Addressing the Data Gap With Tarlatamab in Brain Metastatic SCLC

At The 2026 Society of NeuroOncology (SNO) ASCO CNS Metastases Conference in Boston, MA, Laura Alder, MD, discussed a retrospective analysis she presented evaluating tarlatamab (Imdelltra) in patients with small cell lung cancer (SCLC) and brain metastases.¹ More specifically, this population was largely excluded from the phase 3 DeLLphi-304 trial (NCT05740566)that supported the drug’s approval. She detailed the clinical uncertainty that exclusion created, the 2 objectives that shaped her study, the reasoning behind sequencing systemic therapy and local radiation, and how tarlatamab’s intracranial activity compares with existing chemotherapy and radiation options.

Alder also addressed safety findings related to immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS), the practical steps her team takes to monitor and educate patients and community providers, and where she sees the biggest open questions for future prospective trials and the broader CNS metastases field.

Laura Alder, MD, is an assistant professor of medicine at Duke University School of Medicine, where her research and clinical practice focus on thoracic oncology, including SCLC and its management in the central nervous system (CNS).

CancerNetwork: DeLLphi-304 excluded patients with brain metastases, which is a problem with CNS metastases across the board. What clinical uncertainty did that create for patients who received tarlatamab for SCLC?

Alder: In SCLC, up to 80% of patients will develop brain metastases during their course of disease, and we need to know how well these new novel drugs work in the CNS. It became something we see in clinic every day, and it became a big question that we wanted more answers to.

What we can do is look at the data, and [the developers] did include treated or asymptomatic brain metastases, [which was allowed] a bit later in the trial; these numbers are very small, and the vast majority were already treated with radiation. But from other drugs, in general, if something works well in the body, it usually tends to work well in the brain too. Because we’re rather limited with how many options we have for SCLC, we always want to make sure we’re giving them the best treatment. Then the question that arises is the sequencing of systemic therapy and local treatment, preferably always stereotactic radiosurgery, and then taking into account the size of the brain lesions, the location, any symptoms, and trying to do our best to meet each patient individually when we’re making such treatment decisions. Of course, having more data always helps with that.

What was the rationale for this analysis?

Three things, really. Three objectives. One, we wanted to see how well tarlatamab worked in active, untreated—no history of radiation—brain metastases that were actively progressing because we thought that was really important. Secondly, we wanted to know the safety of receiving radiation while on tarlatamab because we know there’s a risk of ICANS, which is a type of neurotoxicity, and there really hasn’t been any reported data, again, excluded in the trials, of active radiation while receiving tarlatamab for progressing brain metastases. Similar to that, we wanted to see: what if someone progressed only in the brain, isolated CNS progression, and everything was stable in the body? What was the benefit of continuing tarlatamab after local therapy like SRS [stereotactic radiosurgery]? What was the degree of benefit that the patients received? So those are the 3 aims we sought to answer with this study.

What was your primary takeaway?

[There are] a couple. One, tarlatamab does seem to have intracranial efficacy, happily so. Then 2, these numbers are small, and we need a prospective validation, but it seems very promising to continue tarlatamab with isolated CNS progression after local therapy, again preferably SRS and not whole brain [radiation] because those patients derive multiple months of additional benefit from continuing that tarlatamab.

You found a 37% intracranial ORR, with 3 CRs, which is a good signal. How does that compare with what you would expect from CNS-directed radiation or chemotherapy in that setting?

We know a lot of our chemotherapy drugs for [SCLC] don’t tend to work too well. We know carboplatin and etoposide work well in the front-line setting. We can see nice shrinkage and responses. Of course, [SCLC] is notorious for coming back aggressively, and we know a retrial of that same chemotherapy doesn’t give the same benefits when you use it again. Likewise, lurbinectedin doesn’t have great CNS penetrance or efficacy. Similarly, with topotecan and irinotecan, these can be harsh drugs [without] great CNS efficacy. Now that tarlatamab is standard of care for second line, it’s great to have that and then use local therapies, which also have their own toxicities. Whole brain radiation can have a strong detriment to neurocognitive behaviors and health and patient quality of life.

