Solange Peters, MD, PhD, discusses findings for obrixtamig plus atezolizumab/chemotherapy in first-line extensive-stage small cell lung cancer.

Dr Peters on Obrixtamig Plus Atezolizumab/Chemo in First-Line ES-SCLC

Higher doses [of obrixtamig] were [evaluated later in the study], so we need to wait to see [how] these patients [do] over time [in terms of] toxicity. However, if this continues to be feasible and safe, the main question is, is it better to give this T-cell engager immediately [at] cycle 1, day 1? Or should we wait for maintenance or wait for the second line?

Solange Peters, MD, PhD, chair of the Medical Oncology Department at Lausanne University Hospital in Switzerland, discussed findings from the phase 1 DAREON-8 trial (NCT06077500), which evaluated obrixtamig (BI 764532) in combination with carboplatin, etoposide, and atezolizumab (Tecentriq) as first-line treatment for patients with extensive-stage small cell lung cancer (ES-SCLC).

, investigators presented results from the dose-escalation portion of the study, which assessed dose-limiting toxicities, the maximum tolerated dose (MTD), and overall tolerability of the regimen.

Efficacy findings demonstrated that evaluable patients treated in the first-line setting (n = 28) achieved a confirmed overall response rate (ORR) of 68% (95% CI, 49%-82%) and a confirmed disease control rate of 89% (95% CI, 73%-96%). Best overall responses comprised complete response (4%), partial response (64%), stable disease (21%), progressive disease (4%), and not evaluable/missing (7%).

The median duration of response was 7.3 months (95% CI, 4.4-not calculable). Additionally, the median progression-free survival (PFS) was not reached, and patients experienced 3-, 6-, and 9-month PFS rates of 96% (95% CI, 89%-100%), 73% (95% CI, 55%-92%), and 52% (95% CI, 27%-77%), respectively.

According to Peters, the combination demonstrated a manageable safety profile with no unexpected toxicities, and the MTD was not reached. Obrixtamig-related adverse effects (AEs) of any grade occurred in 96% of patients, including 39% who had grade 3 or higher AEs related to the agent. The most common AEs related to obrixtamig in at least 25% of patients included cytokine release syndrome (any-grade, 50%; grade ≥3, 0%), dysgeusia (39%; 0%), decreased appetite (32%; 0%), neutropenia (29%; 21%), pyrexia (29%; 0%), anemia (25%; 0%), and fatigue (25%; 4%). No instances of grade 3 or higher immune effector cell–associated neurotoxicity syndrome (ICANS) were reported; grade 1 and grade 2 ICANS were reported in 1 patient each (4%).

In terms of the overall safety profile of the combination, the most common grade 3 or higher treatment-emergent AEs (TEAEs) were cytopenias and were related to chemotherapy. Grade 3 or higher TEAEs occurred in 79% of patients, including 75% who had grade 3 or higher TEAEs related to chemotherapy. The most common grade 3 or higher TEAEs included neutropenia (all instances, 54%; related to chemotherapy, 54%), anemia (18%; 18%), decreased neutrophil count (14%; 14%), asthenia (11%; 4%), and thrombocytopenia (7%; 7%).

Peters explained that future analyses will help determine the optimal timing of obrixtamig administration—whether it should be given at cycle 1, day 1 alongside chemotherapy and immunotherapy, or whether it should be held for maintenance or as a second-line treatment. These forthcoming data will guide the design of subsequent phase 3 randomized trials.

Peters S, Dziadziuszko R, Kalinka E. DAREON-8: A phase I trial of first-line obrixtamig plus chemotherapy and atezolizumab in extensive-stage small cell lung carcinoma (ES-SCLC). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 2759MO.

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Dr Halmos on Differentiating Neuroendocrine Tumors From Neuroendocrine Carcinomas

“Patients with NECs are at the very aggressive end of the differentiation spectrum. Recognizing these and hopefully now building on new treatment options for these patients will be very important.”

Balazs Halmos, MD, associate director of clinical science at Montefiore Einstein Cancer Center; director of the Multidisciplinary Thoracic Oncology Program and director of the Section of Thoracic Medical Oncology for Montefiore Health Systems; as well as a professor in the Department of Oncology (Medical Oncology) and the Department of Medicine (Oncology & Hematology) and director of Clinical Cancer Genetics at the Albert Einstein College of Medicine, discussed the importance of differentiating between neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs).

The distinction between NETs and NECs is clinically significant, Halmos began. Well-differentiated NETs, such as typical lung carcinoids or low-grade gastrointestinal NETs, are characteristically indolent and often follow a slow clinical course, he said. Importantly, the therapeutic paradigm for these tumors is expanding, he noted.

In contrast, NECs represent the high-grade, poorly differentiated end of the neuroendocrine neoplasm spectrum, according to Halmos. These malignancies, which include entities like small cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma, are defined histopathologically by features including poor cellular differentiation, elevated mitotic indices, and high Ki-67 proliferation levels, he explained. Although relatively uncommon, these tumors are encountered periodically in clinical practice, he stated.

