Approval of Tarlatamab-dlle for Subsequent-Line Treatment of Extensive-Stage Small Cell Lung Cancer

Nagashree Seetharamu, MD, MBBS

On May 16, 2024, the Food and Drug Administration granted accelerated approval to tarlatamab-dlle (Imdelltra®, Amgen, Inc.) for extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy. As is the case for all accelerated approvals, this treatment was granted accelerated approval based on overall response rate and duration of response. Continued approval may be contingent upon verification of clinical benefit. 

Why is this approval a breakthrough in the treatment of small cell lung cancer, in my opinion?

Small cell lung cancer is an aggressive disease with dismal outcomes. The addition of immunotherapy to chemotherapy has modestly improved outcomes for extensive stage disease in the first line setting. Agents that are currently used in second line setting have limited efficacy with median duration of response (DOR) less than 6 months. Innovative therapies based on scientific discoveries that break through these gory statistics have been an imminent need for this disease. Tarlatamab, which is a delta-like ligand 3 (DLL3)–targeting therapy, seems to have addressed this need, at least for some patients, by demonstrating long-lasting responses in patients with small cell lung cancer who had been previously treated with platinum-based chemotherapy.

What is tarlatamab and why this agent is suitable for SCLC?

Tarlatamab is a bispecific T-cell engager immunotherapy that redirects the patient’s T cells to cancer cells expressing DLL3 by binding to both DLL3 on cancer cells and CD3 on T cells and thereby resulting in T-cell–mediated lysis of cancer cells. DLL3 is expressed in 85% to 94% of patients with small cell lung cancer, making it an attractive target with wide therapeutic potential.

What was the FDA approval based on?

Efficacy of tarlatamab was evaluated in the open-label, multicenter, multicohort, phase 2 DeLLphi-301 trial (NCT05060016), which included 99 patients with relapsed/refractory ES-SCLC with disease progression after platinum-based chemotherapy. Results from the trial indicated that the objective response rate (ORR) was 40% (95% CI, 31%-51%) and the median duration of response (DOR) was 9.7 months (range, 2.7-20.7+). Among the 69 patients with evaluable platinum-sensitivity status, objective responses were noted in 27 patients with platinum-resistant disease (defined as progression within 90 days after last dose of platinum therapy), ORR 52% (95% CI, 32%-71%). On the contrary, responses were noted in 42 patients with platinum-sensitive disease, ORR 31% (95% CI, 18%-47%).

Eligible patients were at least 18 years of age with histologically or cytologically confirmed relapsed/refractory SCLC with progression or recurrence following one platinum-based regimen and at least one other prior line of therapy, with good ECOG performance status of 0 or 1, a minimum life expectancy of 12 weeks, and measurable lesions per RECIST 1.1 criteria on scans performed within 21 days prior to the first dose of study therapy. Patients with treated brain metastases were eligible to enroll if they met other criteria. Patients with symptomatic brain metastases and interstitial lung disease or non-infectious pneumonitis were excluded. However, positivity for DLL3 expression on tumor cells was not required for inclusion.

The study was conducted in three parts: in Part 1, patients were randomly assigned 1:1 to receive 10 mg (n=88) or 100 mg (n=88) of tarlatamab. In both arms, patients received 1 mg of the agent on Day 1, followed by their assigned dose on Days 8 and 15 and every 2 weeks thereafter. In Parts 2 (n=12) and 3 (n=34), the dose-expansion and reduced inpatient monitoring periods cohorts respectively, patients received 10 mg of tarlatamab in the same dosing schedule as in Part 1. Tarlatamab was continued until disease progression or unacceptable toxicity. The primary and secondary efficacy end points were ORR and DOR, respectively, per RECIST 1.1 criteria assessed by both investigator and blinded independent central review. Other end points included disease control rate, progression-free survival (PFS), overall survival (OS), and safety.

Results from the trial published in the New England Journal of Medicine in 2023 showed that tarlatamab resulted in a median PFS of 4.9 months (95% CI, 2.9-6.7) in the 10-mg cohort and 3.9 months (95% CI, 2.6-4.4) in the 100-mg cohort for patients with advanced SCLC and disease progression on or after platinum-based chemotherapy. Median OS, though not yet mature with over 50% of patients in both cohorts still alive at last follow-up, was 14.3 months (95% CI, 10.8–not evaluable [NE]) and NE (95% CI, 12.4-NE) in the 10-mg and 100-mg cohorts, respectively. The median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group.

