Is Tarlatamab Effective in Atypical Carcinoid and Large-Cell Neuroendocrine Carcinoma? What Does DLL3 Indicate?
In this article
Beyond Small Cell Lung Cancer: Tarlatamab, DLL3 and Rare Neuroendocrine Tumors
Tarlatamab (Imdelltra) is an immune-based medicine that targets a protein called DLL3. It is approved in the US and in Europe for small cell lung cancer (SCLC), based on a phase 3 trial in which it prolonged overall survival. Over the past two years, reports have appeared showing that the same drug can also produce striking responses in rarer neuroendocrine tumors of the lung, such as atypical carcinoid and large cell neuroendocrine carcinoma (LCNEC). In an 11-patient series published in August 2026, tumors shrank markedly in 8 of the patients with lung carcinoid. Data gathered over the same period suggest that the amount of DLL3 in the tumor may be a biomarker that predicts who will respond to this drug. In this article, we explain how accurate these reports are, how strong the evidence is, how a DLL3 test is interpreted and what patients need to know today. We covered the approval of tarlatamab in small cell lung cancer in our article on the FDA's full approval.
- Is what you heard true? Partly. In an 11-patient retrospective series of lung carcinoid (mostly atypical), the objective response rate was 73% and tumors shrank in every patient. In LCNEC, however, there are so far only isolated case reports. These data are promising, but early and small.
- Approval status: Tarlatamab is approved only for small cell lung cancer that has progressed after platinum-based chemotherapy. In carcinoid and LCNEC, it is currently used only in clinical trials or as off-label use.
- Is DLL3 a biomarker? A strong candidate. In extrapulmonary neuroendocrine carcinoma, the reported response rate was about 40% in patients with high DLL3 and 3% in those with low DLL3; in neuroendocrine prostate cancer, responses were seen only in DLL3-positive tumors. However, the cutoff value and the testing method have not yet been validated.
- Safety: The most important side effect is cytokine release syndrome (CRS). It occurred in 9 of 11 patients in the carcinoid series; treatment should be given at experienced centers with close monitoring.
Why does this matter?
Neuroendocrine tumors of the lung are not a single disease. They form a spectrum that runs from slow-growing typical carcinoid, through moderately fast-growing atypical carcinoid, to the aggressive large cell neuroendocrine carcinoma and small cell lung cancer (the difference between small cell and non-small cell lung cancer). In advanced carcinoid, response rates to drug treatments are low; published studies report rates of roughly 2% to 25%. In metastatic carcinoid, the 5-year survival rate is about 25%. LCNEC, because it is rare, has no large trials of its own and is mostly treated like small cell lung cancer.
That is why hearing that a new drug produces a high rate of response in these tumors is exciting for both patients and doctors. Still, it is important to remember that results from small, selected groups of patients may not be repeated in the same way in large trials. Validating DLL3 as a biomarker, on the other hand, could help make sure the drug is given to the right patient, sparing others unnecessary side effects and making treatment choices easier in rare tumors (levels of evidence for biomarkers).
Is tarlatamab effective in atypical carcinoid and large cell neuroendocrine carcinoma?
The first data are promising. In 11 patients with lung carcinoid, most of them atypical, 8 tumors shrank markedly and all of them shrank to some degree. In large cell neuroendocrine carcinoma, there are only case reports. Because the data are small and retrospective, tarlatamab is not yet approved for these tumors; its use is considered within a clinical trial or by tumor board decision.
Neuroendocrine tumors of the lung: from carcinoid to LCNEC
Neuroendocrine cells are specialized cells that release hormone-like substances and are found in many parts of the body. Four different tumors can arise from these cells in the lung. In the World Health Organization classification, they are distinguished by the number of dividing cells (mitoses) in a 2 mm² area under the microscope and by the presence of necrosis (areas of tumor tissue that are no longer viable). Typical and atypical carcinoids are called "well-differentiated neuroendocrine tumors," while LCNEC and small cell lung cancer are called "poorly differentiated neuroendocrine carcinomas" (what is a carcinoma?).
