCLC transformed from previously-treated non-small cell lung cancer (NSCLC), as well as other solid tumors confirmed to express DLL3 and have progressed on prior therapy.[13]
• The NCT06937905 study is a planned Phase 3 trial that will compare Tarlatamab against standard-of-care chemotherapy in patients with pre-treated advanced, pulmonary or gastroenteropancreatic poorly differentiated neuroendocrine carcinomas (NECs). This trial is currently listed as "Not Yet Recruiting".[8] The pursuit of indications in other DLL3-expressing NENs is a rational extension of Tarlatamab's development. Success in these diverse neuroendocrine histologies, many of which also have limited effective treatment options upon progression, could significantly broaden Tarlatamab's clinical impact.

B. Earlier Lines of SCLC Therapy

Efforts are underway to evaluate Tarlatamab in earlier stages of SCLC treatment:

• The DeLLphi-303 study is a Phase 1b trial investigating Tarlatamab in combination with standard-of-care therapies for the first-line treatment of ES-SCLC.[5]
• The DeLLphi-310 study (NCT06898957), a Phase 1b trial planned to commence in April 2025, will explore Tarlatamab in combination regimens for SCLC patients in the second-line setting or beyond.[3]

C. Other Solid Tumors and Specific Populations

• Prostate Cancer: Tarlatamab is reportedly in Phase 1 development for prostate cancer, likely targeting neuroendocrine prostate cancer (NEPC), a subtype known to sometimes express DLL3.[3]
• Brain Cancers with IDH mutations: This has been mentioned as an area of potential investigation, though specific trial details were not provided in the available information.[43]
• Malignant Melanoma: Development of Tarlatamab for malignant melanoma was discontinued during Phase 1.[3] This discontinuation, despite DLL3 being the target, suggests that either DLL3 expression was not sufficiently prevalent or biologically relevant in melanoma, or that the activity/toxicity profile of Tarlatamab was unfavorable in that specific tumor context. This outcome underscores the empirical nature of drug development, where target expression alone does not invariably predict clinical success across different cancer types. Understanding the specific reasons for this discontinuation could offer valuable insights for selecting future indications and for the broader field of DLL3-targeted therapies.

D. Different Administration Routes

While the current formulation of Tarlatamab is for intravenous administration, there is mention of at least one study investigating a subcutaneous (SC) route of administration.[43] An SC formulation, if successfully developed, could offer greater convenience for patients and potentially reduce healthcare resource utilization compared to IV infusions.

X. Summary and Future Directions

A. Recap of Tarlatamab's Profile and Clinical Significance

Tarlatamab (Imdelltra) has emerged as a pioneering, first-in-class, DLL3-targeting bispecific T-cell engager (BiTE) immunotherapy.[1] It has demonstrated statistically significant and clinically meaningful antitumor activity, including durable responses and improved overall survival, in heavily pre-treated patients with extensive-stage small cell lung cancer (ES-SCLC).[1] These compelling efficacy data from the DeLLphi clinical trial program, particularly the Phase 2 DeLLphi-301 study, have led to accelerated and conditional regulatory approvals in the United States and the United Kingdom for patients with ES-SCLC who have progressed on or after platinum-based chemotherapy.[1] The recent positive topline overall survival results from the confirmatory Phase 3 DeLLphi-304 trial, showing superiority over standard-of-care chemotherapy in second-line ES-SCLC, further solidify its clinical importance.[2]

Tarlatamab's safety profile is characterized by manageable, yet potentially serious, toxicities common to T-cell engaging therapies, most notably Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). These require specific management strategies, including step-up dosing and vigilant monitoring, particularly during the initial treatment cycles.[1]

Tarlatamab represents a significant therapeutic breakthrough for ES-SCLC, a malignancy that has seen limited treatment advances and has been associated with dismal prognoses for decades. Its novel mechanism of action, redirecting the patient's own T-cells to target DLL3-expressing tumor cells, has translated into substantial clinical benefit. The consistent findings across Phase 1, Phase 2, and now positive Phase 3 outcomes, coupled with rapid regulatory recognitions through special designations, underscore the drug's strong benefit-risk profile in a patient population with high unmet medical needs. The transition from efficacy demonstrated by ORR and DOR in single-arm studies to a proven OS advantage in a randomized Phase 3 trial represents the highest level of clinical evidence, positioning Tarlatamab to reshape clinical practice.

B. Potential Impact on SCLC and Neuroendocrine Tumor Treatment Landscape

Tarlatamab is poised to become a new standard of care for patients with relapsed ES-SCLC, particularly in the second-line setting following the DeLLphi-304 results, and offers a valuable new option for patients in later lines of therapy.[2] Its efficacy in this historically difficult-to-treat disease addresses a profound unmet medical need. Furthermore, ongoing investigations into its use in other DLL3-expressing neuroendocrine neoplasms, such as poorly differentiated NECs and various NENs, hold promise for extending its benefits to a broader range of patients with these challenging malignancies.[8]

C. Unanswered Questions and Areas for Future Research

Despite the significant progress, several questions remain, and numerous avenues for future research are apparent:

• Long-Term Outcomes: Full analysis of long-term survival benefits, the durability of responses, and patterns of relapse from the Phase 3 DeLLphi-304 trial and other ongoing studies are awaited.
• Earlier Lines of Therapy: The efficacy and safety of Tarlatamab in earlier lines of SCLC treatment, including as first-line therapy (DeLLphi-303) or as consolidation treatment, need to be established.
• Combination Strategies: Identifying optimal combination regimens is a key area. Combining Tarlatamab with chemotherapy, other immunotherapies (e.g., checkpoint inhibitors), or targeted agents could potentially enhance efficacy, overcome resistance, or broaden its applicability. The DeLLphi-303 and DeLLphi-310 trials are exploring some of these avenues.[3]
• Biomarkers: While DLL3 expression is the primary selection criterion, further research is needed to identify additional biomarkers that can predict response, resistance, or susceptibility to toxicities. This could involve assessing the tumor microenvironment, baseline immune cell status, or genomic/proteomic markers.[6]
• Mechanisms of Resistance: Understanding the mechanisms by which tumor cells may develop resistance to Tarlatamab is crucial for developing strategies to overcome or prevent it.
• Intracranial Efficacy: The promising signals of intracranial activity from DeLLphi-300 require more thorough characterization in larger patient cohorts with systematic CNS imaging and follow-up to determine Tarlatamab's true impact on the management of brain metastases in SCLC.[12]
• Diverse Populations: Ensuring that efficacy and safety are consistent across diverse patient populations, including various ethnic groups and those with different comorbidities, is important.
• Toxicity Management Optimization: Continued refinement of monitoring protocols and management strategies for CRS, ICANS, and other adverse events, potentially facilitating broader and safer outpatient administration, will be beneficial.[37]
• Subcutaneous Formulation: The development of a subcutaneous formulation could significantly improve patient convenience and adherence.[43]

The success of Tarlatamab is likely to invigorate further research and development into BiTEs and other DLL3-targeted therapies, not only for SCLC but also for other NENs and potentially other DLL3-expressing cancers. It validates the therapeutic strategy of leveraging highly tumor-associated surface antigens for T-cell redirection. The experiences gained with Tarlatamab, including the management of its characteristic toxicities and the potential for outpatient administration, will provide valuable lessons for the development of next-generation T-cell engaging immunotherapies, ultimately aiming to improve outcomes for patients with these aggressive and often fatal cancers.

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