Breakthroughs in ES-SCLC Immunotherapy: The DeLLphi-303 Study

Extensive-stage small cell lung cancer (ES-SCLC) is an aggressive solid tumor malignancy with high likelihood of relapse and poor prognosis despite initial high response rates to first-line platinum-based chemotherapy. In recent years, patients have been found to respond positively to the addition of immunotherapy to chemotherapy in the frontline and maintenance settings, yet overall survival remains relatively low.

In an interview with Targeted Oncology, Kelly Paulson, MD, PhD, Swedish Cancer Institute Medical Oncology, delves into findings from the maintenance portion of the phase 1b DeLLphi-303 study (NCT06211036) evaluating the combination of tarlatamab (Imdelltra) with checkpoint inhibitors in patients with SCLC, its clinical implications, and next steps for continued research and development.^1–3

Targeted Oncology: What are some of the unmet needs in this patient population that prompted this line of research, and how does it build on the previous research that we've seen with tarlatamab?

Kelly Paulson, MD, PhD: ES-SCLC is, of course, a very aggressive form of lung cancer that affects about 35,000 Americans each. Most SCLC presents in the metastatic setting or extensive stage, and outcomes for ES-SCLC have historically been really poor.

About 5 years ago, we had the addition of anti–PD-L1 drugs to chemotherapy in the frontline and maintenance settings, and we were glad to see that patients were, on average, doing a little bit better by adding immunotherapy to chemotherapy. But still, on average, median overall survival [OS] from the start of maintenance has ranged in the US from 10 to 13 months, depending on the study, with adding PD-L1 to chemotherapy. So, there's a huge unmet need for patients.

Functionally, when I see a patient that has [ES-SCLC], a lot of times after they get done with their initial chemotherapy and they're on their maintenance immunotherapy, I have to tell the patient: For most patients, this is the eye of the hurricane. We don't know when the storm’s coming back, but it's most likely coming back, and, I'm sorry that time is likely to be shorter than we would like it to [be]. The PD-L1 drugs—they work to take the safety off. They work on that immune checkpoint. And there's been a lot of interest in SCLC how [we can] pull the trigger. We know that the immune system can sometimes be effective at eradicating SCLC. So, what happens if we work on this trigger switch?

Last year, we had the FDA approval of tarlatamab, which is a bispecific T-cell engager. One end of it sticks to the surface of the tumor cell, and the other end of it sticks to the T cell on the CD3 and activates that T cell. With tarlatamab, we saw responses in the advanced refractory setting that were much better than anything that we had seen before.

Recently, in June of this year, we saw a randomized controlled trial in the second-line setting, showing that [with] tarlatamab, randomized against chemotherapy, patients did better. But still, many of the patients we know with SCLC never make it to [the] second line, with chemotherapy or now immunotherapy. And, more importantly, we thought that it made a lot of sense biologically to deliver these therapies that might synergize together with tarlatamab, pulling the trigger on the immune response and then the anti–PD-L1 agent blocking. We also felt like it made sense to do that in the maintenance setting when the patient is well,they're in a good shape to withstand a bispecific antibody, and they might be at a spot where their disease burden is lower, so potentially less cytokine release syndrome [CRS]or other [adverse] effects from the bispecific antibody.

Could you discuss this study’s design and methodology?

In the DeLLphi-303 study, it was an open label phase 1b study. There were multiple arms, and I'm talking about the maintenance arms of the study. In the study, patients received either atezolizumab [Tecentriq] or durvalumab [Imfinzi] as their anti–PD-L1 [agent] along with the tarlatamab. Patients [had an] ECOG performance status of 0 or 1 at the time of study entry at the start of maintenance. Patients received 4 to 6 cycles of chemotherapy, along with, if it was available, a checkpoint inhibitor as part of their induction therapy as part of what would be [the] standard of care in the US.

Importantly, the study enrollment criteria were pretty broad. So, if patients didn't have access to a checkpoint inhibitor for whatever reason...those patients were still allowed to come on study. I think that that's really important. This was a real-world group of patients [with SCLC] that made it onto this trial, including ones [whom] did not have to consent the day they were diagnosed. They could have been diagnosed anywhere, gotten their initial therapy, and as long as they made it to the center and looked good at the time of maintenance, that's when we looked at them for enrollment.

At the time that patients enrolled, they were put onto a specific arm based on slot availability. They could have switched PD-L1 [inhibitors] depending on what arm was open and what were available, but there was not a planned PD-L1 switch as part of the study.

[For] our primary end points, we're looking at safety. [For] our secondary end points, we're looking at our response and survival endpoints.

Could you discuss the findings of safety or response?

I think it is important to talk about safety, because when we're talking about giving treatments to patients [with SCLC]. It’s an overall sick group of patients, so we want to make sure that what we're doing is safe.

We were very pleasantly surprised by the good safety outcomes. We saw a lot less CRS than had been seen in some of the other studies. In terms of significant CRS, grade 3 or higher CRS was really rare. Most of the CRS that we saw was grade 1, and it was all pretty early in treatment days. If we saw it later, it was often in the setting of a gap and a rechallenge.

