DeLLphi-303 study

In this video, Dr Dieter Stevens, pulmonologist and thoracic oncologist at the Ghent University Hospital, and Dr Lizza Hendriks, pulmonologist at the Maastricht UMC, discuss the results of the DeLLphi-303 study, presented at ESMO 2025.

DeLLphi-303 is a phase I study evaluating the addition of the T-cell engager tarlatamab to first-line chemoimmunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). Previously, tarlatamab already demonstrated superiority over chemotherapy in the second-line setting, and this trial aims to explore its potential benefits earlier in the treatment course.

Part of the rationale to evaluate tarlatamab in first line is that many patients with ES-SCLC do not reach the second line setting due to rapid disease progression. Furthermore, previously untreated patients have a stronger, less exhausted immune system which may enhance the therapeutic effect of T-cell engagers. Preclinical data suggest possible synergy between tarlatamab and immune checkpoint inhibitors, justifying its combination with chemoimmunotherapy in this trial. In DeLLphi-303, patients received one cycle of standard chemoimmunotherapy before tarlatamab was added for three cycles after which maintenance therapy was given with an anti-PD-L1 agent and tarlatamab.

The primary objective of the study was safety. Tarlatamab in combination with chemoimmunotherapy exhibited manageable toxicity, comparable to what was seen with this agent in the second-line setting. CRS occurred in just over 50% of patients but was generally mild to moderate with infrequent grade ≥3 events. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in approximately 6–7% of patients, again predominantly low grade. Hematologic toxicity was attributable primarily to chemotherapy, and immune-related adverse events did not exceed those associated with chemoimmunotherapy alone.

Preliminary efficacy signals were encouraging. The overall response rate was reported at 68%, although interpretation of this endpoint is complicated by the prior administration of chemotherapy. The median progression-free survival (PFS) reached 10.3 months with a 1-year PFS rate of 43.1%. In addition,  the 1-year OS rate was 80.6%, which is substantially higher than historical benchmarks. 

Looking ahead, Dr Hendriks highlighted the importance of ongoing phase III studies to further define the optimal combination strategy for tarlatamab and establish its role within the rapidly evolving treatment landscape of ES-SCLC.