Figure 1 · The four neuroendocrine tumors of the lung
From slow-growing carcinoid to aggressive carcinoma
The treatment of these tumors also differs. In advanced carcinoid, somatostatin analogs, everolimus, peptide receptor radionuclide therapy (PRRT) and temozolomide-based chemotherapy are used, but responses are mostly limited. In LCNEC, platinum and etoposide-based chemotherapy is usually given, much as in small cell lung cancer, and some patients also receive immunotherapy (lung cancer guide). Once the disease progresses, effective options are few in both groups.
What is DLL3?
DLL3 (delta-like ligand 3) is a protein that works in the Notch signaling pathway, which regulates how cells develop. In normal adult cells, it is mostly found inside the cell, in the Golgi apparatus, with very little on the surface. In neuroendocrine tumor cells, however, it is produced in large amounts under the influence of a master regulator gene called ASCL1 and is carried to the cell surface. Being on the surface makes it an ideal "address" for drugs, and its scarcity in normal tissues limits the risk of side effects.
Figure 2 · Where is DLL3 found?
A normal cell versus a neuroendocrine tumor cell
However, the amount of DLL3 varies widely by tumor type and from patient to patient. In a study of 155 surgically removed lung neuroendocrine tumors, DLL3 staining in at least half of the cells was found in 12% of typical carcinoids, 24% of atypical carcinoids, 54% of LCNECs and 75% of small cell lung cancers. In atypical carcinoid, high DLL3 was associated with shorter disease-free survival, suggesting that DLL3 may mark a more aggressive subgroup.
High DLL3 expression in lung neuroendocrine tumors
Proportion of patients with DLL3 staining in at least 50% of tumor cells, %. 155 surgically removed tumors (Alì et al., 2021).
The less differentiated (more aggressive) the tumor, the more often and more strongly DLL3 is expressed. However, DLL3 expression varies from patient to patient within every histologic type, so DLL3 should be measured individually in any patient being considered for treatment. In atypical carcinoid, high DLL3 was associated with shorter disease-free survival.
How does tarlatamab work?
Tarlatamab is a bispecific T-cell engager antibody. One end binds to the CD3 molecule on the surface of the immune system's T cells, and the other end binds to DLL3 on the surface of the tumor cell. This brings the two cells side by side; the T cell is activated and destroys the tumor cell with the granules it releases. This mechanism suggests that the drug's effect should depend largely on the presence of its target, DLL3 (bispecific antibodies).
Figure 3 · How tarlatamab works
A bridge between the T cell and the tumor cell
The evidence: what is known in which tumor?
Small cell lung cancer (approved use). This is where the evidence for tarlatamab is strongest. In the phase 3 DeLLphi-304 trial, which compared tarlatamab with standard chemotherapy in patients whose disease had progressed after platinum-based chemotherapy, median overall survival was 13.6 months with tarlatamab and 8.3 months with chemotherapy; tarlatamab lowered the relative risk by 40% compared with chemotherapy (HR 0.60). The objective response rate was 35% versus 20%, and grade 3 or higher treatment-related side effects were less common with tarlatamab (27% versus 62%). Based on these results, the FDA granted full approval in November 2025; approval in the European Union followed in May 2026 (second-line results with tarlatamab, 2026 map of options).
Lung carcinoid. In December 2024, a response to tarlatamab was reported in a patient with metastatic atypical carcinoid that had progressed despite several treatments and strongly expressed DLL3. In August 2026, the first series, from Memorial Sloan Kettering Cancer Center, expanded on this observation: in 11 patients with metastatic lung carcinoid who had received a median of 2 prior lines of treatment, the objective response rate was 73% (8/11); disease control was achieved in every patient, and all measurable tumors shrank. At the data cutoff, the disease had progressed in only one patient, and median progression-free survival had not yet been reached. On pathology re-review, 3 patients were confirmed to have atypical carcinoid, and the other 8 were judged most consistent with atypical carcinoid. All tumors expressed DLL3 before treatment.
These results stand out when compared with the 2–25% response rates reported with standard drugs in carcinoid. However, the study is single-center and retrospective, includes only 11 patients, selected patients who were DLL3-positive and has short follow-up. The authors themselves describe the results as "hypothesis-generating."
