FDA Grants Fast Track Designation to BI 764532 for DLL3+ Large-Cell NEC of the Lung

The FDA has granted a fast track designation to BI 764532 for use as a therapeutic option in patients with advanced or metastatic DLL3-expressing large-cell neuroendocrine carcinoma (NEC) of the lung who experienced disease progression after treatment with 1 or more lines of therapy, including platinum-based chemotherapy.¹

BI 764532 is an investigational DLL3/CD3 immunoglobulin G–like T-cell engager that is designed to redirect T cells toward tumors expressing the DLL3 protein.

“We are delighted about the clinical development to help address unmet needs for people living with small cell lung cancer [SCLC] and other NECs,” Christian Rohlff, chief executive officer of Oxford BioTherapeutics, stated in the press release.¹ “This is an important milestone for our teams and exciting news for the community.”

The therapy is currently being evaluated in the open-label, multicenter, dose-selection, phase 2 DAREON™-5 trial (NCT05882058), which is enrolling patients aged 18 years and older with histologically or cytologically confirmed SCLC, extrapulmonary NEC, medullary thyroid cancer, neuroendocrine prostate cancer, or large-cell NEC of the lung.²

Patients must have experienced disease progression or recurrence following standard treatment. If they had SCLC, they must have received at least 2 previous lines of therapy, including at least 1 platinum-containing regimen. If they had extrapulmonary NEC or large-cell NEC, they must have received at least 1 platinum-based regimen. Additional inclusion criteria include an ECOG performance status of 0 or 1, measurable lesions according to RECIST v1.1 criteria within 21 days of the first dose of the agent, availability of a tumor tissue sample, and adequate organ function.

Patients with untreated or symptomatic brain metastases, or the presence of leptomeningeal disease, are not eligible for enrollment onto the clinical trial. Other exclusion criteria include active or prior interstitial lung disease; previous treatment with DLL3-targeting agents or other another anticancer drug within 4 weeks of the first dose of the study drug; prior receipt of extensive field radiotherapy within 2 weeks of study drug administration; and unresolved toxicity from prior anticancer therapies.

Patients will be randomly assigned to receive BI 764532 at 1 of 2 dosing levels. The study’s primary end points include objective response rate (ORR) per RECIST v1.1 criteria and treatment-emergent adverse effects (TEAEs). Secondary end points consist of duration of response (DOR), progression-free survival, disease control rate (DCR), overall survival, quality-of-life measures, and TEAEs leading to treatment discontinuation.

In October 2023, Oxford BioTherapeutics announced that the first patient had been dosed in the trial.³

Earlier in October 2023, BI 764532 was granted FDA fast track designation for the treatment of patients with ES-SCLC that has progressed following at least 2 prior lines of treatment including platinum-based chemotherapy, and for those with advanced or metastatic extrapulmonary NEC that had progressed after at least 1 line of treatment that included platinum-based therapy.⁴

Data from an ongoing, first-in-human phase 1 trial (NCT04429087) were presented at the 2023 ASCO Annual Meeting in which the agent showed activity at doses of 90 µg/kg or higher (n = 71). The overall ORR achieved with the agent was 25%, and this was comprised entirely of partial responses.5 The DCR in this group was 52%.

In patients with SCLC (n = 39), extrapulmonary NEC (n = 27), and large-cell NEC (n = 5), the ORRs were 26%, 19%, and 60%, respectively. Tumor shrinkage was reported across all enrolled tumor types. The DCRs in these patients 51%, 44%, and 100%, respectively. As of April 21, 2023, the median DOR had not yet been reached and responses appeared to be durable.

In a total of 107 patients, 5 dose-limiting toxicities (DLTs) occurred; 2 patients experienced grade 3 or 4 cytokine release syndrome, 1 had grade 3 confusion state, 1 had grade 2 infusion-related reaction, and 1 experienced a grade 3 nervous system disorder. DLTs were noted to be reversible, and all patients recovered. The maximum tolerated dose of the agent had not yet been reached.

“It’s an exciting time for an immuno-oncologist seeing all these great compounds and making progress for our patients,” Martin Wermke, MD, head of the Early Clinical Trial Unit of the National Center for Tumor Diseases Dresden at the University Hospital Carl Gustav Carus in Dresden, Germany, said in an interview with OncLive® on BI 764532. “It’s rewarding to see patients who would otherwise lose in a matter of months living on this drug for more than 1 year; that’s something that makes you feel great if you’re able to do that.”BI 764532 was also granted orphan drug designation by the FDA for the treatment of patients with SCLC.¹ The agent is currently being investigated in the phase 2 DAREON™-5 trial (NCT05882058) of patients with relapsed/refractory ES-SCLC and other relapsed/refractory NEC.

Additional findings from the trial presented at the 2023 IASLC World Conference on Lung Cancer showed that treatment with at least 90 µg/kg of BI 764352 was well tolerated and resulted in tumor shrinkage in those with SCLC and NEC.⁶

The agent has also received orphan drug designation from the FDA for the treatment of patients with SCLC.¹

References

1. Oxford BioTherapeutics announces partner Boehringer Ingelheim received US FDA fast track designation for BI 764532 for potential treatment of advanced or metastatic large-cell neuroendocrine carcinoma of the lung. News release. Oxford BioTherapeutics. November 30, 2023. Accessed December 4, 2023. https://www.catapult-ventures.com/news/oxford-biotherapeutics-announces-partner-boehringer-ingelheim-received-u.s-fda-fast-track-designation-for-bi-764532 
2. 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 November 29, 2023. Accessed December 4, 2023. https://clinicaltrials.gov/study/NCT05882058
3. 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 December 4, 2023. http://www.oxfordbiotherapeutics.com/uploads/9/5/4/2/9542591/obt620_bi764532_ph2_fpd_-_pr_fv_24.10.2024.pdf
4. 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 December 4, 2023. http://www.oxfordbiotherapeutics.com/uploads/9/5/4/2/9542591/03_10_23_bi_764532_fast_track_pr.pdf
5. Wermke M, Felip E, Kuboki Y, et al. First-in-human dose-escalation trial of BI 764532, a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager in patients (pts) with DLL3-positive (DLL3+) small-cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC). J Clin Oncol. 2023;41(suppl 16):8502. doi:10.1200/JCO.2023.41.16_suppl.8502
6. Wermke M, Kuboki Y, Felip E, et al. Phase I dose escalation trial of the DLL3/CD3 Igg-like T cell engager BI 764532 in patients with DLL3+ tumors: focus on SCLC. Presented at: 2023 IASLC World Lung Cancer Conference; September 9-12, 2023; Singapore, Republic of Singapore. Abstract OA01.05.