Current therapeutic strategies for patients with NECs often parallel those used for SCLC, including categorization by limited vs extensive stage and the use of platinum-based chemotherapy and immune checkpoint inhibitors for patients with metastatic disease, he reported. However, clinical outcomes remain poor, and treatment options are limited, he emphasized.

Accurate recognition of NECs is essential for appropriate clinical decision-making, Halmos highlighted. Furthermore, there is a critical need to develop and refine therapeutic approaches specifically targeting this aggressive subset of neuroendocrine neoplasms to improve prognosis and expand clinical options, he concluded.

Balazs Halmos, MD, discusses the differences in presentation and available treatments between neuroendocrine tumors and neuroendocrine carcinomas.

After demonstrating response rates well above those of chemotherapy and a manageable safety profile in patients with extrapulmonary neuroendocrine carcinoma (epNEC) in a phase 1 study (NCT04429087), obrixtamig (BI 764532) is being further evaluated in the phase 2 DAREON-5 trial (NCT05882058) and could soon offer a much-needed effective treatment option for these patients, according to Balazs Halmos, MD.

, updated data from the phase 1 trial showed that patients who received the DLL3-targeted bispecific T-cell engager (BiTE; n = 60) achieved a confirmed overall response rate (ORR) of 22% (95% CI, 13%-34%) and a disease control rate (DCR) of 47% (95% CI, 35%-59%). Notably, those with DLL3-high disease (n = 30) achieved a confirmed ORR of 40% (95% CI, 25%-58%) and a DCR of 67% (95% CI, 49%-81%).

“[Data from] this phase 1 study identified activity, identified the biomarker enriching for that activity, and showed a reasonable tolerance of this drug,” Halmos, said in an interview with 

Halmos is the associate director of clinical science and a professor in the Departments of Oncology and Medicine at Montefiore Einstein Comprehensive Cancer Center in the Bronx, New York. In the interview, he discussed targeting DLL3 in patients with epNEC, prior data with obrixtamig, and the design of DAREON-5.

: Why is it important to differentiate neuroendocrine tumors from neuroendocrine carcinomas?

: This distinction is critical as neuroendocrine tumors [such as] lung carcinoid [tumors], low-grade gastrointestinal [tumors], or neuroendocrine neoplasms, tend to be indolent, and we have an expanding range of new treatments that we can offer to such patients. Patients with neuroendocrine carcinomas are at the aggressive end of the differentiation spectrum. Pathologically, these are cases similar to small cell lung cancer [SCLC] or large cell neuroendocrine carcinoma with very poor differentiation, a high mitotic rate, and a high percentage of Ki67-positive cells.

[Neuroendocrine carcinomas] are not a common entity, [and] treatment is poorly defined. We tend to follow treatment patterns similar to SCLC, [including] chemotherapy and immunotherapy for patients with metastatic disease. But there are poor outcomes and a limited number of choices. Recognizing this and building upon new treatment options for these patients is important.

What evidence supports DLL3 as an actionable target in epNEC?

DLL3 is frequently expressed in [patients with] SCLC and neuroendocrine carcinoma in general. This protein is intricately involved in modulating Notch signaling, and this is key for the development of neuroendocrine differentiation and the behavior of small cell type carcinomas. The frequency of expression is as high as 95% in [patients with] SCLC. As a result, many trials are not necessarily looking at expression specifically, as almost all patients will have it. The expression is more variable but still commonly high in [patients with] neuroendocrine carcinoma, [ranging from approximately] 70% to 90% depending on what subsite you’re talking about. The expression is much lower for neuroendocrine tumors [as these are] more well differentiated tumor types.

What is the mechanism of action of obrixtamig?

[Obrixtamig] is a normalized IgG-like CD3/DLL3 BiTE. It binds to DLL3-positive cancer cells and cytotoxic T cells with its two arms, thereby creating what we call the cytolytic synapse. The cytolytic synapse can then lead to tumor killing but also to adverse effects [AEs] similar to CAR T-cell [agents], including cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS].

What prior research set the stage for DAREON-5?

A decade of fantastic research from many groups and excellent sponsors [has led to this moment where we] understand small cell neuroendocrine carcinoma and DLL3 biology. There was also prior work on different ways to target DLL3, ultimately yielding a number of exciting biomolecules. Some of these have been more developed and one of them is available for the treatment of patients with SCLC.

Identifying that the same molecules can have treatment relevance for patients with epNEC [was also important]. Prior clinical data with obrixtamig in this rare subset of patients have shown activity and reasonable tolerance, setting the stage for focused studies exploring this agent [in patients with] epNEC.

What was your interpretation of the data from the phase 1 trial of obrixtamig and how do they support DAREON-5?

This study was a hidden gem at ASCO and was a nice presentation on the dose-finding [portion of the] study with obrixtamig. Looking at the activity of obrixtamig, the ORR was 22%, which is somewhat on the modest side. But when the investigators looked at patients with DLL3-high vs -low expression, defined at least 50% of the cells positive for DLL3 by immunohistochemistry vs less than 50%, [respectively], the ORR [in the DLL3-high group] was 40% and the median duration of response [DOR] was 7.9 months [95% CI, 6.2-not estimable (NE)]. This compared favorably with the DLL3-low cohort [n = 30], which had an ORR of 3% [95% CI, 1%-17%] and a median DOR of 2.8 months [95% CI, NE-NE].