We think that part of the reason that the CRS was lowered may have been that we were treating patients when they had a lower burden of disease. In analogy to liquid tumors like lymphomas, where the bispecifics have been around a little bit longer, they've also seen that higher burden of disease tends to correlate with more CRS. So, we did not see increased CRS; if anything, we saw better CRS than had been seen [in] prior reports.

We also saw a very low rate of immune-related adverse events [IRAEs] to the atezolizumab or durvalumab. That may also have been related to timing on the study, because patients could not have had an IRAE in their first induction treatment. But we know from the treatment of these patients that, out in the real world, people develop IRAEs at any time, all the time. So, we observed a very low IRAE rate in this study. It was less than 5%.

[However, we just don't know a lot mechanistically, at this point, about why that low IRAE rate was observed.

Of course, co-investigators worldwide and I, are so excited about the survival outcomes on this study. The median OS from the start of maintenance was 25.3 months. [It] compares very favorably to other published data in this space, and many of those patients [had] ongoing responses.

Importantly, the OS was substantially longer than the progression-free survival, and that's because 29 patients received treatment beyond progression. They might have had an isolated lesion that was effectively approached in a multidisciplinary format, typically with radiation, and then been able to continue on their immunotherapy and be able to derive a durable benefit. So, we did see that a lot of patients were able to continue treatment beyond progression and derive ongoing benefit from that.

That's something that I think can be an immediate take home to how we look at tarlatamab overall right now—even if we're giving it in the second-line or greater setting, if you've got a single area of progression, we have data now from these studies showing that if you spot-weld something with, whether stereotactic radiosurgery or radiation and keep pushing on, you're going to be able to continue to get benefit from that drug in many cases.

What were the important implications or take-home messages from this research?

I think that there are 3 important take-homes from this.

The first is that we know tarlatamab and checkpoint inhibition [are] safe in combination. I think that this is important for the way that we think about approaching immunotherapy. We know from other diseases that dual immunotherapy is better than single immunotherapy, and so I was excited to see that this combination was safe and well tolerated.

A second thing we learned from this study is that we saw unprecedented survival from the start of maintenance by doing combined immunotherapy early and doing it in maintenance. We're very excited. There's a phase 3 study that is close on the heels, DeLLphi-305 [NCT06211036], to find the long-term survival in the randomized controlled setting, although there's going to be a lot of real-world crossover now that tarlatamab is widely available. But we saw that giving the immune therapy upfront was leading to wonderful outcomes that were dramatically better than what had been observed before in this phase 1b study of 88 patients. [It was a] substantial group of patients.

The third thing is that we saw this ongoing benefit from treatment beyond progression with tarlatamab—29 of 88 were able to get treatment beyond progression. We see from the spider plots that a lot of patients continue to have ongoing benefit beyond that treatment, beyond progression. I think that's something that we need to take back to our clinics right now, because historically, the second you saw a treatment failing a patient with small cell, you immediately jumped to that next treatment. That’s not the case with tarlatamab. It's really paradigm-shifting in the way that we approach this. We know from this study that we need to be thinking about our immune therapies differently than we thought about chemotherapies.

What questions do you still have unanswered from this research?

There are a few things. The first is, we love randomized controlled trials in oncology, so we're all very excited to see the results of DeLLphi-305.

[Another question is that] we were able to give the tarlatamab starting with maintenance. Do things go well if you give it even earlier? We look forward to seeing the induction arms of DeLLphi-303 presented upcoming, about starting the tarlatamab with the second cycle of chemo and immunotherapy.

The third piece is, should we be giving combination immunotherapy in the relapsed/refractory setting? Right now, our FDA approval is for tarlatamab monotherapy, but we know we can give these things safely together in the maintenance setting. So, should we be looking at combined immunotherapy?

REFERENCES:

1. Paulson KG, Lau SCM, Ahn MJ, et al. Safety and activity of tarlatamab in combination with a PD-L1 inhibitor as first-line maintenance therapy after chemo-immunotherapy in patients with extensive-stage small-cell lung cancer (DeLLphi-303): a multicentre, non-randomised, phase 1b study. Lancet Oncol. Published online September 1, 2025. doi:10.1016/s1470-2045(25)00480-2

2. Tarlatamab with Anti-PD-L1 as First-Line Maintenance After Chemo-Immunotherapy for ES-SCLC Demonstrates Acceptable Safety Profile and Unprecedented Overall Survival. News release. IASLC. Published September 8, 2025. Accessed September 19, 2025. https://tinyurl.com/yc2b2c7m

‌3. Amgen Presents New Data for First-in-Class IMDELLTRA™ (tarlatamab-dlle) in Small Cell Lung Cancer at WCLC 2024. News release. Amgen. Published September 9, 2025. Accessed September 19, 2025. https://tinyurl.com/bp4rmd8k