BI 764532 Yields Promising Safety and Efficacy Results in DLL3+ SCLC and Neuroendocrine Carcinomas

The novel T-cell engager BI 764532 demonstrated a clinically acceptable safety profile and early efficacy when administered at doses of 90 μg/kg or greater in patients with DLL3-positive small cell lung cancer (SCLC) and neuroendocrine carcinomas (NECs), groups who historically do not have many efficacious treatment options, according to Martin Wermke, MD.

“The next steps are for dose optimization,” Wermke said. “We will try to find a schedule [that] is convenient for smaller hospitals and private practice oncology [clinics] and will try to move this compound to earlier lines of treatment, combining it with first-line chemotherapy [as well as] standard maintenance regimens, and finding novel combinations with other immunotherapeutics.”

At the 2023 ASCO Annual Meeting, Wermke presented data from a phase 1 study (NCT04429087) showing that at doses of 90 μg/kg or more, BI 764532 elicited a partial response rate of 25% in the overall population (n = 71), 26% in the SCLC group (n = 39), 19% in those with extrapulmonary NECs (n = 27), and 60% in patients with large cell NECs (n = 5). He noted that although the median duration of response (DOR) has not been reached, responses appeared to be durable, with a disease control rate of 52% for all patients given the 90 μg/kg or more dose.

Further, drug discontinuation due to treatment-related adverse events was low. Dose limiting toxicities occurred in 5 of 107 patients treated on the study at all dose levels but were reversable and patients recovered. The toxicities included grade 3/4 cytokine release syndrome (CRS) occuring in 2 patients, as well as grade 3 confusional state, grade 2 infusion-related reaction, and a grade 3 nervous system disorder occuring in 1 patient each.

In an interview with OncLive®, Wermke, 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, discussed why the novel agent may serve as a promising treatment option targeting DLL3.

OncLive: What was the rationale for this research?

SCLC and other NECs are an area of great unmet clinical need. We do have an established first-line treatment which induces remissions; however, these remissions are usually short lived and [if] patients relapse, [they] receive another chemotherapy with a lower response rate, [shorter] DOR, and quickly run out of the therapeutic options.

It was discovered that NECs express DLL3 on their surface. This molecule is virtually absent from any other adult human tissue, so it’s an [ideal] target for immunotherapeutics. BI 764532 is a molecule which binds to DLL3 on the tumor cells and to CD3 on the T cells, thereby redirecting T cells to the tumor, inducing an immune cytologic cell death to the tumor cell.

[Because] DLL3 is expressed on the surface of the tumor cells but not on the surface of healthy tissue, you have the chance to redirect the T cells exactly where you want them to act. It’s relatively stably expressed, so this is not a problem of downregulation [where] you lose the antigen [as] the tumors evolving. It’s a fairly stable target for different lines of treatment and that also differentiates it from other targets in SCLC.

What findings from this trial were presented at the 2023 ASCO meeting?

We included a total of 107 patients thus far who were treated according to 3 different dose-escalation regimens. We started with a 3-weekly application, switched to a weekly regimen, and then to a weekly regimen with a step-wise dose increase to reduce the occurrence of CRS. Looking at all these regimens and entities, we [saw] a response rate of 18%.

Focusing on the potentially efficacious dose levels above 90 µg per kg, the response rate was 25%, and these responses [did] not seem to be restricted to any of the sub entities included. It’s not just [patients with] SCLC, extrapulmonary neuroendocrine carcinoma, [or] large cell NEC for lung, [that responded to treatment]—it’s all 3 of them. The responses seem to be durable too. At the time of the data cut off, 14 out of 18 responses were ongoing and we do have patients responding for 1 year or more.

It’s an exciting time for an immuno-oncologist seeing all these great compounds and making progress for our patients. 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.

What other data presented at ASCO stood out to you?

I was impressed by the ADAURA trial [NCT02511106] data on adjuvant osimertinib [Tagrisso] in non–small cell lung cancer, this is something new and unexpected. During the Developmental Therapeutics—Immunotherapy session, there was a good presentation on the GDF-15 antibody, which was quite promising to my understanding.

Reference

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