Promising abstracts surrounding DLL3 targeting for patients with lung and neuroendocrine cancer were presented at WCLC 2024.
New directions in DLL3 targeting were highlighted at the World Conference on Lung Cancer 2024 meeting, including innovative approaches in small cell lung cancer (SCLC) and the latest research initiatives in mesothelioma, thymoma, and other thoracic tumors.1
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Lauren Averett Byers, MD, began the presentation by explaining the expansion of mechanisms to target lung cancer by using surface targets, including antibody drug conjugates (ADC), chimeric antigen receptor (CAR) therapy, and bi-specific T-cell engager (BiTE). Overall, there is a clear increase in the number of DLL3-targeting T-cell engagers that are currently being investigated.
As part of the DeLLphi-301 trial, tarlatamab (Amgen) in combination with both atezolizumab (Tecentriq; Genentech) (n = 30) and durvalumab (Imfinzi; AstraZeneca) (n = 25), both PD-(L)1 inhibitors, as first-line management of ES-SCLC. Disease control rate (DCR) was similar between both combinations, each having a DCR of 62.5%. The median duration of disease control for tarlatamab and atezolizumab was 7.2 months, while it was non estimable for the tarlatamab and durvalumab combination.
Trial Name: A Study in Participants With Advanced Cancers Associated With Expression of DLL3 (MK-6070-001/HPN328-4001)
ClinicalTrials.gov ID: NCT04471727
Sponsor: Harpoon Therapeutics, Inc
Estimated Study Completion: January 30, 2026
Byers continued, presenting efficacy results from a population of patients with large cell neuroendocrine cancer of the lung (LCNEC-L). With DLL3 targeting, about half of the patients in the cohort had some form of tumor regression, according to Byers. Additionally, the duration of response (DOR) in these patients was sustained, with many having a DOR of 22.4 or 15.9 months.
“I’m hopeful that we’ll see something similar to what we’ve seen in SCLC, which is that not only is there a real response rate, but also durability as we follow this out further,” Byers told the session.
HPN328-4001 (NCT04471727), the "Harpoon" study, enrolled patients with and without brain metastases because of their SCLC. In total 52 patients participated in the study and received MK-6070 (Merck), with 28 having a history of brain metastases and 24 without such a history. Key assessments of response were overall response rate (ORR) and extracranial ORR.2
Upon completion of the trial, among the 20 participants with brain metastases at baseline, 5 (25%) had a complete response in the brain. Additionally, of the 24 that did not have a history of brain metastases, none had any central nervous system cancer progression.
Trial Name: A Study to Test Different Doses of BI 764532 in Patients With Small Cell Lung Cancer and Other Neuroendocrine Tumours That Are Positive for DLL3
ClinicalTrials.gov ID: NCT04429087
Sponsor: Boehringer Ingelheim
Estimated Study Completion: September 22, 2025
“Historically, there’s been some variation of how brain [metastases] are followed,” Byers said, noting that some studies require “serial follow-up and surveillance.” For this trial, she needed that such a follow-up would be important, as patients with SCLC are at high risk for the development of CNS disease.
Byers then shifted to an analysis of patients with LCNEC led by Carl Gay, MD, which identified 2 intrinsic subtypes of LCNE, characterized by high or low expressions of YAP1. Investigators found that patients with relatively low expressions of YAP1 tumors had high expressions of DLL3, showing potential for this status to be used as a biomarker for LCNEC.3
“This will be another area, together with SCLC, where we really need to continue to study, who are the patients that are benefitting, especially in the context of SCLC as well as LCNE,” Byers explained. Noting the increase in treatment options for patients, Byers cautioned that strategies will be necessary to match treatments with specific patients.