Are there any safety concerns with obrixtamig?

This class of agents, including CAR T cells and BiTEs, have similar AE profiles. They yield a high frequency of CRS and neurological events such as ICANS. These tend to [occur] mostly in the first couple of weeks of treatment. Fortunately, in this trial, it did seem that although the frequency of any-grade CRS was high at 65%, very few of these were high-grade events that called for interventions. The same goes for ICANS, which occurred in 13% of patients but was mostly grade 1 or 2.

We’ve learned as a community how to identify patients with these AEs. We have grading and treatment guidelines, as well as algorithms for the management of these AEs. At this point, I do not believe that they are of particular concern. They are expected and manageable AEs associated with these molecules. The continued development of obrixtamig seems to be reasonable and hopefully it will ultimately be used for the treatment of our patients in clinic.

What questions are DAREON-5 designed to answer?

DAREON-5 is being reshaped based on the current understanding of which patients obrixtamig could be the most effective in. In its present form, the study will be enrolling patients with DLL3-high epNEC. It is identifying a patient pool where there might be a clinical niche for a drug that’s needed and one with a higher level of activity that’s been noticed in prior trials.

The primary end point is ORR. Secondary end points include progression-free survival, overall survival, and safety.

There are a lot of questions related to AEs that we need to answer. Are inpatient management [and] monitoring critical for the first couple of doses? Can patients be managed in the outpatient setting? [In terms of] the biomarker [of DLL3], I’m certain that the study team will continue to invest [in learning more from] this high-risk cohort of patients. Can we learn even more about the right patient profiles who could benefit the most from this exciting new drug?

How do you see obrixtamig positioning itself in the treatment landscape and are there other investigational agents in development that could fill the same role?

Our hope is that we’ll have more [treatments] for our patients with epNEC who presently have limited options and poor outcomes. It will be welcome news to have a new agent with significant activity. Having seen how other DLL3-targeted agents are transforming the SCLC treatment landscape, I’m hopeful that we’ll see exciting data with obrixtamig as well. If that is the case and there’s sufficient activity for its approval, then this platform can be expanded to combination and maintenance studies to find even more of a role for patients with epNEC and maybe some other cohorts as well.

[In terms of other agents], whenever we see one successful drug, many times we see a lot of other successful drugs follow in its footsteps. There are a wide range of DLL3-targeted drugs, not just BiTEs but antibody-drug conjugates and other molecules in development. The next couple of years will be exciting to understand how this biology and this class of agents will shape the treatment landscape in oncology.

What is important to know to not miss the window for enrollment for DAREON-5?

Patients [will need] to be identified correctly and new grading classification systems are important to be aware of. We need to recognize that despite [this being] a rare disease, there are efforts ongoing to make a difference, such as DAREON-5. I presume it will be available at a [small] number of sites around the US, so it might be one of those trials that patients might need to travel for. But many of these new studies have resources built in that make it feasible for a patient who is farther away from the site to still participate.

It’s also important to be aware that the trial will be selective. [Investigators] will not be enrolling every patient with SCLC or epNEC, because [the patient must have a] specific pathology. I’m sure there will be some patients who would love to qualify but who ultimately might not be able to. Hopefully in the future, the horizon will be expanding for them with other clinical trials.

Capdevila J, Gambardella V, Kuboki Y, et al. Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: results from an ongoing phase I trial. 

. 2025;43(suppl 16):3004. doi:10.1200/JCO.2025.43.16_suppl.3004

Articles

Balazs Halmos, MD, discusses the DLL3-targeted BiTE obrixtamig for the treatment of patients with extrapulmonary neuroendocrine carcinoma.

Obrixtamig Leverages DLL3 Targeting to Offer a Potential Treatment Option in Extrapulmonary Neuroendocrine Carcinoma

Dr Starr on the Rationale for Targeting DLL3 in Extrapulmonary Neuroendocrine Carcinomas

“The expression rate of DLL3 in [patients with epNECs] is up to 80%, which is quite high. We used the data that were evolving in SCLC to identify that this protein does exist and is overexpressed epNECs.”

Jason S. Starr, DO, an oncologist in the Department of Internal Medicine at Mayo Clinic, discussed the potential utility of delta-like ligand 3 (DLL3) as a treatment target in patients with extrapulmonary neuroendocrine carcinomas (epNECs).

DLL3, which is involved in a cell-to-cell signaling pathway, was first discovered in small cell lung cancer (SCLC), Starr began. SCLC is classified as a neuroendocrine carcinoma and DLL3 expression is observed on the cell surface of approximately 80% to 90% of SCLC cases, he continued. Due to the similarities between SCLC and epNECs, investigators evaluated the rate of DLL3 expression in patients with epNECs and found the rate to be approximately 80%, Starr explained.

