Exploring T-Cell Engager Use in Chemotherapy-Resistant ES-SCLC

According to Bingnan Zhang, MD, MBA, before the approval of tarlatamab-dlle(Imdelltra), a bispecific T-cell engager, in patients with extensive-stage small cell lung cancer (ES-SCLC) who experienced disease progression on or after platinum-based chemotherapy in May 2024, the standard-of-care for second-line therapy and beyond included cytotoxic agents. Since then, ongoing research has been focused on developing additional bispecific T-cell engagers, antibody drug conjugates (ADCs), and tarlatamab-based regimens to better optimize outcomes for this patient population.

Zhang, an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the treatment landscape for this key patient population, and specifically those who are harboring untreated brain metastases, in light of the May 2024 approval. First, she outlined standard treatment options for the second-line treatment of these patients, highlighting an absence of options beyond cytotoxic agents with immunotherapy maintenance, mainly topotecan or lurbinectedin (Zepzelca), with atezolizumab (Tecentriq) or durvalumab (Imfinzi) as maintenance.

However, the approval or tarlatamab provided a new option with enhanced efficacy outcomes, including tumor shrinking in patients with intracranial metastases identified in the phase 1 DeLLphi-300 trial (NCT05361395) and verified in subsequent studies such as the phase 3 DeLLphi-304 trial (NCT05740566),as well as prolonged progression-free survival (PFS) and overall survival (PFS), vs cytotoxic agents in patients with ES-SCLC.^2,3 Although certain toxicities have emerged with tarlatamab, mainly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), many such instances are lower grade and easily managed.

Furthermore, Zhang discussed next steps for research, highlighting proposed strategies for mitigating toxicities and bolstering efficacy outcomes with tarlatamab, as well as emphasizing a need for biomarker research among developing therapies being evaluated for this patient population. Finally, she expressed that tarlatamab, as well as newer agents in clinical trial contexts, are available for patients undergoing treatment for relapsed ES-SCLC.

CancerNetwork: What have standard treatment options looked like for patients with ES-SCLC harboring brain metastases, and what are some strengths and limitations associated with these strategies?

Zhang: About 70% [of patients with lung cancer] are diagnosed with extensive-stage or with metastatic disease. [The standard of care] is a chemoimmunotherapy combination in the first-line treatment followed by immunotherapy maintenance. That is our PD-L1 inhibitors, atezolizumab or durvalumab.

If the patient’s disease progresses after this initial treatment, then the previous standard-of-care has been different types of chemotherapy medications. Topotecan has been the only chemotherapy approved for many years, and in more recent years, lurbinectedin has also been used in these settings. Tarlatamab, which is a DLL3/CD3 T-cell engager, has recently demonstrated superior efficacy and overall survival data in [patients with] relapsed ES-SCLC. Now it is becoming more standard to use tarlatamab in the relapsed second line [setting] and beyond.

What does the recent approval of tarlatamab mean for patients with ES-SCLC and, more specifically, for those with untreated brain metastases?

SCLC treatment has been limited… to chemoimmunotherapy and a few different options for chemotherapy after relapse. Tarlatamab is a brand-new mechanism of drug. It is a bispecific T-cell engager. It is the second approved bispecific [T-cell] engager in solid tumors. It is an innovative type of treatment, and it has shown superior PFS and OS in patients with relapsed ES-SCLC. They are becoming used [more frequently].

The initial adoption is a bit challenging because of the unique [adverse] effects associated with these drugs, with the bispecifics, including cytokine release syndrome and neurotoxicity. That required the first 2 doses to be administered mostly in-house, [in the] health care inpatient setting, because that requires 20- to 24-hour monitoring, post-dosing. However, because of the superior efficacy, and I will mention the intracranial efficacy as well, because it was initially noticed in the phase 1 [DeLLphi-300 trial] when patients who had treated brain metastases, had ongoing shrinkage after being on tarlatamab, and later trials included a small set of patients with untreated brain metastases and had shown benefit.

If you look at the phase 3 DeLLphi-304 data when they included a small subset of patients with untreated brain metastases, their HR is lower, suggesting [great activity] in this population. We also have observed real-world patient data, when we started tarlatamab in patients with numerous untreated brain metastases who would otherwise require whole brain radiation to experience a rapid initial response, and those patients will have symptom improvement as well.

Thankfully, we can delay the brain radiation because the whole brain radiation has its own set of toxicities and long-term sequelae with cognitive decline. For many of those patients, we can safely defer radiation, but it is always a multi-disciplinary discussion with our radiation oncologists as well to best sequence the medication and the timing of radiation.

Regarding safety data, are there any toxicities that clinicians should be aware of, and then what are some of the best practices for managing and or mitigating them?

The unique toxicities associated with the T-cell effector cell therapy, such as CAR T or bispecifics, are CRS and neurotoxicity, which is thought to be from inflammation in the brain.For providers who are used to treating lymphoma, leukemia, or myeloma, where many of the CAR Ts and bispecifics are approved, these may not be new to them. For the thoracic medical oncology or solid oncology world, this is a new toxicity that providers and health care teams are becoming more familiar with.