Large cell neuroendocrine carcinoma (LCNEC). Here the evidence is even more limited. In a case published from Japan in July 2026, a patient with LCNEC that had progressed after five lines of treatment had about a 40% reduction in tumor burden with tarlatamab, a marked fall in the tumor marker pro-GRP and a response that lasted 8 months; the only side effect was grade 1 CRS. Of the 48 patients enrolled in a multicenter real-world series in the US, only one had LCNEC. With obrixtamig (BI 764532), another DLL3-targeted T-cell engager, a partial response was reported in 60% of the small number of LCNEC patients in an early-phase trial. No systematic study of tarlatamab in LCNEC has been published yet.
Extrapulmonary neuroendocrine carcinomas. In poorly differentiated neuroendocrine carcinomas arising in organs such as the gastrointestinal tract, pancreas, cervix and bladder (extrapulmonary NEC), early-phase data covering about 60 patients showed a response rate of about 40% in patients with high DLL3 expression (more than 50% of cells) and 3% (a single patient) in those with low expression. These figures were shared in an expert presentation in June 2026 and have not yet been published in a peer-reviewed journal (neuroendocrine cancer of the cervix and DLL3).
Neuroendocrine prostate cancer. In the phase 1b DeLLpro-300 trial, 40 patients were treated. The objective response rate was 22% in 18 DLL3-positive patients (at least 1% staining), while no responses were seen in 13 DLL3-negative patients (subtypes of prostate cancer).
Response to tarlatamab in different neuroendocrine tumors
Proportion of patients whose tumors shrank markedly (objective response), %. Study designs and patient numbers differ greatly.
Apart from the phase 3 trial, the data come from small, single-center or early-phase studies; the rates for extrapulmonary NEC come from an expert presentation, not a peer-reviewed publication. Still, a common pattern stands out: responses cluster in tumors with high DLL3 expression. Comparisons across different studies are indirect; patient populations, prior treatments and follow-up durations differ.
Figure 4 · Level of evidence
From phase 3 trial to case report
| Tumor | Study type | Number of patients | Response | Approval status |
|---|---|---|---|---|
| SCLC | Phase 3, randomized (DeLLphi-304) | Hundreds | 35% (20% with chemotherapy); overall survival 13.6 vs. 8.3 months | FDA (full), EU approved |
| Lung carcinoid (mostly atypical) | Retrospective series (MSK, 2026) + case | 11 + 1 | 73%; disease control 100% | Not approved |
| LCNEC | Case reports | Isolated cases | Cases of partial response | Not approved |
| Extrapulmonary NEC | Phase 1 (presentation) | About 60 | High DLL3: ~40%; low: 3% | Not approved |
| Neuroendocrine prostate cancer | Phase 1b (DeLLpro-300) | 40 | DLL3-positive: 22%; negative: 0% | Not approved |
Does DLL3 work as a biomarker?
A biomarker is a measurable feature that shows in advance who is likely to benefit from a drug. For DLL3, there are two different pictures. In small cell lung cancer, DLL3 is present in the great majority of patients (about 85–94%), so tarlatamab was approved without a DLL3 testing requirement; DLL3 testing is not routine in this disease today. In the phase 3 trial of the earlier DLL3-targeted drug Rova-T, results also did not differ by DLL3 level.
In rare neuroendocrine tumors, the situation appears to be different. Because DLL3 expression is more variable in these tumors, knowing who has enough of the target matters more. Response rates of 40% versus 3% in extrapulmonary NEC and 22% versus 0% in neuroendocrine prostate cancer suggest that DLL3 may genuinely guide treatment in these tumors. In the carcinoid series, too, all patients were DLL3-positive.
New research goes even further. In a small preprint study published in February 2026, the DLL3 level in tumor RNA distinguished responders in small cell lung cancer with high accuracy, and DLL3 was found to decrease in tumors that developed resistance (RNA sequencing). Another study presented at the AACR meeting in April 2026 reported that the DLL3 level in circulating tumor cells in the blood predicted response to tarlatamab. Both studies are small and await validation.
Figure 5 · How is DLL3 staining read?
Negative, low and high expression
Some obstacles still stand in the way of DLL3 testing. Different studies use different cutoffs; assessing staining intensity is partly subjective; and the DLL3 level can vary between different areas of the tumor and over time. For these reasons, DLL3 today is not a validated test that answers the question "who will definitely respond," but a strong candidate that can help guide treatment decisions. Before a test can enter clinical use, prospective studies need to establish which method and which cutoff should be used to measure it; this is exactly what ongoing trials are investigating (strengths and weaknesses of biomarker testing by immunohistochemistry, PD-L1 staining scores).