, investigators presented data from a phase 1 trial (NCT04429087) which evaluated the novel DLL3/CD3 IgG-like T-cell engager obrixtamig (BI 764532) in patients with epNECs with high (≥ 50% of tumor cells) or low (< 50% of tumor cells) expression of DLL3. The coprimary end points were determining the maximum tolerated dose (MTD) and dose-limiting toxicities during the MTD evaluation period. Secondary end points included objective response rate (ORR) per RECIST 1.1 criteria and pharmacokinetic parameters.

The ORR in the overall population was 22% (95% CI, 13%-34%) and the disease control rate (DCR) was 47% (95% CI, 35%-59%). The ORR and DCR among patients with high DLL3 expression (n = 30) was 40% (95% CI, 25%-58%) and 67% (95% CI, 49%-81%), respectively. In patients with low DLL3 expression (n = 30), the ORR and DCR were 3% (95% CI, 1%-17%) and 27% (95% CI, 14%-44%), respectively. The median duration of response in the DLL3-high and -low groups was 7.9 months (95% CI, 6.2-not evaluable [NE]) and 2.8 months (95% CI, NE-NE), respectively.

In terms of safety, any-grade treatment-related adverse effects (TRAEs) were reported in 95% of patients in the overall population. The most common any-grade TRAEs included cytokine release syndrome (65%), pyrexia (32%), and dysgeusia (25%).

In October 2023, the FDA granted fast track designation to obrixtamig

 for the treatment of patients with extensive-stage SCLC who experienced disease progression following at least 2 prior lines of treatment including platinum-based chemotherapy, and for patients with advanced or metastatic epNECs following disease progression with at least 1 prior line of treatment including platinum-based chemotherapy. The agent is being further evaluated in patients with relapsed/refractory DLL3-high epNECs in ongoing the phase 2 DAREON-5 trial (NCT05882058).

Jason S. Starr, DO, discusses DLL3 as a treatment target in extrapulmonary neuroendocrine carcinomas.

Preliminary data for the combination of the novel DLL3/CD3 bispecific T-cell engager obrixtamig (BI 764532) and topotecan have demonstrated that this regimen could fill a treatment gap in the second-line setting and beyond for patients with relapsed/refractory advanced small cell lung cancer (SCLC), according to Martin Wermke, MD.

Findings from the phase 1b DAREON-9 trial (NCT05990738) presented during the 

 showed that evaluable patients (n = 23) experienced an unconfirmed overall response rate (ORR) of 70% (95% CI, 47%-87%) and a confirmed ORR of 69% (95% CI, 39%-91%). Best responses comprised complete response (4%), partial response (65%), stable disease (17%), and progressive disease (9%). One patient (4%) was not evaluable, and the disease control rate (DCR) was 87% (95% CI, 66%-97%).

“It's rewarding to see that we are finally making progress in the treatment of SCLC [by] not just adding more toxic therapy that offers a limited survival benefit to patients,” Wermke said. “With DLL3[-targeted] bispecific antibodies, we're seeing long-term responses…and that is something we never [previously saw] with chemotherapy.”

Regarding safety, the maximum tolerated dose of obrixtamig was not reached. Three dose-limiting toxicities (DLTs) were reported, which occurred during step-up dosing at dose level 1 (grade 3 tumor pain), step-up dosing at dose level 3 (grade 2 increased blood creatinine levels), and at the target dose for dose level 3 (grade 3 fatigue). Any-grade CRS occurred in 48% of patients, but all instances were grade 1 (44%) or grade 2 (4%). Potential neurotoxicity related to obrixtamig, including ICANS, was reported in 8% of patients, although no instances were grade 3 or higher. Treatment-related adverse effects (AEs) did not lead to the discontinuation of obrixtamig in any patients.

Furthermore, data from another phase 1 trial (NCT04429087) presented at the 2025 ASCO Annual Meeting demonstrated that obrixtamig monotherapy was safe and active in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression.

 Among all treated patients (n = 80), the ORR was 22% (95% CI, 13%-34%), and the DCR was 47% (95% CI, 35%-59%). In patients with high DLL3 expression (n = 30), the ORR and DCR were 40% (95% CI, 25%-58%) and 67% (95% CI, 49%-81%), respectively.

, Wermke expanded the rationale for investigating obrixtamig in patients with relapsed/refractory SCLC and other neuroendocrine tumors; detailed the key findings from DAREON-9; and spotlighted future directions for the investigation of this regimen.

Wermke is the leader of the Thoracic Oncology Group, professor for experimental cancer therapy, head of the Early Clinical Trial Unit and of the Trial Management at NCT Dresden in Germany.

 What was the rationale for conducting the DAREON-9 Trial?

: DAREON-9 was a phase 1b trial [designed to] test the combination of the DLL3-directed bispecific T-cell engager, [obrixtamig, in combination] with topotecan, a well-known chemotherapeutic that has been used for long time in relapsed/refractory SCLC.

[Patients with] SCLC that relapses after PD-[L]1–based chemoimmunotherapy still have a dismal prognosis. Survival times are short and response rates are low; therefore, it's urgent to find novel treatment options.

