Small Cell Lung Cancer in 2026: Tarlatamab Changes the Arc, and a New Wave of ADCs Is Coming

Small cell lung cancer has long resisted the treatment advances that transformed non-small cell disease. In 2026, that is beginning to change. Tarlatamab — a DLL3 × CD3 bispecific T-cell engager — has improved overall survival in the second-line setting and received FDA approval. Dr. Rafael Santana-Davila reviews the current standard of care, tarlatamab's practical use, and the ADC pipeline redefining what's next for this disease.

Introduction: The Ugly Brother of Lung Cancers Is Starting to Change

Small cell lung cancer has a reputation that is entirely warranted. It accounts for 10 to 15% of lung cancers in the United States. Most patients present with metastatic disease. Median overall survival has historically been 8 to 13 months, and that figure remained stubbornly constant across decades. Every oncologist has a story of a patient who seemed fine on Monday and was gone within weeks. The cancer is fast, aggressive, and until recently, largely impervious to the immunotherapy advances that have transformed non-small cell lung cancer.

That is changing. Tarlatamab, a DLL3 × CD3 bispecific T-cell engager, has improved overall survival in the second-line setting and received FDA approval. It is the first treatment in years to meaningfully change the arc of this disease, and it is generating a wave of related approaches across the ADC and bispecific pipeline.

A Note on Diagnosis: Distinguish Small Cell from Carcinoid

Before treating, get the diagnosis right. Neuroendocrine tumors span a spectrum: high-grade small cell lung cancer and large cell neuroendocrine carcinoma carry TP53 and RB1 pathway abnormalities and behave with extreme aggression. Other neuroendocrine tumors such as low grade neuroendocrine cancer (often referred as low grade carcinoids) lack these pathway alterations and behave very differently. They are frequently less responsive to platinum-based chemotherapy and should not be treated as small cell.

Approximately once a year, a referral arrives of a patient labeled as small cell who, in retrospect, likely had a low grade neuroendocrine tumor. The misclassification matters enormously, for treatment decisions and for prognosis. Sequencing patients when there is any diagnostic uncertainty is worthwhile. SMARCB1-mutated tumors represent another entity that can superficially resemble small cell but behaves differently; these patients often respond poorly to platinum.

Standard of Care: Chemoimmunotherapy Since 2018

The current first-line standard for extensive-stage small cell lung cancer was established by two trials in 2018 and 2019: the CASPIAN study (durvalumab plus platinum/etoposide) and IMpower133 (atezolizumab plus platinum/etoposide). Both combine chemotherapy with checkpoint inhibition. There are subtle differences in design; CASPIAN allowed cisplatin and up to six cycles rather than four, and was not placebo-controlled, but the survival curves are strikingly similar between the two.

The comparison to non-small cell lung cancer is humbling. In NSCLC, adding pembrolizumab to chemotherapy produces PFS curves that separate early and stay separated, with a meaningful long-term tail of survivors reaching 20% or more at five years. In small cell, the curves don't separate until later, and the tail, while present, is small, perhaps 10 to 15% of patients. Why a cancer with extremely high tumor mutational burden responds less well to immunotherapy than expected remains poorly understood. The working hypothesis involves immune evasion strategies that differ from NSCLC, but the mechanisms are not yet characterized well enough to target.

Limited-Stage SCLC: The ADRIATIC Trial

In limited-stage small cell lung cancer, chemoradiation is the standard treatment, and the ADRIATIC trial has now established a role for consolidation immunotherapy. ADRIATIC added durvalumab after four cycles of chemotherapy and after completion of radiation, and demonstrated an overall survival benefit.

A comparable trial (LU005) added atezolizumab concurrent with radiation from the start of treatment, and was negative. The key differences between the trials include: durvalumab added after radiation completion versus atezolizumab added at the beginning; ECOG performance status 0-1 required in ADRIATIC versus 0-2 in LU005; and slightly different sequencing relative to chemotherapy cycles. Which difference drove the outcome discrepancy is unknown. For now, durvalumab after chemoradiation in limited-stage SCLC is the approach supported by positive evidence.

