The combination of durvalumab and tarlatamab significantly improved overall survival in patients with extensive-stage small cell lung cancer (ES-SCLC) receiving first-line maintenance therapy, according to positive high-level results from the Phase III DeLLphi-305 trial (NCT06211036).
At a pre-specified interim analysis, the study met its primary endpoint, with durvalumab plus tarlatamab demonstrating a statistically significant and highly clinically meaningful improvement in overall survival (OS) compared with durvalumab alone.
The combination also demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR), key secondary endpoints of the study. Detailed efficacy results, including median survival estimates and hazard ratios, have not yet been disclosed.
According to Amgen, DeLLphi-305 is the first Phase III study involving a bispecific T-cell engager to demonstrate an overall survival benefit in the first-line maintenance setting for ES-SCLC.
DeLLphi-305 Phase III Trial
DeLLphi-305 is a global, randomized, open-label Phase III trial evaluating tarlatamab plus durvalumab versus durvalumab alone as first-line maintenance treatment for patients with ES-SCLC whose disease had not progressed following initial treatment with durvalumab, platinum-based chemotherapy, and etoposide.
The induction regimen included durvalumab with etoposide and the investigator’s choice of carboplatin or cisplatin.
A total of 563 patients who completed durvalumab-based induction treatment were randomized 1:1 to receive either:
- tarlatamab plus durvalumab, or
- durvalumab alone,
with treatment continuing until disease progression or unacceptable toxicity.
The trial also included patients with treated or untreated asymptomatic brain metastases at baseline.
Overall survival is the primary endpoint. Secondary endpoints include progression-free survival and objective response rate.
Following tarlatamab administration on Cycle 1 Day 1 and Cycle 1 Day 8, patients in the study were monitored in a healthcare setting for 1 to 2 hours, or 6 to 8 hours in certain regions, including Europe.
Addressing an Unmet Need in ES-SCLC
Small cell lung cancer is an aggressive form of lung cancer characterized by rapid tumor growth and early metastatic spread, including to organs such as the brain and liver.
Approximately 15% of lung cancers are classified as SCLC, and about two-thirds of patients with SCLC are diagnosed with extensive-stage disease. Five-year survival remains particularly poor, with approximately 3.6% of patients with ES-SCLC alive five years after diagnosis, according to data cited by AstraZeneca.
Although the introduction of immune checkpoint inhibitors has improved outcomes and changed first-line treatment, prognosis remains poor.
In 2026, an estimated 195,000 people worldwide are expected to be treated for ES-SCLC. Median overall survival with the current standard of care remains approximately one year.
Amgen additionally noted that only about 40% of patients with ES-SCLC receive second-line therapy, highlighting the importance of achieving greater disease control and survival benefits earlier in the treatment pathway.
Jacob Sands, MD, Associate Chief of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, emphasized this challenge:
“Many patients quickly relapse on current therapy and never reach second-line treatment.”
He described the DeLLphi-305 findings as among the most compelling survival results he has seen during his career treating ES-SCLC and said the study suggests meaningfully longer survival may become possible for more patients.
Moving Tarlatamab Earlier in the Treatment Pathway
Tarlatamab is a DLL3-targeting bispecific T-cell engager designed to simultaneously bind DLL3 on tumor cells and CD3 on T cells, activating T cells to attack DLL3-expressing cancer cells.
DLL3 is expressed on the surface of SCLC cells in approximately 85% to 96% of patients, while its expression in healthy cells is minimal, making it an important therapeutic target in SCLC.
Tarlatamab is already approved in the United States for adults with ES-SCLC whose disease has progressed on or after platinum-based chemotherapy. DeLLphi-305 therefore evaluates the treatment considerably earlier in the disease course, as maintenance therapy following first-line induction treatment.
The Phase III study builds on the DeLLphi-303 trial, which previously evaluated tarlatamab in combination with PD-L1 checkpoint inhibition in first-line ES-SCLC. Amgen is also investigating tarlatamab across several other trials in both extensive-stage and limited-stage SCLC, including different treatment lines, dosing approaches, and combination regimens.
Jay Bradner, MD, Executive Vice President of Research and Development, Artificial Intelligence and Data at Amgen, highlighted the significance of the findings:
“Substantial improvements in survival are rare, underscoring the importance of these findings.”
According to Bradner, the results suggest that moving tarlatamab earlier in the treatment journey could meaningfully shift the treatment paradigm for patients with ES-SCLC.
Durvalumab and Tarlatamab: Two Immunotherapy Approaches
Durvalumab is a PD-L1-targeting monoclonal antibody that blocks the interaction of PD-L1 with PD-1 and CD80, helping counter tumor-mediated immune suppression and restore antitumor immune responses.
Durvalumab-based therapy is already established as a first-line treatment approach for ES-SCLC based on results from the Phase III CASPIAN trial. Durvalumab is also used in limited-stage SCLC based on the Phase III ADRIATIC trial.
The DeLLphi-305 strategy combines PD-L1 checkpoint inhibition with DLL3-directed T-cell engagement, providing two distinct approaches to activating antitumor immunity.
Safety Profile and Next Steps
The overall safety and tolerability profile of tarlatamab plus durvalumab was consistent with the known safety profiles of the individual treatments, and no new or unexpected safety signals were identified in DeLLphi-305.
Detailed efficacy and safety findings from the study have not yet been reported. Amgen and AstraZeneca said the full DeLLphi-305 results will be presented at an upcoming medical congress and shared with regulatory authorities worldwide.
The DeLLphi-305 trial is sponsored by Amgen, with partial funding and durvalumab provided by AstraZeneca.
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