It's known that SCLC and other neuroendocrine carcinomas express DLL3, which is an atypical Notch ligand on the surface of the cells. [DLL3] is not expressed on normal, nonmalignant tissue, [making it] an ideal target for cancer immunotherapy. Obrixtamig is a novel, bispecific T-cell engager that has an immunoglobulin-like structure and binds to DLL3 on the tumor cells and CD3 on T cells, attracting the T cell to the tumor cell to elicit a potent anti-immune response.

We have tested obrixtamig in a phase 1 dose-escalation trial that has already been published, and 

we found it to be safe and efficacious in patients with relapsed/refractory SCLC and other neuroendocrine carcinomas

. Now, we wanted to see whether we could build on this by combining it with a classical chemotherapy [agent], which is topotecan.

What makes obrixtamig’s mechanism of action unique?

Bispecific antibodies that [target] CD3 and a tumor antigen usually drag T cells to the tumor cells. Typically, the CD3 binding component is structured in a way that activates the T cell. What you get is a tumor immune response that is targeted to your antigen and spares normal tissue, and that's why it's a pretty clean drug.

The good thing regarding tolerability with bispecific antibodies is that you have [some noteworthy] AEs during the first applications, such as CRS and maybe a bit of ICANS. However, that [tends to] abate after you cross the second, third, or fourth application, and then it's easy for the patient to tolerate.

What were the enrollment criteria for this study?

We enrolled patients with SCLC, provided they had received at least their first line of chemotherapy, which needed to be platinum based. Ninety-two percent of the patients also had had prior PD-[L]1 exposure. Patients were required to have an adequate performance status, good organ function, and controlled brain metastases. This was a typical phase 1 population.

This was a dose-escalation trial. We gave topotecan at the approved standard doses 5 days per week [at the start of each 21-day cycle]. Obrixtamig was added on day 1 and was given weekly thereafter. We were allowed to dose reduce topotecan after the first cycle, and we were able to skip topotecan after 2 cycles if clinically indicated. Obrixtamig was given as a step-up dose and then gradually increased to reach the target dose. We tested a total of 3 dose levels.

The safety [profile] was largely as expected. What we saw is the topotecan associated cytopenias. [We] saw a lot of neutropenia and thrombocytopenia; however, we didn't have any infectious complications or bleeding complications.

With obrixtamig, we saw [any-grade] CRS in 48% of the patients, with the majority being grade 1. No grade 3 or 4 [CRS was reported]. [The incidence of CRS] was less than we expected.

We saw hardly any neurotoxicity. There were two [AEs] that matched the wide definition of neurotoxicity [used for] the trial. For example, muscle spasms are not a classical symptom of ICANS, but [this occurred in] 2 patients [8%] at grade 1. The maximum tolerated dose has not been reached over these 3 dose levels, and we just had 3 DLTs, which occurred mainly in the ramp-up period and not at the target dose.

The combination is safe. Topotecan has a safety profile we’ve known [about for some time], and for obrixtamig, we see less toxicity compared with the agent given as monotherapy.

We observed an unconfirmed ORR of 70%. The follow-up was quite short. We only had 13 patients undergo [at least 2 post-baseline tumor assessments]; however, in these patients who had the chance to confirm their response, the response rate remained stable. The confirmed ORR was still 69%, which is pretty remarkable if you compare it with the results [of] a single-agent T-cell engager targeting DLL3, [where the] ORR is approximately 20% to 40%. The ORR with a single-agent topotecan is, unfortunately, just 10% to 15%. 

We [appear to] have something that goes beyond the effect of either component alone, at least [based on] the limited dataset we have thus far. It's certainly something we need to follow up on.

Are there any future analyses planned to further investigate the role of obrixtamig in this setting or beyond?

This is a phase 1 study in just 25 patients, and we have immature follow-up, so we need to wait for the data to mature. We will also follow up with a randomized trial to see if that [benefit with the combination] is substantiated.

We’ll get some more follow-up on the patients we already treated, get some more data on why there is some kind of synergism between these 2 drugs, then the obvious next move will be to start the phase three trial testing this in a randomized fashion.

Wermke M, Alt J, Bozorgmehr F, et al. DAREONTM-9, a phase Ib study of obrixtamig plus topotecan in patients (pts) with advanced small cell lung cancer (SCLC): Interim analysis results. 

. 2025;43(suppl 16):8094. doi:10.1200/JCO.2025.43.16_suppl.8094

Capdevila J, Gambardella V,  Kuboki Y, et al. Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: Results from an ongoing phase I trial. 

Obrixtamig combined with topotecan demonstrated favorable safety and early efficacy in relapsed/refractory SCLC.

Obrixtamig Plus Topotecan Could Address a Second-Line Need in SCLC

WERMKE

“We really have something that goes beyond the effect of either component alone, at least this is what we think from the limited data set we have thus far, but it's certainly something we need to follow up on.”

Martin Wermke, MD, group leader, Thoracic Oncology Group, professor for experimental cancer therapy, head of the Early Clinical Trial Unit and of the Trial Management National Center for Tumor Diseases Dresden (NCT/UCC) Clinical Trial Center, highlighted the clinical potential of obrixtamig, a DLL3/CD3-directed bispecific T-cell engager, in combination with topotecan for the treatment of patients with advanced small cell lung cancer (SCLC), based on early-phase data from the ongoing phase 1 DAREON-9 trial (NCT05990738).

