Clinical Summary

• The phase 3 DeLLphi-305 trial demonstrated a substantial overall survival benefit with tarlatamab plus durvalumab versus durvalumab alone as first-line maintenance therapy for extensive-stage small cell lung cancer (ES-SCLC), with median overall survival of 21.1 versus 12.7 months (HR, 0.42).
• The combination also improved median progression-free survival (7.4 vs 1.9 months; HR, 0.34), with 38% of patients remaining progression-free at 1 year compared with 10% receiving durvalumab alone.
• Tarlatamab plus durvalumab demonstrated a manageable safety profile, with cytokine release syndrome (CRS) occurring in approximately 50% of patients, predominantly grade 1, and immune effector cell-associated neurotoxicity syndrome (ICANS) reported in 1.1%.

Jacob Sands, MD, a thoracic medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts, discusses the primary analysis of the phase 3 DeLLphi-305 trial, presented at the 2026 European Society for Medical Oncology (ESMO) Congress. The randomized study evaluated tarlatamab plus durvalumab versus durvalumab alone as first-line maintenance therapy following induction treatment with platinum, etoposide, and durvalumab in patients with extensive-stage small cell lung cancer (ES-SCLC). Building on promising results from the phase 1b DeLLphi-303 trial, DeLLphi-305 demonstrated substantial improvements in median overall survival (21.1 vs 12.7 months; HR, 0.42) and progression-free survival (7.4 vs 1.9 months; HR, 0.34). At 1 year, 38% of patients receiving the combination remained progression-free compared with 10% receiving durvalumab alone, suggesting the potential for durable disease control in a population with historically limited treatment options.

Sands also highlights the combination's safety profile, noting no apparent synergistic toxicity between tarlatamab and durvalumab. Although CRS occurred in approximately half of patients receiving the combination, most events were grade 1, with grade 2 CRS reported in 7.4% and grade 3 CRS in only 1 patient. ICANS occurred in 1.1% of patients, a lower incidence than previously reported in some tarlatamab studies. Sands emphasizes that these findings represent an important advance in ES-SCLC treatment and support tarlatamab plus durvalumab as a potential new first-line maintenance standard, although longer follow-up and real-world safety data will help further define its clinical role.

Transcript

Jacob Sands, MD: I'm Dr. Jacob Sands, a thoracic medical oncologist from Dana-Farber Cancer Institute in Boston, joining you from ESMO 2026. 

I have the honor of presenting DeLLphi-305. This is a randomized trial in the setting of extensive-stage small cell lung cancer in the maintenance setting. But first, a little background.

Small cell lung cancer is an aggressive disease that has historically been very challenging to treat. Some years back, we did have the studies with PD-L1 inhibitors incorporated into the first-line setting. And we do see some modest improvement in median overall survival, but frankly, it's the tail of the curve. It's the subset of patients that get these extraordinary ongoing responses to therapy.

And I'd highlight a subset that appears like they may actually be cured of their incurable disease. It's an extraordinary statement to make, but we do have a subset of patients where we're seeing that kind of durable benefit. And what this highlighted for us is that, although the checkpoint inhibitors were not working for everybody, there is a group where we get this durability that goes beyond everything we've seen with the cytotoxics, but a lot of work still to do.

Now, building upon that, DeLLphi-303 was presented at the World Conference on Lung Cancer. This was a phase 1b study incorporating tarlatamab in the maintenance setting with a PD-L1 inhibitor. It could have been atezolizumab or durvalumab. Now, that drew a lot of attention when it showed a median overall survival of 25.3 months. That was a shocking number to many people.

In the last year, that now has been updated, and that was reported here at ESMO this year as well. With a longer follow-up, about a 30-month follow-up, we now see that the median overall survival of DeLLphi-303 is 37.9 months. That has actually increased by more than a year as the data have matured. And keep in mind, it is still a median follow-up of 30 months with a median overall survival of 37.9, so that's not the final median overall survival. Even that could evolve even further.

But this sets the stage now for the randomized trial DeLLphi-305. To be eligible for DeLLphi-305, patients had to have had platinum, etoposide, plus durvalumab for 4 cycles. Durvalumab had to be at least for 3, but the majority did have 4. They were then randomized to tarlatamab plus durvalumab or durvalumab alone. Now, patients were eligible with asymptomatic untreated brain metastases.

There was a hierarchical statistical plan looking at overall survival, then progression-free survival, and then response rate. The median overall survival benefit was 21.1 months versus 12.7 months, a hazard ratio of 0.42. The median follow-up for this was still only at 16 months, so this is not the final. We'll have to see how this evolves as the data mature. As far as progression-free survival, we saw an improvement in median PFS to 7.4 versus 1.9 months, with a hazard ratio of 0.34. I'd also highlight that at the 1-year time frame, 38% were still progression-free in the tarlatamab plus durvalumab arm as compared to 10% in the durvalumab arm. Not only are we getting these very impressive median PFS and median OS benefits, we're also getting a durability, a tail of the curve, with a substantial number of patients that are getting that durable ongoing control.

From a toxicity standpoint, we saw no indication of any kind of synergistic toxicity. We see, if anything, a little bit less toxicity for the tarlatamab-specific toxicities.

Cytokine release syndrome, of course, is a common one among T-cell engagers. A CRS rate of 50%. This is in line with what we've seen in prior tarlatamab trials, maybe slightly less, but only 21 patients, 7.4%, with grade 2 CRS. Grade 1 is a fever. That's what the majority of the CRS events were. Patients get antipyretics. Some of them also got dexamethasone because this is all outpatient. This study was a 1- to 2-hour observation time. In Europe, it was a 6- to 8-hour observation time. There were some patients who got dexamethasone along with antipyretics. As far as grade 2, that's hypotension and/or hypoxia. There were 21 patients, 7.4%, and only a single patient with grade 3 CRS, which did end up resolving as well. Quite a tolerable CRS profile.

For ICANS, we saw only 3 patients, 1.1%, who had ICANS. This is substantially lower than what we've seen from other tarlatamab studies. But we also did a broad search across neurological terms, saying maybe there were people who reported ICANS but didn't use the term ICANS. And we really didn't see much of a difference between the 2 arms there, reassuring us that I don't think we're missing ICANS cases. Now, this is a trial population. I'm not saying that the real-world population per se is going to have these exact numbers, but it does seem that we're not missing cases. And this is a very reassuring toxicity profile.

In all, we have unprecedented improvement in median OS, unprecedented improvement in median PFS, along with what looks like a substantial percentage of patients who are getting durable ongoing disease control, all with what is truly a manageable toxicity profile.

And this sets DeLLphi-305 as the new standard of care with maintenance tarlatamab plus durvalumab after induction therapy for extensive-stage small cell lung cancer.

Source

Sands J, Yoshida T, Ahn MJ, et al. Tarlatamab plus durvalumab (durva) vs durva as 1L maintenance (1LM) therapy following durva, platinum, and etoposide (1L durva + EP) in extensive-stage small cell lung cancer (ES-SCLC): primary analysis of the phase 3 DeLLphi-305 trial. Presented at: ESMO Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA3.