Figure 6 · How can DLL3 testing be used in practice?
A suggested path based on current evidence
Safety: cytokine release syndrome and neurological side effects
Because tarlatamab strongly activates T cells, its most important side effects are also a result of this activation. Cytokine release syndrome (CRS) is a condition in which substances released by immune cells cause fever, chills, low blood pressure and a need for oxygen; it mostly occurs with the first doses. Immune effector cell-associated neurotoxicity syndrome (ICANS) can cause confusion, difficulty writing or speaking, problems with balance and, rarely, seizures. Both can be treated with medicines such as tocilizumab and corticosteroids when recognized early.
How often does cytokine release syndrome (CRS) occur?
Proportion of patients who developed CRS during the first treatment cycle, %.
CRS is an immune reaction that mostly occurs with the first doses and causes fever, low blood pressure and a need for oxygen. In the carcinoid series, CRS developed in 9 of 11 patients, two of them grade 3; the authors emphasize that this rate is markedly higher than in small cell lung cancer trials. Comparisons across different studies are indirect; patient populations, prior treatments and follow-up durations differ.
The higher frequency of CRS in the carcinoid series is noteworthy. The reason is not yet known; the small number of patients, different monitoring practices or a different way in which carcinoid cells stimulate the immune system may play a role. The practical meaning is clear: in rare tumors, tarlatamab should be used at centers experienced in recognizing and managing these side effects, with close monitoring (tarlatamab side effect management guide, preparation and administration guide).
Figure 7 · The first doses and side effects
Step-up dosing, close monitoring and warning signs
Other DLL3-targeted drugs
The success of tarlatamab has accelerated the development of new drugs that target DLL3. Some of them have shown signals of activity in early trials in neuroendocrine tumors other than small cell lung cancer as well. Other surface targets such as B7-H3 are also being studied (what is B7-H3?, ifinatamab deruxtecan).
| Drug | Type | Data reported in neuroendocrine tumors |
|---|---|---|
| Obrixtamig (BI 764532) | T-cell engager | Partial response in 60% of the small number of LCNEC patients in an early-phase trial |
| MK-6070 (HPN328) | Trispecific T-cell engager | Objective response rate of 46% in 13 patients with neuroendocrine tumors other than small cell lung cancer |
| DLL3-targeted antibody-drug conjugates and radiopharmaceuticals | Drug-loaded antibody, radioligand | Early-phase trials ongoing |
| DLL3-targeted CAR-T and CAR-NK cells | Cell therapy | Phase 1 trials |
The situation in Türkiye
- As of the date this article was prepared, the licensing and SGK reimbursement status of tarlatamab in Türkiye could not be verified. In small cell lung cancer, use may be possible by importing the drug from abroad (cancer drugs imported from abroad).
- Tarlatamab is not approved in any country for carcinoid, LCNEC or extrapulmonary neuroendocrine carcinoma. In these patients, use is possible only within a clinical trial or with off-label use authorization from TİTCK.
- DLL3 immunohistochemistry staining is not performed routinely in every pathology laboratory in Türkiye; it is worth finding out in advance which center can perform the test.
- In rare tumors, the decision should be made at a tumor board that includes a pathologist, a medical oncologist and a nuclear medicine specialist; a second opinion should be sought if needed.
Questions you can ask your doctor
- Is my tumor a typical carcinoid, an atypical carcinoid or a neuroendocrine carcinoma? What are the mitotic count and the Ki-67 value?
- Can DLL3 staining be done on my tumor tissue? How will the result be reported as a percentage?
- What other approved and proven options are there for my tumor type? Which ones have we tried?
- Can I join a DLL3-targeted clinical trial? (what is a phase 1 trial?)
- If off-label use is considered, how can I get the drug, and at which center will the treatment be given?
- How will I be monitored for side effects during the first doses? Which symptoms at home should prompt me to call you?
- "Tarlatamab has been approved for carcinoid." No. The only approved use is small cell lung cancer that has progressed after platinum-based chemotherapy.
- "If 73% of 11 patients responded, everyone will respond." No. Results from small, selected series are usually lower in large trials; all of the patients were DLL3-positive.