The trial utilized a step-up dosing strategy for obrixtamig to mitigate immune-mediated toxicities. The study enrolled patients who progressed after 1 or more lines of platinum-based treatment with or without a PD-1/PD-L1 inhibitor. Three dose levels of obrixtamig were evaluated in the study. 

Interim results showed an encouraging overall response rate (ORR) of 70% (95% CI, 47%-87%), with responses maintained at 69% (95% CI, 39%-91%) among the 13 patients who underwent confirmatory imaging. Wermke noted that these early findings may suggest synergistic activity between obrixtamig and topotecan, warranting further exploration.

Wermke noted that safety outcomes were consistent with expectations based on the known toxicity profiles of each agent alone. Topotecan-associated cytopenias were reported, including neutropenia (68%) and thrombocytopenia (92%), though no associated infectious or bleeding complications occurred.

Obrixtamig-related cytokine release syndrome (CRS) occurred in 48% of patients; these were mostly grade 1 effects (44%), with a few grade 2 cases (4%). No grade 3 or higher CRS was observed. Additionally, neurotoxicity including immune effector cell–associated neurotoxicity syndrome was rare, with only two patients experiencing grade 1 or 2 muscle spasms.

Martin Wermke, MD, discusses obrixtamig in combination with topotecan for the treatment of patients with  advanced small cell lung cancer. 

Dr Wermke on the Efficacy and Safety of Obrixtamig With Topotecan in Advanced SCLC

Jonathan Strosberg, MD, discusses safety data for 212Pb-DOTAMTATE in metastatic somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors.

Dr Strosberg on Research Clarifying the Role of Obrixtamig in SCLC and Other Neuroendocrine Cancers

"Currently, there’s no standard…treatment beyond platinum etoposide for poorly differentiated neuroendocrine carcinomas. [Accordingly, the DAREON-5] study is looking at obrixtamig [for] patients [with SCLC and NECs] who have at least received 1 prior line of treatment."

Jonathan Strosberg, MD, a professor and leader of the Neuroendocrine Tumor Division and the Department of Gastrointestinal Oncology Research Program at Moffitt Cancer Center, discussed how 

the ongoing phase 2 DAREON-5 trial (NCT05882058)

 may clarify the role of obrixtamig (BI 764532)—a bispecific T-cell engager targeting delta-like ligand-3 (DLL3) and CD3—in the treatment of patients with extensive-stage small cell lung cancer (SCLC), extrapulmonary neuroendocrine carcinomas (NECs), and large-cell NEC of the lung.

Strosberg noted that patients with poorly differentiated NECs currently have limited treatment options beyond platinum-based chemotherapy. In gastrointestinal NECs, regimens such as FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) may be employed, and dual checkpoint inhibition with ipilimumab (Yervoy) and nivolumab (Opdivo) has demonstrated modest activity, with response rates of approximately 10% to 15% in real-world datasets, he added. However, there remains no widely accepted or effective second-line standard of care (SOC), Strosberg emphasized.

DAREON-5 is an open-label, multicenter trial evaluating obrixtamig in adult patients with extensive-stage SCLC and other NECs, Strosberg continued. Eligible patients with SCLC must have received at least 2 prior lines of therapy, including platinum-based chemotherapy and a PD-L1 inhibitor, if SOC in their region. Patients with extrapulmonary or large-cell NEC of the lung must have received at least 1 prior platinum-based regimen. Part 1 of the study includes safety run-in and dose expansion phases, and part 2 focuses on efficacy.

The primary end point for parts 1 and 2 is objective response rate (ORR) as assessed by RECIST 1.1 criteria, and rate of treatment-emergent adverse effects (TEAEs) is an additional primary end point for part 1. Secondary end points include duration of response, progression-free survival, disease control rate, overall survival, health-related quality of life, and TEAEs leading to treatment discontinuation.

Strosberg emphasized that ORR is an appropriate primary end point in this single-arm study, given the absence of effective therapies in this setting and the observation that responses to obrixtamig appear to be durable. The trial may offer insights into the utility of DLL3-targeted therapies across NEC subtypes and help address an urgent unmet need, he concluded.

Jonathan Strosberg, MD, discusses how the phase 2 DAREON-5 trial could address questions about the use of DLL3/CD3-targeted agents in SCLC and other NECs.

Dr Strosberg on Research Clarifying the Role of Obrixtamig in SCLC and Other Neuroendocrine Cancers  

After showing promising phase 1 efficacy in patients with small cell lung cancer (SCLC), extrapulmonary neuroendocrine carcinomas (NECs), and NECs of the lung, obrixtamig(BI 764532) is being further evaluated in this patient population in the ongoing phase 2 DAREON-5 trial (NCT05882058).

