BI 764532 Shows Early Efficacy, Manageable Tolerability in DLL3+ SCLC and Neuroendocrine Carcinoma

When administered at doses of 90 μg/kg or higher, the novel DLL3-targeting T-cell engager, BI 764532, was found to have an acceptable toxicity profile and to elicit encouraging responses in patients with DLL3-positive small cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC), according to findings from a phase 1 trial (NCT04429087).¹

Data presented during the 2023 ASCO Annual Meeting showed that the maximum tolerated dose (MTD) had not yet been reached. Five dose-limiting toxicities (DLTs) were reported and included grade 3 or 4 cytokine release syndrome (CRS; n = 2), grade 3 confusional state (n = 1), grade 2 infusion-related reaction (n = 1), and grade 3 nervous system disorder (n = 1). All DLTs were reversible, and all patients recovered.

Moreover, giving the agent at doses of 90 μg/kg or higher resulted in an overall response rate (ORR) of 25% in the overall population (n = 71). The disease control rate (DCR) in this group was 52%.

Notably, tumor shrinkage was observed across all tumor types enrolled to the trial. When broken down my disease entity, BI 764532 elicited an ORR of 26% in those with SCLC (n = 39), 19% in those with extrapulmonary neuroendocrine carcinoma (epNEC; n = 27), and 60% in those with large cell neuroendocrine carcinoma (LCNEC; n = 5).

Responses achieved with the T-cell engager appear to be durable, with the median duration of response not having been reached.

“At clinically efficacious BI 764532 dose levels, safety is clinically acceptable and manageable,” Martin Wermke, MD, who is the lead study author and 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 a presentation of the data. “The drug discontinuation rate due to treatment-related adverse effects [TRAEs] was low, at just 4%. We did see a lot of CRS as you would expect for a bispecific antibody but mostly of grade 1 and 2, and [this was] easily managed with standard supportive care measures.”

BI 764532 has an immunoglobulin-like structure and binds to lyse DLL3 on the surface of neuroendocrine carcinoma cells. Notably, DLL3 is virtually absent from the surface of healthy adult human tissue, according to Wermke. With the other part of the molecule, the agent binds to CD3, thus redirecting T cells to the tumor sites and inducing cell death.

The non-randomized, open-label, multicenter, first-in-human trial enrolled patients with locally advanced or metastatic SCLC, LCNEC, or NEC that was not amenable to curative treatment and expressed DLL3.² They were required to have progressed on or been ineligible for available standard treatments and have received at least 1 line of treatment.1 In those with SCLC, this line of treatment needed to be platinum-based chemotherapy. Other inclusion criteria included having an ECOG performance status of 0 or 1, and acceptable liver, bone marrow, and renal function.^1,2

Patients could not have previously received a T-cell engager or another DLL3-targeted cell therapy, nor could they have unresolved toxicity from a prior treatment. They also could not have undergone a major surgical procedure within 28 days of the first dose of study treatment.²

The dose-escalation trial followed a Bayesian logistic regression model for dose escalation with overdose control, Wermke noted.1 The trial began with a dosing regimen of every 3 weeks, which was later switched to a weekly dosing regimen based on emerging pharmacokinetic (PK) findings, he said.

Even more recently, the trial has shifted to examining a regimen that includes a step-wise dose increase over the first 3 administrations of the agent to reduce CRS incidence and infusion-related reactions. Treatment is continued until disease progression or a total of 36 months.

The primary end points of the research are to identify the MTD of BI 764532 and to examine DLTs in the MTD evaluation period. Secondary end points include ORR by RECIST v1.1 criteria and PK parameters.

As of March 2023, a total of 107 patients were enrolled to the trial; 57 had SCLC, 41 had epNEC, and 9 had LCNEC. The median age of these patients was 60 years (range, 32-79) and 57% were male. Most patients (67%) received 1 to 2 prior lines of therapy, and 31% had received 3 or more prior lines. Regarding ECOG performance status, 26% had a status of 0 and 73% had a status of 1. Forty-nine percent of patients previously received a PD-1 or PD-L1 inhibitor. Notably, 38% and 56% of patients had brain or liver metastases, respectively.

Additional efficacy findings showed that BI 764532 resulted in a DCR of 51% in those with SCLC, 44% in those with epNEC, and 100% in those with LCNEC. Of the 18 responses observed across the indications, 14 were still ongoing at the time of data cutoff, Wermke noted. “We do have responders who responded for around a year or even more,” he said.

To further illustrate the efficacy of the drug, Wermke shared a case from his practice. The female experienced an early relapse following curative-intent radiochemotherapy for SCLC. “This was not only a local relapse, but also new onset visceral metastases in the pancreas,” Wermke said. Six weeks after beginning treatment with BI 764532, shrinkage of the relapse and the pancreatic metastases was observed. “This is maintained and deepened in the most recent CT scan done 1 year after initiation of treatment,” he added.

Regarding safety, at least 1 all-grade TRAE was reported in 86% of patients (n = 107); 59% of the events were grade 1 or 2, and 27% of the events were grade 3 to 5. The most common TRAEs reported in more than 10% of patients included CRS (grade 1-2, 57%; grade 3-5, 2%), decreased lymphocyte count (4%; 16%), dysgeusia (20%; 0%), asthenia (18%; <1%), pyrexia (18%; 0%), increased aspartate aminotransferase (12%; 2%), fatigue (13%; <1%), and nausea (12%; 0%).

Further dose optimization is ongoing.

References

1. 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
2. A study to test different doses of BI 764532 in patients with small cell lung cancer and other neuroendocrine tumours that are positive for Delta-Like Ligand 3 (DLL3). ClinicalTrials.gov. Updated May 16, 2023. Accessed June 3, 2023. https://clinicaltrials.gov/ct2/show/NCT04429087