Tarlatamab: What It Is and What It Does

Tarlatamab is a bispecific T-cell engager targeting DLL3 on one arm (a surface protein highly expressed in small cell lung cancer and other neuroendocrine tumors) and CD3 on the other (the T-cell activation receptor). By bringing T cells into direct contact with DLL3-expressing cancer cells, tarlatamab activates an immune attack directly at the tumor site.

Tarlatamab has been shown to improve overall survival after progression on platinum chemotherapy versus chemotherapy and received FDA approval. The survival benefit is meaningful for a disease where second-line options have historically been inadequate.

Cytokine release syndrome (CRS): Approximately 50% of patients develop CRS with tarlatamab, but the severity distribution is important context. The majority of events are grade 1, fever only, with no hemodynamic instability. Approximately 20% develop grade 2 (fever plus oxygen need, hypotension requiring fluids, or other organ involvement). Grade 3 (requiring vasopressors or tocilizumab) is less common. The first dose is 1mg; the second dose steps up to 10mg. CRS risk decreases with subsequent cycles.

A clinical case illustrating the potential: An 80-year-old woman with metastatic small cell lung cancer progressed through platinum chemotherapy with minimal benefit. She was started on tarlatamab and developed grade 3 CRS requiring two doses of tocilizumab, a rough course. When she came back to clinic after hospital discharge, she mentioned almost incidentally that a subcutaneous nodule near her sternum that had been visible and palpable was simply no longer there. She decided to continue. A second cycle produced only grade 1 fever. Her most recent scan showed a near-complete response. She continues on tarlatamab today afgter more than a year with good tolerance and excellent quality of life.

This case captures something important about tarlatamab: the early CRS can be severe enough to make patients (and clinicians) want to stop, but it does not predict poor response. The tumor response and the CRS are independent phenomena. If the first CRS episode resolves and the patient is willing to continue, the second cycle almost invariably produces less severe CRS.

Outpatient Tarlatamab: A Practical Protocol

Tarlatamab was initially administered inpatient. Swedish, Emory and Mayo Clinic have all now published experience with outpatient administration, demonstrating safety with appropriate protocols.

The Swedish outpatient approach: patients are educated on vital sign monitoring at home, given explicit temperature and symptom thresholds for calling, and provided a prescription for dexamethasone not to take until instructed. If they develop fever at home, they call; they are instructed to take the dexamethasone and go to the emergency room. The ER has a standing protocol to administer tocilizumab if indicated, regardless of time of day. Patients stay in clinic for several hours post-infusion, then go home.

With this protocol: approximately 20% of patients require hospitalization for CRS management; no ICU admissions to date. Mayo Clinic's published experience used Bluetooth-enabled vital sign monitors, a higher-tech version of the same approach with similar outcomes. The key elements are patient education, clear action thresholds, and an ER protocol that doesn't leave the patient waiting hours for tocilizumab.

The clinical implication: tarlatamab does not require automatic inpatient admission. For most patients, outpatient administration with a robust monitoring and response protocol is feasible and appropriate.

Moving Tarlatamab Earlier: Maintenance and First-Line Trials

Tarlatamab's approval in the second line has generated immediate interest in moving it earlier.

Maintenance after 4 cycles of chemotherapy: A study by Kenny Paulson and colleagues at Swedish, published in Lancet Oncology, evaluated tarlatamab as maintenance after four cycles of platinum/etoposide. PFS results compared favorably to historical controls.

DeLLphi-305 trial (tarlatamab after induction): This phase 3 trial has completed accrual at 550 patients enrolled worldwide. It will be presented at World Lung Conference. Word from those close to the trial suggests it may be a positive study, though the data have not been presented and this should be interpreted cautiously.

DELFI-212 (tarlatamab plus frontline chemo from diagnosis): Open at Swedish. Accrual has been challenging because asking newly diagnosed patients to understand the tarlatamab protocol on top of absorbing a new diagnosis is a significant burden. Furthermore this patients needs to start treatment soon and getting everything ready for a trial is challenging. The biology is appealing, early T-cell engagement at full tumor burden, and the trial is designed to answer whether frontline combination is feasible and effective.

The ADC Pipeline in SCLC

Beyond tarlatamab, a substantial ADC pipeline is advancing in small cell:

B7H3-targeting ADC: FDA review pending as of writing. Phase 2 data: 137 patients, ORR approximately 48%, CNS ORR approximately 46%. ILD occurred in approximately 12.4% of patients with some grade 5 events, a toxicity that requires careful monitoring given the already challenging patient population.