In general, from the clinical trials, the CRS [and] ICANS grades [are] low. [They are] grade 1 or 2. They tend to be more common in the first 2 doses. That is why the label also recommends having more intense monitoring for 20 to 24 hours after the first 2 doses. The ICANS medium onset is 30 days, so it is around the time of cycle 2, day 1. The symptoms can be a bit more varied, but in terms of the grading and management of these toxicities, there are established guidelines.

The [International Society for Stem Cell Research (ISSCR)] has the [American Society for Transplantation and Cellular Therapy (ASTCT)] guidelines, and MD Anderson has also put out the [IEC Therapy Toxicity Assessment and Management (CARTOX)] guidelines based on the CAR T and bispecifics data from the hematologic malignancies.^4,5 The current management guidelines are modeled after these guidelines, but as we become more familiar with using these agents in patients [with] lung cancer, we will probably come up with more refined management guidelines for patients with solid tumors and with lung cancer.

What are the next steps for researching tarlatamab, or improving outcomes among this patient population?

There is a lot of research ongoing, even for tarlatamab. Ongoing clinical trials are testing different formulations of tarlatamab. The subcutaneous formulation may have lower toxicity, for CRS and ICANS, and that is an active clinical trial. Also, exploring different dosing schedules; right now, it is every 2 weeks. Also, potentially moving it to an outpatient regimen, so optimizing the tarlatamab medication itself.

In terms of improving patient outcomes and for better efficacy long-term, we need biomarker research to figure out which patients are more likely to derive benefit and response––to have a durable response to tarlatamab––because DLL3 as a target is widely present in patients [with SCLC]; about 80%. The response rate to tarlatamab is around 40%. There is a subset of patients who can derive long-term benefit, but there is also a substantial percentage who may not respond at all or have a short-term response.

One aspect is to figure out how to better select this treatment to match patients who are most likely to respond, and learning mechanisms of resistance and why patients are not responding to [tarlatamab]. We can come up with rational combination therapies, either combining different cytotoxic agents like chemotherapy or antibody drug conjugates, which are a new class of agents coming to the treatment of SCLC paradigm, or figuring out a way to make the immune system more responsive or less exhausted over the course of tarlatamab treatment. These are all active areas of translational and biomarker research.

What emerging challenges have been identified in the treatment of extensive-stage small cell lung cancer?

We have made [many] advances in the treatment of SCLC in the last few years. There are newer agent classes entering the clinical space, such as tarlatamab, which is a T cell engager. Other T cell engagers, targeting DLL3, are also in clinical trials now. The other class of medications is the ADCs. There are several different targets for developing ADCs. As we are using these novel agents, 1 unmet need is to [identify] biomarkers for treatment selection in patients, because a lot of them are overlapping in terms of targets, or in the ADC world, overlapping in terms of the payload.

Another aspect is provider and health care member education in terms of recognizing and learning about these new agents and [their] unique toxicities. Using tarlatamab as an example, CRS and ICANS and even some of the less severe toxicities were a big quality of life issue for patients––taste changes and dysgeusia, and [similar] symptoms. We are also, as a field, learning how to better manage and support our patients through the treatment.

The ADCs also have their unique toxicities to traditional chemotherapy, such as pneumonitis, and some ADCs have ocular toxicities. Again, learning more about both the scientific and translational biomarker aspects of these drugs, as well as clinically practical management of these new agents, and education is needed. Overall, these will help us figure out better treatment sequencing or combinations that will, over time, improve patient outcomes in the long run.

What do you hope others take away from this conversation?

As we discussed, mostly focusing on relapsed, [patients with ES-SCLC], I hope, as a community, we recognize that there are more treatment options available now for patients, including the bispecific T-cell engager tarlatamab [which] is already approved and established as a new standard of care for patients who have progressed after chemotherapy, and also has significant activity intracranially. There are also [many] active clinical trials and newer agents available in clinical trial contexts for our patients. [What is] urgently needed as a field is to study predictive biomarkers for treatment response and durability, both exploring the target and immune aspects [of ES-SCLC].

References

1. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. News release. FDA. May 16, 2024. Accessed September 23, 2025. https://tinyurl.com/48k34rw5
2. Paz-Ares L, Champiat S, Lai WV, et al. Tarlatamab, a first-in-class DLL3-targeted bispecific T-cell engager, in recurrent small-cell lung cancer: an open-label, phase I study. J Clin Oncol. 2023;41(16):2893-2903. doi:10.1200/JCO.22.02823
3. Mountzios G, Sun L, Cho BC, et al. Tarlatamab in small-cell lung cancer after platinum-based chemotherapy. N Engl J Med. 2025;393(4):349-361. doi:10.1056/NEJMoa2502099
4. International Society for Stem Cell Research. Guidelines for Stem Cell Research and Clinical Translation, August 2025 update version 1.2. Accessed September 23, 2025. https://tinyurl.com/3v6n4fpe
5. MD Anderson Cancer Center. IEC Therapy Toxicity Assessment and Management (also known as CARTOX) – Adult. Revised December 13, 2023. Accessed September 23, 2025. https://tinyurl.com/kbchy2vt