Our goal of transforming DLL3-positive carcinomas

Neuroendocrine carcinomas (NECs) are highly aggressive cancers that can occur in multiple organs including the lung, gastrointestinal tract, urogenital tract, and skin. These cancers are associated with a poor prognosis and 5-year survival rate ranging between 3-13% in advanced stages.^1,2

Small cell lung cancer (SCLC) is the most common form of NEC and accounts for 13% of all lung cancer cases.³ Both SCLC and extrapulmonary NEC (epNEC) share key attributes which set them apart from many other tumors. These include: late symptom presentation resulting in the majority of patients receiving a late-stage diagnosis, rapid tumor growth rate and progression, and poor prognosis.⁴

Burden on patients and carers

Receiving a SCLC or NEC diagnosis can be life-changing. These cancers can have a detrimental physical, psychological, and emotional impact on the daily lives of those diagnosed, as well as on families and those who care for them.⁵ Current treatment options for advanced NECs include chemotherapy and immunotherapy, but they are associated with limited duration of response.⁶ There is an urgent need for additional targeted therapies for people living with SCLC and other NECs, and addressing this unmet treatment need could lessen the significant burden they face.

Danielle Hicks, Chief Patient Officer at GO2 for Lung Cancer, commented, “Industry, healthcare professionals, and patient organizations have an opportunity to partner more closely to prioritize SCLC and NECs to ensure that those impacted by these more aggressive cancers get the care they need. There is an urgent need for additional treatment options for the SCLC community as many unmet needs still exist for this population.”

Addressing some of the most challenging, but potentially most impactful areas of cancer research, our robust pipeline comprises homegrown and partnered assets with a diverse range of mode of actions. This includes cancer cell-directed and immuno-oncology investigational therapies. Through this combined approach, we believe that we may offer the greatest benefit for people living with cancer.

T-cell engagers are targeted immunotherapeutics, which have the potential to directly activate T cells (a type of white blood cell that helps the immune system fight disease). This could potentially result in the selective killing of tumor cells by the body’s own immune system.⁷

Development of a new targeted immunotherapy

Delta-like ligand 3 (DLL3) is a protein that is expressed specifically on the surface of up to 85% of SCLC tumor cells and around 77% of NECs. In normal tissue, DLL3 is minimally expressed, which makes it an ideal therapeutic target.

We are investigating BI 764532, an investigational DLL3 targeting T-cell engager, for the treatment of people living with relapsed SCLC and epNEC.^9,10The DLL3 protein as a new potential target was identified through the Oxford BioTherapeutics' OGAP® platform. BI 764532 is being investigated in a phase II trial (clinicaltrials.gov identifier: NCT05882058) for treatment of people living with extensive stage SCLC (ES-SCLC), epNEC, and large cell neuroendocrine carcinoma of the lung (LCNEC-Lung)^9,10. BI 764532 might selectively redirect T cells towards cancer cells expressing the DLL3 protein, potentially resulting in the destruction of SCLC or other NEC tumors by the body’s own immune system.

Evelyn Fahrenkrug, DLL3 Global asset team lead at Boehringer Ingelheim, said, “By utilizing the body’s own immune system, we are hopeful that we can bring an innovative targeted immunotherapeutic to people living with SCLC and NEC.

The Phase I first-in-human dose-escalation trial data were presented during the ASCO 2023 Annual Meeting. We saw encouraging results from the trial and therefore, in line with our pipeline approach, we increased our efforts to accelerate the compound’s development and initiate the Phase II clinical trial.

DAREON™-5 is an open-label, multi-center Phase II dose selection trial of intravenous BI 764532 in patients with relapsed/refractory ES-SCLC and other relapsed/refractory NECs. The clinical trial recently initiated and is now actively recruiting patients.

As of November 2023, the U.S. Food and Drug Administration (FDA) granted BI 764532 with:

Fast Track designation in advanced or metastatic LCNEC-Lung expressing DLL3 whose disease has progressed following at least one prior line of treatment including platinum based chemotherapy.

Orphan-drug designation for SCLC.
Fast Track designation in ES-SCLC with disease progression following at least two prior lines of treatment including platinum-based chemotherpay and for epNEC with advanced or metastatic disease following at lest one prior line of treatment including platinum-based chemotherapy.

This compound is investigational and has not been approved for use by any regulatory authority, including the U.S. FDA. The efficacy and safety of this compound have not been established.

Accelerating progress through strategic collaboration

The successful partnership between Boehringer Ingelheim and Oxford BioTherapeutics was established to discover selective targets to deliver first-in-class treatments for people with cancer and address unmet needs. Utilizing Oxford BioTherapeutics’ OGAP^®drug discovery platform and Boehringer Ingelheim’s longstanding expertise in oncology, the successful alliance has accelerated the identification of the novel immunotherapy target and the overall transition into clinical development. To learn more about the trial and partnership, read Oxford BioTherapeutics’ press release.

Christian Rohlff, PhD, Chief Executive Officer of Oxford BioTherapeutics, said, “We are delighted about the clinical development for BI 764532 to help address unmet needs for people living with SCLC and NECs. This is an important milestone for our teams and exciting news for the community.”

As part of the broader clinical trial program for BI 764532, additional trials will be initiated in 2024.

Read more about our commitment to advancing immuno-oncology and how we are driving innovation in this area.

Date updated: January 2024

References

1. Lung Cancer Survival Rates. American Cancer Society. Accessed October 2023.

2. Dasari A, Mehta K, Byers LA, Sorbye H, Yao JC. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. Cancer. 2018.

3. Lung Cancer Survival Rates. American Cancer Society. Accessed October 2023.

4. Wermke: BI 764532 ph 1 trial in progress (ASCO 2020 poster) – data on file.

5. Living with Neuroendocrine Cancer. Neuroendocrine Cancer UK. Accessed October 2023.

6. Yao J et al. DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms. Oncologist 2022.

7. Huehls AM, Coupet TA, Sentman CL. Bispecific T-cell engagers for cancer immunotherapy. Immunology & Cell Biology. 2014;93(3):290-296.

8. Hipp: BI 764532 preclinical paper (CCR 2019) – data on file.

9. Wermke: BI 764532 ph 1 trial in progress (ASCO 2020 poster) – data on file.

10. Hazini A. et al., J Immunotherapy Cancer 2021.