SRS is a great tool, but again, it’s knowing when to use it and when we need it because we always want to have options in our back pocket. Unfortunately, with [SCLC], we tend to see multiple recurrences in the brain too, which can be challenging, because you can only radiate so much. As much as possible, we’re always trying to do our best to optimally sequence and provide patients the longest term of benefit while also focusing on quality of life at every step.

ICANS was higher when CNS radiation was given within 14 days before starting tarlatamab: 47% vs 23%. Why was this, and what’s the practical takeaway for sequencing?

It’s important to remember that these are small numbers, so some of these effects can be taken with a grain of salt; these are descriptive rather than statistically meaningful, and this really deserves prospective validation. But…those patients who were getting radiation before starting tarlatamab had a higher burden of disease. It was more urgent for them to get radiation, and so we know that the risk of any inflammatory response, CRS and ICANS, is more prominent in the first couple of doses, day 1 and day 8. When all of these things come together, the higher burden of brain metastases, the inflammation from the radiation, and cycle 1, day 1 and cycle 1, day 8 of tarlatamab, I think that created the higher rate of some of these toxicities that we were seeing.

CRS occurred in a little over half of patients. For a community oncologist who has more limited resources than someone at an academic institution, what’s important to know about monitoring patients with known brain metastases who are going to be receiving tarlatamab?

A few things. Making sure that we’re having detailed conversations with a patient and a patient’s caregiver and supportive system, so they understand these risks and what to look out for. Tarlatamab is one of those medications where having a supportive care system and a caregiver is essential. Then the other thing is good education. At Duke, we give wallet cards, so the patient always has that with them. If they do go to the [emergency department], the local providers can know, “Hey, what drug are they on, what are we looking for, what’s the treatment.” Sometimes we send them home with dexamethasone, like a “pill-in-the-pocket”. If they start having any of these symptoms, they can take the steroid—the dexamethasone—on the way to the hospital.

Then, education for our community providers, and education for the patients and their families, is key. The more that we’re learning about tarlatamab, the more we’re beginning to risk-stratify these patients a bit. That could help us decide who needs to be inpatient vs who could be outpatient with close monitoring, and how we can best support the patient with where they are and what resources they have.

Where does this data present questions that a prospective trial needs to answer going forward?

One of the things I’m really interested in seeing in a prospective trial is the whole treatment beyond progression. With tarlatamab, we know that the patterns of progression with any cancer, SCLC included, can vary, so we like to get every drop of benefit we can out of the treatment. Having a prospective trial that’s randomized and looks at that degree of benefit, and some of the unique translational biomarkers from getting samples along the way, so we can better advise patients. Now is a time where we can do radiation and continue, or maybe it’s better to switch to a new therapy, and learning more about that degree of benefit in a prospective manner that helps reduce that selection bias and has a larger overall number to support, would be great. Additionally, we would learn more about the safety, about the safety of the timing of radiation, and what that looks like depending on disease burden, et cetera.

More broadly in the CNS metastases field, are there any specific trials you’re keeping your eye on or anticipating soon?

There’s a lot with tarlatamab. There are a few trials looking at tarlatamab in the first-line setting as maintenance: the phase 1/2 DeLLpji-303 trial [NCT05361395] was very promising, so a lot of us are really looking out to the readout of that phase 3 [DeLLphi-305 trial (NCT06211036)]. We know that the attrition for SCLC is high, moving from line to line of treatment, so the idea of bringing our best drugs up front, hopefully making sure that everyone has access to these, is exciting. Likewise, there’s a lot of really interesting ADCs directed at DLL3, CEACAM5, B7-H3, et cetera. They’re looking promising in the refractory/relapsed setting. There are some studies looking at some of these in the front-line setting too. There are lots of interesting combinations, and I’m looking forward to seeing how they will play out, and what’s the best sequencing, as well as combination strategies to make sure that we can optimize our patients’ outcomes.

References

Alder L, Hess DL, Green AL, et al. Intracranial efficacy and treatment beyond CNS progression with tarlatamab in small cell lung cancer: a multi-institutional real-world analysis. Presented at the 2026 SNO ASCO CNS Metastases Conference; August 13-15, 2026; Boston, MA.