Obrixtamig Could Broaden the Reach of DLL3/CD3-Targeted BiTEs in Small Cell Lung and Other Neuroendocrine Cancers

Jonathan Strosberg, MD

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).¹

“[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 CD3-mutated T cells,” Jonathan Strosberg, MD,said in an interview with OncLive®. “[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.

In May 2024, the 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.²

Obrixtamig an investigational DLL3/CD3 IgG-like T-cell engager that is being developed for treatment of patients with SCLC and other NECs.³ 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.⁴

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 .⁵ 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 (Figure).¹ 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-5.⁶ The estimated primary completion of the study is in October 2026.¹

“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.”

References

1. 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
2. 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
3. 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
4. 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
5. 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. Ann Oncol. 2024;35(suppl 2):S525-S526. doi:10.1016/j.annonc.2024.08.736
6. 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