“[Obrixtamig] is a bispecific T-cell engager [BiTE] targeting delta-like ligand-3 [DLL3] which is expressed on prodifferentiated neuroendocrine cancer cells, as well as 

-mutated T cells,” Jonathan Strosberg, MD,said in an interview with 

®. “[DLL3 expression] seems to be highest in [patients with] SCLC; I’ve seen estimates up to [approximately] 85% to 90% [of patients]. There are also different cutoffs of what’s considered DLL3 positive; some consider it more than 1% and others more than 50%. Interestingly, in [patients with DLL3]-positive disease, it’s usually very positive.”

Strosberg is a professor specializing in the management of neuroendocrine malignancies at Moffitt Cancer Center in Tampa, Florida. He also leads Moffitt’s Neuroendocrine Tumor Division and the Department of Gastrointestinal Oncology Research Program.

FDA granted accelerated approval to the first-in-class DLL3-targeted BiTE tarlatamab-dlle

 (Imdelltra), becoming the first DLL3-targeted BiTE to receive an indication for patients with extensive-stage SCLC with disease progression on or after platinum-based chemotherapy.

Obrixtamig an investigational DLL3/CD3 IgG-like T-cell engager that is being developed for treatment of patients with SCLC and other NECs.

 To date the agent has received FDA fast track designation in multiple lung cancer subtypes. In October 2023, 

the agent was granted fast track designation by the FDA

 for the treatment of patients with extensive-stage SCLC that has progressed after at least 2 prior lines of treatment including platinum-based chemotherapy, and for those with advanced or metastatic extrapulmonary NEC with disease progression after at least 1 prior line of treatment including platinum-based chemotherapy. Then, 

in November 2023, it received fast track designation

 for the treatment of patients with advanced or metastatic DLL3-expressing large-cell NEC of the lung who experienced disease progression after 1 or more lines of treatment including platinum-based chemotherapy.

Obrixtamig Shows Encouraging Activity in Hard-to-Treat Lung Cancer Subtypes

The first-in-human phase 1 study (NCT04429087) of obrixtamig examined the agent in patients with DLL3-positive advanced or metastatic SCLC and other NECs .

 Patients were required to have experienced disease progression following treatment with standard therapies, including at least 1 line of platinum-based chemotherapy, or be ineligible for standard treatment, have an ECOG performance status of 0 or 1, and adequate organ function.

Patients received intravenous (IV) obrixtamig at various dose levels either once every 3 weeks (regimen A); once per week (regimen B1); once per week after step-in-dosing (regimen B2); or once per week after step-in-dosing with an additional IV regimen (regimen B3). The primary end points were determining the maximum tolerated dose (MTD) of obrixtamig and dose-limiting toxicities in the MTD evaluation period.

Updated findings presented during the 2024 ESMO Congress showed that, at the February 21, 2024, data cutoff, response-evaluable patients who received obrixtamig at any dose level (n = 154) achieved a confirmed overall response rate (ORR) of 18%; all responses were partial. The disease control rate (DCR) was 42% and 20% of patients were not evaluable.

Among patients who received obrixtamig at a dose of at least 90 μg/kg, the median duration of response (DOR) was 8.5 months (95% CI, 6.2-not reached [NR]) and the preliminary median progression-free survival (PFS) was 1.5 months (95% CI, 1.4-2.4).

Specifically, in patients with SCLC (n = 65), extrapulmonary NECs (n = 60), and large cell NEC of the lung (n = 10) who received at least 90 μg/kg of obrixtamig, the respective confirmed ORRs were 17%, 20%, and 40%. The DCRs were 43%, 45%, and 90%, respectively. The median DOR was 8.5 months (95% CI, 4.6-NR), 6.2 months (95% CI, 2.9-19.4), and NR (95% CI, 2.3-NR), respectively. The estimated 6-month PFS rates were 20% (95% CI, 10%-30%), 18% (95% CI, 8%-29%), and 28% (95% CI, 0%-57%), respectively.

Notably, the MTD of obrixtamig was NR. In the overall safety population (n = 168), 4 patients experienced treatment-related adverse effects (TRAEs) leading to dose reduction and 6 had TRAEs leading to dose discontinuation. Two patents died due to adverse effects (AEs) that were considered to be related to treatment: 1 due to immune effector cell–associated neurotoxicity syndrome (ICANS) in regimen B2 and another due to confusional state in regimen B3.

Eighty-eight percent of patients experienced an any-grade TRAE. The most common any-grade TRAEs included cytokine release syndrome (CRS; 57%), dysgeusia (23%), and pyrexia (21%). Grade 3 or higher TRAEs occurred in 24% of patients including decreased lymphocyte count (13%), CRS (3%), increased aspartate aminotransferase (2%), and anemia (2%).

“BiTEs almost uniformly cause CRS,” Strosberg said. “That’s an issue, although it doesn’t seem to be too severe in most cases. There’s also a risk of ICANS [but] it seems to be manageable. There [can be] other AEs, such as fatigue, nausea, and mild cytopenias, but CRS and ICANS are the most significant risks.”

