Dr Starr on the Rationale for Targeting DLL3 in Extrapulmonary Neuroendocrine Carcinomas

“The expression rate of DLL3 in [patients with epNECs] is up to 80%, which is quite high. We used the data that were evolving in SCLC to identify that this protein does exist and is overexpressed epNECs.”

Jason S. Starr, DO, an oncologist in the Department of Internal Medicine at Mayo Clinic, discussed the potential utility of delta-like ligand 3 (DLL3) as a treatment target in patients with extrapulmonary neuroendocrine carcinomas (epNECs).

DLL3, which is involved in a cell-to-cell signaling pathway, was first discovered in small cell lung cancer (SCLC), Starr began. SCLC is classified as a neuroendocrine carcinoma and DLL3 expression is observed on the cell surface of approximately 80% to 90% of SCLC cases, he continued. Due to the similarities between SCLC and epNECs, investigators evaluated the rate of DLL3 expression in patients with epNECs and found the rate to be approximately 80%, Starr explained.

, investigators presented data from a phase 1 trial (NCT04429087) which evaluated the novel DLL3/CD3 IgG-like T-cell engager obrixtamig (BI 764532) in patients with epNECs with high (≥ 50% of tumor cells) or low (< 50% of tumor cells) expression of DLL3. The coprimary end points were determining the maximum tolerated dose (MTD) and dose-limiting toxicities during the MTD evaluation period. Secondary end points included objective response rate (ORR) per RECIST 1.1 criteria and pharmacokinetic parameters.

The ORR in the overall population was 22% (95% CI, 13%-34%) and the disease control rate (DCR) was 47% (95% CI, 35%-59%). The ORR and DCR among patients with high DLL3 expression (n = 30) was 40% (95% CI, 25%-58%) and 67% (95% CI, 49%-81%), respectively. In patients with low DLL3 expression (n = 30), the ORR and DCR were 3% (95% CI, 1%-17%) and 27% (95% CI, 14%-44%), respectively. The median duration of response in the DLL3-high and -low groups was 7.9 months (95% CI, 6.2-not evaluable [NE]) and 2.8 months (95% CI, NE-NE), respectively.

In terms of safety, any-grade treatment-related adverse effects (TRAEs) were reported in 95% of patients in the overall population. The most common any-grade TRAEs included cytokine release syndrome (65%), pyrexia (32%), and dysgeusia (25%).

In October 2023, the FDA granted fast track designation to obrixtamig

 for the treatment of patients with extensive-stage SCLC who experienced disease progression following at least 2 prior lines of treatment including platinum-based chemotherapy, and for patients with advanced or metastatic epNECs following disease progression with at least 1 prior line of treatment including platinum-based chemotherapy. The agent is being further evaluated in patients with relapsed/refractory DLL3-high epNECs in ongoing the phase 2 DAREON-5 trial (NCT05882058).

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Jason S. Starr, DO, discusses DLL3 as a treatment target in extrapulmonary neuroendocrine carcinomas.

Jason Starr, DO, medical oncologist, the Department of Internal Medicine, the Mayo Clinic, discusses the characterization of 

Investigators conducted a real-world study of a large cohort of patients with colorectal cancer (CRC) to further examine the association between 

 mutations and susceptibility to immunotherapy. Data were pooled from 9,136 patients. Of these patients, 217 harbored 

 mutations, including 203 patients with 

mutations, and 1 patient with both. Although germline 

 mutations are a possibility in CRC, no instances of these germline mutations were observed in this study. 

Once investigators identified patients with 

 mutations, they focused on classifying the alteration types, such as frameshift mutations, point mutations, or copy number alterations. Notably, 58.5% of 

 copy number loss, where the gene was not being transcribed, leading to instability of the DNA, Starr notes.

Historically, patients with microsatellite instability–high (MSI-H) CRC benefit from immunotherapy. However, among evaluable patients with 

 wild-type disease (n = 8865), 6.1% had MSI-H disease, and only 1.8% of patients with 

 mutations were MSI-H. The mechanism of the immunotherapy working is not mismatch repair deficiency or MSI-H in the majority of patients; rather, this hypermutated genotype is creating neoantigens that stimulate the immune system, Starr says.

 mutations had a high tumor mutational burden, defined as greater than 10 mut/Mb. Among patients with 

 wild-type tumors, 9.9% had a high tumor mutational burden. These findings suggested that 

 mutations are not synonymous with a high tumor mutational burden, which was disappointing for investigators, who hoped to identify more patients that could benefit from immunotherapy, Starr concludes.

Jason Starr, DO, discusses the characterization of POLE/POLD1 mutations in colorectal adenocarcinoma.

Jason Starr, DO

Articles

Dr Starr on the Rationale for Targeting DLL3 in Extrapulmonary Neuroendocrine Carcinomas

Dr. Starr on the Characterization of POLE/POLD1 Mutations in Colorectal Adenocarcinoma