- "If DLL3 is negative, it definitely won't work." There are not enough data to say this for certain; however, in rare tumors, responses are seen largely in tumors with high DLL3.
- "The same effect can be expected in typical carcinoid." This is not known. The series consisted mostly of atypical carcinoids, and DLL3 is less common in typical carcinoid.
- "Because it is immunotherapy, it has few side effects." No. CRS and neurological side effects can be serious and require close monitoring at an experienced center.
Frequently Asked Questions
- Is tarlatamab effective in atypical carcinoid and large cell neuroendocrine carcinoma?
- The first data are promising. In 11 patients with lung carcinoid, most of them atypical, the objective response rate was 73% and tumors shrank in every patient. In large cell neuroendocrine carcinoma, there are only case reports. Because the data are small and retrospective, the drug is not approved for these tumors.
- What is DLL3, and why does it matter?
- DLL3 is a protein that is abundant on the surface of neuroendocrine tumor cells but scarce on the surface of normal tissues. Tarlatamab binds to this protein and directs T cells to the tumor. The more DLL3 a tumor has, the more likely the drug appears to be effective.
- Can DLL3 testing be used as a biomarker?
- It is a strong candidate. In extrapulmonary neuroendocrine carcinoma, the reported response rate was about 40% in patients with high DLL3 and 3% in those with low DLL3; in neuroendocrine prostate cancer, it was 22% in DLL3-positive and 0% in DLL3-negative patients. However, the cutoff value and testing method have not yet been validated; in small cell lung cancer, the test is not required.
- What are the most important side effects of tarlatamab?
- The most important are cytokine release syndrome (fever, low blood pressure, need for oxygen) and neurological side effects (confusion, difficulty speaking). They mostly occur with the first doses. In the carcinoid series, CRS developed in 9 of 11 patients; for this reason, treatment should be given at experienced centers with close monitoring.
Glossary
- Neuroendocrine tumor (NET)
- A well-differentiated, usually slow-growing tumor that arises from cells that release hormone-like substances; in the lung, typical and atypical carcinoid.
- Neuroendocrine carcinoma (NEC)
- A poorly differentiated, fast-growing cancer arising from the same family of cells; small cell lung cancer and LCNEC.
- Atypical carcinoid
- A moderately aggressive lung carcinoid with more mitoses and/or focal necrosis than typical carcinoid.
- LCNEC
- Large cell neuroendocrine carcinoma; a rare, aggressive neuroendocrine cancer of the lung.
- DLL3
- Delta-like ligand 3; a protein that is abundant on the surface of neuroendocrine tumor cells and serves as a drug target.
- Bispecific T-cell engager
- An antibody that binds to a T cell at one end and to a tumor cell at the other, bringing the two cells together.
- Biomarker
- A measurable feature used to predict response to a treatment or the course of a disease.
- Immunohistochemistry
- A method that shows a specific protein in a tissue section using an antibody and a stain.
- Cytokine release syndrome (CRS)
- A condition of fever, low blood pressure and need for oxygen caused by excessive activation of immune cells.
- Off-label use
- Use of a drug for a disease other than the one it is approved for, based on the doctor's justification and authorization from the regulatory authority.
DROZDOGAN Academy Commentary
What you have heard is basically true: tarlatamab has produced surprising responses in lung carcinoid, and evidence is growing that DLL3 may help guide treatment. But this is still at the stage of "a strong clue," not "a proven treatment."
⚡ Why it matters
In advanced atypical carcinoid and LCNEC, response rates with standard treatments are low and options are limited. A 73% response rate and 100% disease control in an 11-patient series is a signal of activity at a level we have not seen before in these patients.
✅ Strengths
Tarlatamab has been shown in a phase 3 trial to prolong overall survival in small cell lung cancer, so the drug itself is well known. Data from different tumors point in the same direction: when DLL3 is high, a response is more likely. In the carcinoid series, pathology was centrally re-reviewed.
⚠️ Limitations
The carcinoid data come from an 11-patient, single-center, retrospective series with short follow-up. In LCNEC, there are only case reports. The extrapulmonary NEC figures are not from a peer-reviewed publication. The cutoff and method for DLL3 testing are not standardized. The frequency of CRS in carcinoid is higher than expected.
