Phase 1 Study of BI 764532 in DLL3+ Small Cell Lung Cancer Continues


Responses to BI 764532 in patient siwth DLL3-positive small cell lung cancer appear to be durable and are ongoing in the dose optimization portion of a phase 1 study.

BI 764532 dosed at a minimum of 90 μg/kg achieved tumor size reduction and was well-tolerated in in patients with small cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC), according to findings from a phase 1 trial (NCT04429087) that were presented at the 2023 IASLC World Conference on Lung Cancer.1

Results showed that the maximum tolerated dose (MTD) was not reached in the overall population (n = 107), although 5 dose-limiting toxicities (DLTs) occurred––all reversible––including grade 3/4 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).

“The safety profile of BI 764532 is acceptable and manageable at clinically efficacious dose levels in patients with SCLC and large cell NEC. Responses to date appear to be durable and are ongoing [as is] dose optimization,” lead study author Martin Wermke, of Technische Universität Dresden in Germany, said in a presentation of the data.

BI764532, a novel DLLC-targeting T-cell–engager, is designed to redirect a patient’s T cells to lyse DLL3-expressing tumor cells. Previously, preclinical data has shown that the agent has robust antitumor activity against DLL3-positive cells and xenograft models.2

The first-in-human dose-escalation trial was designed with a Bayesian logistic regression method to evaluate 2 regimens of BI 764532 in patients with SCLC and NEC. Regimen A was dosed intravenously once every 3 weeks. After reaching the highest dose with regimen A, patients switched to regimen B1 or B2, which adopted step-in dosing, administered once weekly.

To be eligible for enrollment, patients had to have centrally confirmed DLL3-positive, advanced SCLC, large cell NEC, or extrapulmonary NEC after experiencing failure with or being ineligible for available standard therapies, which had to include at least 1 line of platinum-based chemotherapy. Adequate liver, bone marrow, and renal function; and an ECOG performance status of 0 or 1 was also required.

Patients were treated for 36 months or until disease progression, whichever occurred first.

MTD and DLTs in the MTD evaluation period served as primary end points. Secondary end points included objective response per RECIST v1.1 criteria and pharmacokinetic parameters.

As of March 26, 2023, among patients who had received at least 1 dose of BI 764532 (n = 107), the median age was 60 years (range, 32-79) and most were male (57%). Patients with SCLC comprised the majority of the overall population, at 53%; 38% and 8% of patients had extrapulmonary NEC and large cell NEC, respectively.

Regarding prior therapy, most patients had received between 1 and 2 lines (67%), although 31% had received 3 or more. Approximately half of patients (49%) had received prior PD-(L)1 inhibitors. An ECOG performance status of 1 represented the majority of enrolled patients (73%). Brain and liver metastases were present in 38% and 56% of patients, respectively.

Efficacy was evaluated in patients who had undergone at least 1 post-baseline tumor assessment or permanently discontinued treatment prior to tumor assessment. Among all evaluable patients (n = 99), 18% achieved partial response (PR), 23% had stable disease (SD), and 45% experienced progressive disease (PD). Thirteen patients were not evaluable (NE), leading to a disease control rate (DCR) of 41%.

In the SCLC cohort (n = 54), the DCR was 39% (PR, 19%; SD, 20%). Forty-three percent of patients experienced PD and 19% were NE. In the large-cell NEC cohort (n = 8), 38% of patients achieved either PR or SD, reflecting a DCR of 75%. The remaining 25% of patients experienced PD.

Efficacy was also evaluated in patients with SCLC and large cell NEC who received at least 90 μg/kg of BI 764532. In the SCLC population (n = 39), 26% of patients experienced PR or SD (DCR, 51%), 31% experienced PD, and 18% were NE. In the large-cell NEC cohort (n = 5), patients experienced either PR (60%) or SD (40%), translating to a 100% DCR.

As of April 21, 2023, responses were ongoing in 10 of 13 responders (range, <1 to 10.6). “Although it is too early to assess median duration of response, responses are ongoing in the majority of those who showed a response,” Wermke stated.

Regarding safety, all-cause adverse effects (AEs) occurring in more than 15% of all patients were CRS (grade 1/2, 47%; grade 3-5, 2%), asthenia (29%; 3%), dysgeusia (27%; 0%), constipation (27%; 0%), decreased lymphocyte count (6%; 18%), nausea (21%; 2%), fatigue (18%; 2%), malignant neoplasm progression (0%; 17%), decreased appetite (15%; 3%), aspartate aminotransferase increase (17%; 2%), headache (18%; 0%), and pyrexia (17%; 0%).

Any AE that led to drug discontinuation occurred in 6% of patients.

Wermke noted that CRS was managed with supportive care, corticosteroids, and/or IL-6R antibodies.


1. 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.

2. A bispecific DLL3/CD3 IgG-like T-cell engaging antibody induces antitumor responses in small cell lung cancer. Clin Cancer Res. 2020;26(suppl 19):5258-5268. doi:10.1158/1078-0432.CCR-20-0926

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