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

Martin Wermke, MD

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 2025 ASCO Annual Meeting 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.2 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.

In an interview with OncLive®, 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.

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

Wermke: 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.

What was observed in terms of safety?

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.

What was observed in terms of efficacy?

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.

References

1. 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. J Clin Oncol. 2025;43(suppl 16):8094. doi:10.1200/JCO.2025.43.16_suppl.8094
2. 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. J Clin Oncol. 2025;43(suppl 16):3004. doi:10.1200/JCO.2025.43.16_suppl.3004