Conference Coverage

SCLC: Bispecific antibody shows phase 1 promise


AT ASCO 2023

In a phase 1 small cell lung cancer (SCLC) trial, a bispecific antibody that targets T cells and the inhibitory notch ligand known as delta-like ligand 3 (DLL3) showed a good safety profile and encouraging signs of efficacy, including one response that lasted more than a year.

The antibody promotes the destruction of tumor cells by T cells by acting as a bridge between T cells and tumors.

SCLC has largely resisted efforts to identify unique surface markers. DLL3 is an exception: It is rarely expressed in normal cells, and it seems to be important to tumor biology, according to Martin Wermke, MD, who presented the study at the annual meeting of the American Society of Clinical Oncology.

A rare SCLC biomarker

“The problem, I think, is that small cell [lung cancer] with its high mutational burden is a bunch of many different subentities and you will probably not find a single driver mutation as you do in non–small cell lung cancer. So in that [way] it’s different in its biology,” said Dr. Wermke, professor of experimental tumor therapy at the National Center for Tumor Diseases in Dresden, Germany.

Nevertheless, DLL3 is a sensitive biomarker, with over 90% of SCLC tumors positive for the surface marker, according to Dr. Wermke. “It’s one of the first which proved to be a reliable [SCLC] biomarker for therapeutic approaches,” said Dr. Wermke.

This isn’t the first clinical experience with DLL3. An anti-DLL3 antibody was used as part of an antibody-drug conjugate called Rova-T, which failed a phase 3 trial in SCLC in 2021 and was subsequently canceled by AbbVie, but Dr. Wermke believes that the issue was with the drug and linker (a chemical tag that links the cytotoxic drug to the antibody, which is designed to release the drug in an appropriate environment such as the interior of a tumor cell after an antibody-drug conjugate has been internalized by the tumor cell), not DLL3. DLL3 is also being investigated as a component of chimeric antigen receptor T-cell therapy, though no clinical results have been reported, Dr. Wermke said.

Study methods and results

The study included 107 patients. The median age was 60.0 years, and 57% were male. To be included, patients had to have advanced SCLC, large cell neuroendocrine carcinoma, or extrapulmonary neuroendocrine carcinoma, as well as test positive for DLL3 expression.

The drug was well tolerated: 86% of patients experienced at least one treatment-related adverse event: 59% with a grade 1-2 TRAE and 27% with a grade 3-5 TRAE. Cytokine release syndrome (CRS) occurred in 59% of patients, but just 2% were grade 3-5. TRAEs led to discontinuation in 4% of patients. Physicians were able to manage CRS with supportive care, steroids, and anti–interleukin-6 receptor antibodies.

The treatment showed signs of efficacy, with partial responses occurring in 18% of patients, stable disease in 23%, progressive disease in 45%, while 13% were not evaluable.

At doses of 90 mg/kg or above, partial response occurred in 25% of patients, stable disease in 27%, and progressive disease in 31%, while 13% were not evaluable. Similar patterns were seen across three tumor types.

Of 18 responders, 14 continued to be responders at the time of the presentation. The longest response lengths were 13.1 months, 10.7 months, and 9.4 months.

Dr. Wermke said that the responses were encouraging, particularly the duration of some responses.

“Having a small cell [lung cancer] patient responding to something for more than a year is extraordinary. It comes with side effects, which are usually seen during the first [doses]. After that, the drug is pretty well tolerable, and that is also something which distinguishes it from alternative second-line approaches,” he said.

Well tolerated, but take efficacy data with a grain of salt

The study was encouraging but should be treated with caution, according to Vamsidhar Velcheti, MD, who moderated the session where the research was presented.

“The toxicity profile is actually very promising and it’s still very early, but there’s certainly a lot of interest in DLL3-targeted [therapies]. We’ve seen some very exciting data with other assets in this category as well,” said Dr. Velcheti, director of thoracic oncology at NYU Langone Health, New York.

Phase 1 efficacy data can be tantalizing but often fails to hold up to further testing, according to Dr. Velcheti. “We’ve seen signals in phase 1 data before, and we’ve been burned. We saw really promising data with Rova-T, and the confirmatory trials were negative, – so we want to be cautiously optimistic,” said Dr. Velcheti.

He also pointed out that patient selection will be important for such studies, considering that SCLC patients often have a lot of comorbidities and the therapy’s potential for causing CRS.

Both Dr. Wermke and Dr. Velcheti have received funding from numerous pharmaceutical companies. Dr. Wermke has consulted with or advised with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck Therapeutics, Immatics, ISA Pharmaceuticals, Lilly, and Novartis.

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