Further Evaluation of Obrixtamig Is Underway

DAREON-5 is an open-label, multicenter study examining obrixtamig in adult patients with extensive-stage SCLC and other NECs (

 Beyond SCLC, the study will also include patients with extrapulmonary NEC and large-cell NEC of the lung. Patients with mixed-histology disease are eligible if the NEC/small cell component is predominant in at least 50% of the overall tumor tissue.

Patients with SCLC are required to have undergone at least 2 prior lines of therapy, including at least 1 platinum-based regimen and a PD-L1 inhibitor plus a platinum-based regimen in countries where the standard of care includes PD-L1 inhibition, unless they are unable to receive a checkpoint inhibitor. Patients with extrapulmonary NEC or large-cell NEC of the lung must have received at least 1 prior platinum-based regimen. In part 2, patients with extrapulmonary NEC must have high DLL3 expression via central assessment. Other key inclusion criteria in both parts include an ECOG performance status of 0 or 1, the presence of measurable lesions per RECIST 1.1 criteria within 21 days prior to the first dose of obrixtamig, and adequate organ function.

“[Potential barriers to enrollment] include the new version of protocol requiring high expression of DLL3 [in some] patients and they also need to have sufficient archival tissue [samples] to be able to investigate for DLL3 expression,” Strosberg noted. “Another issue is that patients with these diseases are often quite sick, especially after 1 or 2 lines of therapy. Finding patients with a sufficiently high performance status and the necessary biomarker testing [characteristics] could be challenging.”

Eligible patients will be randomly assigned to receive obrixtamig at 1 of 2 dosing levels during part 1 and at dose level 1 in the part 2 expansion cohort. The primary end points in parts 1 and 2 are ORR per RECIST 1.1 criteria; the rate of TEAEs is also a primary end point in part 1. Secondary end points include DOR, PFS, DCR, overall survival, health-related quality of life measures, and TEAEs leading to treatment discontinuation.

In October 2023, Oxford BioTherapeutics announced that the first patient had been dosed in DAREON-5.

 The estimated primary completion of the study is in October 2026.

“My hope is that we can get [obrixtamig] approved relatively quickly,” Strosberg said. “[These are] diseases with few effective therapies and terrible prognoses. I’m hoping that we can even move to approval based on single-arm data, although randomized data are the standard. In the future, we may see the drug move to the first line in combination with chemotherapy.”

DAREON-5: a study to test whether different doses of BI 764532 help people with small cell lung cancer or other neuroendocrine cancers. ClinicalTrials.gov. Updated April 18, 2025. https://clinicaltrials.gov/study/NCT05882058

FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. May 16, 2024. Accessed May 5, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer

Oxford BioTherapeutics announces partner Boehringer Ingelheim received US FDA fast track designation for BI 764532 for the treatment of extensive stage small cell lung cancer and extrapulmonary neuroendocrine cancers. News release. Oxford BioTherapeutics. October 3, 2023. Accessed May 1, 2025. https://oxford-biotherapeutics.lon1.cdn.digitaloceanspaces.com/03_10_23_bi_764532_fast_track_pr.pdf

Oxford BioTherapeutics announces partner Boehringer Ingelheim received US FDA fast track designation for BI 764532 for the potential treatment of advanced or metastatic large-cell neuroendocrine carcinoma of the lung. News release. Oxford BioTherapeutics. November 29, 2023. Accessed May 1, 2025. https://www.oxfordbiotherapeutics.com/news-events/oxford-biotherapeutics-announces-partner-boehringer-ingelheim-received-us-fda-fast-track-designation-for-bi764532-for-the-potential-treatment-of-advanced-or-metastatic-large-cell-neuroendocrine-carcinoma-of-the-lung

Wermke M, Gambardella V, Kuboki Y, et al. Phase I trial of the delta-like ligand-3 (DLL3)/CD3 IgG-Like T cell engager BI 764532 in patients (pts) with DLL3-positive tumors: updated data. 

. 2024;35(suppl 2):S525-S526. doi:10.1016/j.annonc.2024.08.736

Oxford BioTherapeutics announces partner Boehringer Ingelheim dosed first patient in phase 2 trial with BI 764532 in small cell lung cancer and other neuroendocrine cancers. News release. Oxford BioTherapeutics. October 24, 2023. Accessed May 1, 2025. https://www.oxfordbiotherapeutics.com/news-events/oxford-biotherapeutics-announced-partner-boehringer-ingelheim-dosed-first-patient-in-phase-2-trial-with-bi-764532-in-small-cell-lung-cancer-and-other-neuroendocrine-cancers

Obrixtamig (BI 764532), a bispecific T-cell engager targeting DLL3 and CD3, is under evaluation in the phase 2 DAREON-5 trial for small cell lung cancer (SCLC) and neuroendocrine carcinomas (NECs). The phase 1 study showed a confirmed overall response rate of 18% and a disease control rate of 42%. The FDA granted fast track designation for obrixtamig in various lung cancer subtypes. The ongoing DAREON-5 trial aims to further assess its efficacy and safety, with primary completion expected in October 2026.

The DLL3- and CD3-targeted BiTE obrixtamig is being evaluated in patients with SCLC and other neuroendocrine cancers in the phase 2 DAREON-5 study.

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