Additional results showed that in the 10-mg arm (n=100), the ORR was 40% (97.5% CI, 29%-52%), with a disease control rate (DCR) of 70% (95% CI, 60%-79%). In the 100-mg arm (n=88), the ORR was 32% (97.5% CI, 21%-44%), with a DCR of 63% (95% CI, 52%-73%). Notably, responses were recorded irrespective of DLL3 expression or availability of tumor tissue.3 The median time to response was 1.4 months (range, 1.1-9.6), and the median DOR was not reached. Of the 68 responders, 59% (n=40) remained in response for 6 months or more.

What are the FDA dosing recommendations?

The recommended dose of tarlatamab is an initial dose of 1 mg administered as an intravenous infusion over 1 hour on Day 1 of Cycle 1, followed by 10 mg on Days 8 and 15, then every 2 weeks thereafter until disease progression or unacceptable toxicity.

What are the potential adverse events to be aware of?

The treatment comes with a cost of some serious potential toxicities. Boxed warnings for the agent include serious or life-threatening cytokine release syndrome (CRS) and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome. The most common adverse effects reported with tarlatamab include CRS, fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, constipation, anemia, and nausea. The most common grade 3 or 4 laboratory abnormalities include decreased lymphocytes, decreased sodium, increased uric acid, decreased total neutrophils, decreased hemoglobin, increased activated partial thromboplastin time, and decreased potassium.

Challenges and lingering questions

While the study did allow patients who had not received checkpoint inhibitors in the first-line setting in regions where this is not approved or available, the current practice at least in the US is to add checkpoint inhibitor to platinum-based chemotherapy for extensive-stage SCLC as first-line therapy. About a quarter of the patients on the trial had not received an immune checkpoint inhibitor as part of their first-line regimen. The data presented thus far (to my knowledge) does not provide insight into the efficacy of tarlatamab based on prior checkpoint inhibitor use.

Side effects are also a concern. There were some severe cases of cytokine release syndrome in the trial and most occurred after the first or second dose of tarlatamab. Additionally, patients in the study had excellent performance status which may limit its adaptability to the real world. With agents such as lurbinectedin also approved in this space, it would be interesting to see what the optimal sequencing should be. Lastly, predictive biomarkers maty help triage patients to this treatment, thereby increasing the benefit-risk ratio.


Despite challenges, tarlatamab presents a promising treatment option for previously-treated patients with SCLC, addressing a huge unmet need. The recent accelerated FDA approval marks a promising new chapter in the history of small cell lung cancer therapeutics.


Ahn MJ, Cho BC, Felip E, et al (2023). Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med, 389(22):2063-2075. DOI:10.1056/NEJMoa2307980

Horn L, Mansfield AS, Szczęsna A, et al (2018). First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med, 6;379(23):2220-2229. DOI:10.1056/NEJMoa1809064

Patel S, Petty WJ, Sands JM (2021). An overview of lurbinectedin as a new second-line treatment option for small cell lung cancer. Ther Adv Med Oncol, 13:17588359211020529. DOI:10.1177/17588359211020529

Zugazagoitia J & Paz Ares L (2022). Extensive-stage small-cell lung cancer: first-line and second-line treatment options. J Clin Oncol, 40(6):671-6880. DOI:10.1200/JCO.21.01881

Paz-Ares L, Champiat S, Lai WV, et al (2023). Tarlatamab, a first-lin-class DLL3-targeted bispecific T-cell engager, in recurrent small-cell lung cancer: an open-label, phase I study. J Clin Oncol, 41(16):2893-2903. DOI:10/1200/JCO.22.02823 (2024). A phase 2 study of tarlatamab in patients with small cell lung cancer (SCLC) (DeLLphi-301). NLM identifier: NCT05060016.

Imdelltra™(tarlatamab-dlle) prescribing information (2024). Amgen Inc. Available at:

US Food and Drug Administration (2024). FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. Available at:

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