At ESMO 2025 we’ve been presenting the data from the DeLLphi-303 trial which studied the combination of tarlatamab, a DLL3 CD3 bispecific T-cell engager, in combination with frontline immunochemotherapy in extensive disease small-cell lung cancer.

The current standard of care for extensive-stage small-cell lung cancer is an immunochemotherapy which is inducing responses in the majority of the patients. However, these responses are rather short-lived, so there’s an urgent need to develop novel compounds that can increase the depth of responses and/or prolong responses and therefore overall survival, and tarlatamab is a bispecific T-cell engager that targets DLL3 on the surface of tumour cells and CD3 on the surface of immune cells, and thereby gets T-cells and tumour cells into close proximity, activating T-cells and eliciting a potent anti-immune response. It has recently proven its safety and efficacy in a phase 3 trial, the DeLLphi-304 trial, which led to approval in the US and approval in the European Union is still pending.

What was the methodology?

DeLLphi-303 was a multicohort phase 1 B-dose expansion study. We did include patients with extensive-stage small-cell lung cancer. They were allowed to have received a single cycle of standard of care immune chemotherapy or chemotherapy. After that they were included provided they had a good performance status, had only treated and asymptomatic brain metastases and no active autoimmune diseases. Patients were then treated with three cycles of chemotherapy plus PD-L1 inhibition with either durvalumab or atezolizumab in combination with tarlatamab, and after these three cycles they proceeded with tarlatamab and PD-L1 maintenance until disease progression or loss of clinical benefit. Primary endpoints of the study were, of course, the safety as measured by the occurrence of dose-limiting toxicities, as well as by the treatment, by the nature and severity of treatment-related and emergent adverse events. Of course we were also interested in preliminary signs of efficacy such as objective response rate, duration of response, disease control rate, PFS and overall survival, which were all secondary endpoints.

What did you find?

First of all, we found that this seems to be a rather safe combination. Of course all the patients had treatment-related adverse events and a third to a half of the patients also had grade 3 and 4 treatment-related adverse events, but this was only due to cytopenias which are associated with chemotherapy, as you would expect with a chemotherapy regimen. We did see only three dose-limiting toxicities in a total cohort of 96 patients. We just had one treatment-related fatality that was a patient who died from sepsis, and this sepsis was deemed related to the chemotherapy component of this regimen. In all, I  think we can say that the toxicity profile is pretty much similar to what you would expect from the single components of this combination regimen.

For tarlatamab we saw again what we’ve seen in other trials and also with other bispecific T-cell engagers: you do see a bit of cytokine-release syndrome in the beginning. This is usually of low grade and after cycle 2 there is almost no CRS anymore. The rate of immune-cell related neurotoxicity is quite low and also this only occurs at low grades and in the first cycle.

And in terms of efficacy?

First of all, we saw the expected response rate, which was at 71% so this is what you would normally expect from an immunochemotherapy. What was not expected and pretty encouraging was the median duration of response, which was 11.0 months. We now have patients who are ongoing for more than a year and are still in remission and when we look at overall survival, by far the most important endpoint for small-cell lung cancer patient trials, we have the median overall survival not being reached thus far, and 12-months overall survival rate of 81%. This is much more than you would expect with all the other agents that are available at the moment. The PFS was also quite encouraging, median PFS was 10.3 months, which is more than a doubling of what you would expect with standard immunochemotherapy, and at 12 months we had a PFS rate of 43%. So even though this is a very preliminary trial, it’s a phase 1b trial and rather small cohort, I think these results are pretty encouraging and are clearly telling us what kind of direction the future standard of care will develop into.

What’s next?

Next is we’re going to have several phase-3 trials going on. From Amgen there’s DeLLphi-305, which is testing the combination of tarlatamab with PD-1 blockade in maintenance after induction immunochemotherapy and we will have a direct successor of the DeLLphi-303 data I’ve presented at this year’s ESMO; this is DeLLphi-312. DeLLphi-312 is currently recruiting and DeLLphi-305, the maintenance trial, has already completed recruitment, so it won’t be long until we have the results and I can tell that I’m pretty sure that what we are looking at right now will be tomorrow’s future standard of care.