🩺 In practice
For our patients with advanced atypical carcinoid and LCNEC who have exhausted standard options, we request DLL3 staining. If DLL3 is high, we first look for clinical trial options; if no trial is available, we consider off-label tarlatamab at the tumor board, discussing the risks and uncertainties openly with the patient. We plan treatment only in a setting experienced in managing CRS and neurological side effects.
❓ Open questions
How durable are the responses in carcinoid? Is it also effective in typical carcinoid? Is the best cutoff for DLL3 1%, 25% or 50%? Can DLL3 measured in the blood replace a biopsy? Why is CRS more common in carcinoid? The answers to these questions will come from basket-type phase 2 trials.
Bottom line: Tarlatamab is a promising treatment candidate in DLL3-expressing lung carcinoid and other neuroendocrine tumors, and DLL3 may help select these patients. For now, however, this use is not approved; the decision should be made at a tumor board, within a clinical trial whenever possible, and at experienced centers.
- This article was prepared in November 2026.
- The carcinoid data are based on a single-center retrospective series (11 patients) and one case report; the LCNEC data are based on case reports. The response rates given for extrapulmonary NEC come from an expert presentation and could not be verified as a peer-reviewed publication.
- Results from different studies are shown in the same chart; because patient groups and study designs differ greatly, this comparison is indirect.
- The licensing and reimbursement status of tarlatamab in Türkiye could not be verified. The drawings are simplified. The Academy commentary is our own.
- This article is not medical advice; make your treatment decisions together with your doctor.
References
- Ross JS, Lee J, Ortiz E, Yildirim O, Aly RG, Solanki P, Rekhtman N, Rudin CM. Clinical responses to tarlatamab among patients with pulmonary carcinoid. J Thorac Oncol 2026 (online August 6, 2026). doi:10.1016/j.jtho.2026.104135. sciencedirect.com
- Cooper AJ, Rekhtman N, Baine MK, Thomas MC, Lynch AC, Gentzler RD. First report of response to tarlatamab in a patient with DLL3-positive pulmonary carcinoid: case report. JTO Clin Res Rep 2024;5:100750. doi:10.1016/j.jtocrr.2024.100750. jtocrr.org
- Mizushima R, Yomota M, Togashi S, Kato T, Hosomi Y. A case of large cell neuroendocrine carcinoma (LCNEC) treated with tarlatamab. Int Cancer Conf J 2026;15:439-442. link.springer.com
- Alì G, Di Stefano I, Poma AM, et al. Prevalence of delta-like protein 3 in a consecutive series of surgically resected lung neuroendocrine neoplasms. Front Oncol 2021. doi:10.3389/fonc.2021.729765. frontiersin.org
- OncLive. FDA grants full approval to tarlatamab for extensive-stage small cell lung cancer (DeLLphi-304). November 2025. onclive.com
- European Medicines Agency. Imdylltra (tarlatamab) EPAR. May 2026. ema.europa.eu
- OncLive. Targeting DLL3 in extrapulmonary neuroendocrine carcinoma (J. Strosberg). June 2026. onclive.com
- OncLive. Clinical development of DLL3-targeted therapies and future directions. June 24, 2026. onclive.com
- OncLive. Tarlatamab demonstrates early safety and activity in DLL3+ neuroendocrine prostate cancer (DeLLpro-300; Clin Cancer Res 2025). onclive.com
- Fenton G, Zhang AL, Zhong S, et al. Multi-institution real-world analysis evaluating safety, efficacy, and ctDNA dynamics after tarlatamab in patients with previously treated SCLC and LCNEC. JTO Clin Res Rep 2026;7:100933. sciencedirect.com
- Cieslak Z, et al. Genomic and transcriptomic correlates of response to tarlatamab in small cell lung cancer. medRxiv 2026 (preprint). medrxiv.org
- ecancer. DLL3 expression in circulating tumour cells predicts response to tarlatamab in small cell lung cancer (AACR 2026). ecancer.org
- Pharmacy Times. Targeting DLL3 in small cell lung cancer and other neuroendocrine carcinomas. February 2025. pharmacytimes.com
- ClinicalTrials.gov. Tarlatamab in advanced DLL3-expressing tumors including neuroendocrine neoplasms. NCT06788938. clinicaltrials.gov
Was this article helpful?
Your feedback helps us improve our content.