DLL3-targeting ADC (Ideaya 849 study, targeting the same DLL3 as tarlatamab but with an ADC payload): Approximately 60% ORR in phase 1 data, including patients who had already progressed on tarlatamab. This is particularly important: if tarlatamab fails, DLL3-directed ADC may still work. Enrollment open at Swedish for neuroendocrine malignancies broadly.

TROP2-targeting ADC: Phase 2 data with 43 patients; ORR approximately 42%, PFS 4.4 months. Short PFS is typical for this disease.

Next-generation TROP2 ADC: ORR 56 to 59% depending on dose cohort, PFS 5.9 months. Published as a preprint in Journal of Thoracic Oncology.

For Patients

If you have been diagnosed with small cell lung cancer, the treatment landscape has changed meaningfully in the past year. A new drug called tarlatamab works by activating your immune system directly against the cancer and has been shown to improve survival in patients whose cancer has returned after initial chemotherapy. Most patients who receive tarlatamab experience some degree of immune reaction (cytokine release syndrome), usually a fever, but serious reactions are less common. Ask your oncologist whether tarlatamab is appropriate for your situation, and whether clinical trials are available. New drugs targeting the same proteins on small cell lung cancer cells are in development and being tested in trials now, including drugs that may work even for patients who have already received tarlatamab.

Key Takeaways

  • Small cell lung cancer remains difficult: 10-15% of lung cancers, mostly metastatic at presentation, median OS 8-13 months with chemoimmunotherapy.

  • Standard first-line: durvalumab or atezolizumab plus platinum/etoposide; similar efficacy curves; immunotherapy tail is smaller than in NSCLC.

  • ADRIATIC: durvalumab after chemoradiation in limited-stage SCLC shows OS benefit; atezo concurrent with radiation (LU005) was negative.

  • Tarlatamab (DLL3 × CD3 bispecific): second-line OS benefit, FDA approved; ~50% CRS but mostly grade 1; second cycle CRS substantially milder than first; outpatient administration is feasible with proper protocols.

  • Tarlatamab maintenance (LP305, 550 patients enrolled, World Lung presentation coming) and frontline combination (DELFI-212) trials are active.

  • ADC pipeline: B7H3 ADC (FDA review pending, 48% ORR, ILD signal); DLL3 ADC (60% ORR including post-tarlatamab); TROP2 ADCs (42-59% ORR); DLL3 ADC open for neuroendocrine malignancies at Swedish.

About the Author

Rafael Santana-Davila, MD, is a board-certified medical oncologist at the Swedish Cancer Institute in Seattle, Washington, specializing in thoracic oncology with a particular focus on small cell lung cancer and neuroendocrine tumors. He completed his medical degree at Universidad Anahuac Escuela de Medicina in Mexico, his internal medicine residency at the University of Minnesota, and his fellowship at Mayo Clinic. He leads clinical trials in small cell lung cancer at Swedish and is actively involved in outpatient tarlatamab administration protocols and supportive care innovation.

References

  1. CASPIAN trial. Durvalumab plus platinum-etoposide in extensive-stage SCLC. Lancet, 2019; updated analysis 2022.

  2. IMpower133. Atezolizumab plus chemotherapy in extensive-stage SCLC. New England Journal of Medicine, 2018.

  3. ADRIATIC trial. Durvalumab after chemoradiation in limited-stage SCLC. New England Journal of Medicine, 2024.

  4. Tarlatamab (DeLLphi-301). DLL3 × CD3 bispecific in previously treated SCLC. New England Journal of Medicine, 2023; OS data 2025.

  5. Paulson KG, et al. Tarlatamab maintenance after platinum-etoposide in SCLC. Lancet Oncology, 2025.

  6. B7H3-targeting ADC in SCLC. Phase 2 data, FDA review 2026.

  7. I-DXd849 (DLL3 ADC) in SCLC and neuroendocrine malignancies. Phase 1 data, 2025-2026.

  8. Santana-Davila R. "Small Cell Lung Cancer." Presented at the 2026 Alaska Hematology Oncology Conference, Anchorage, AK, May 2026.