Advances With Various Therapies Targeting DLL3 in Lung Neuroendocrine Tumors

At the World Conference on Lung Cancer 2024 meeting in San Diego, California, data on DLL3 targeting in lung non-endocrine carcinoma (NETs) using antibody drug conjugates (ADCs) and T cell engagers were presented. Data highlighted promising results of DLL3 targeting cell therapy, despite still being in its early stages.

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Martin Wermke, MD from TU Dresden NCT/UCC Early Clinical Trial Unit Dresden in Germany, led the presentation, discussing results from a phase 1 trial of rovalpituzumab tesirine (Rova-T), which was the first DLL3 target agent to be explored in small cell lung cancer (SCLC). He noted that DLL3 is a market which is expressed on nearly all NETs occurring in the lung. However, it is virtually absent on all healthy human tissue in the adult setting.

“The idea, as with every ADC, is that you combine cytotoxic warhead [drug], a benzodiazepine compound, with a monoclonal antibody, targeting the antigenic choice and thereby bringing a lot of chemotherapeutic toxicity to the tumor while sparing normal tissue from the chemotherapeutic toxicity,” said Wermke.

Initially, the phase 1 study displayed that the overall response rate in the DLL3-high population among heavily pretreated individuals with SCLC was 35% leading it to be much better than other available chemotherapeutic compounds at the time of the study. Additionally, the median duration of response was also encouraging. “The initial results with Rova-T looked pretty encouraging,” Wermke noted.

However, in the phase 3 randomized, double-blinded, placebo-controlled MERU study (NCT03033511) that evaluated the efficacy of Rova-T compared to a placebo as maintenance therapy among patients with extensive-stage-SCLC after platinum-based chemotherapy displayed differing results. Wermke noted that the study demonstrated complete failure for Rova-T as it was not able to increase the median overall survival compared to the placebo.

Following, the phase 3 open-label, 2-to-1 randomized TAHOE study (NCT03061812) that compared Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC presented even worse overall survival. Wermke said that in this study Rova-T was associated with significant toxicity, with pleural effusions, pericardial effusions, edema, and phototoxicity reactions.

“It has to be said that DLL3 as a target was not the issue with Rova-T. The problem with Rova-T was the leakiness of the system leading to a lot of chemotherapy-associated toxicity in healthy tissue. That's why it's good to see that there are still ongoing trials testing novel DLL3 targeting ADCs, such as that one which is currently recruiting patients in the US and China,” said Wermke.

Shifting the discussion to bispecific T-cell engagers, Wermke noted that it’s a simple principle, taking the antigen binding moiety from a monoclonal antibody against DLL3 and combine it with another single chain variable fragment, targeting DLL3 on T-cells. In that process, it results in a molecule that takes a T-cell to the antigen of choice on the tumor, activating it and leading to immune elected cell death. However, when designing a molecule in such a simple way, it creates an inconvenience for the patient due to its short half-life, not meeting requirements for continuous infusion, Wermke said.

“That's why most of the T-cell engagers currently in clinical development use some kind of half-life extension. The first compound which has been introduced to the clinics—tarlatamab simply uses a full-length Fc fragment. Boehinger Ingelheim is trying to rebuild physiologic IgG molecule and Harpoon Therapeutics nowadays, fully owned by Merck, is trying different and very interesting approach,” said Wermke.

Evaluating the clinical data of all 3 compounds, the results for tarlatamab (Amgen) displayed a response rate of 23% with a median duration of response over a year, while BI-764532 (Boehinger Ingelheim) has an overall response rate of 90% and a median duration of response not yet reached. However, Harpoon has an overall response rate of 39% at selected doses, with a median duration of response not reported yet.

“If you look at all these trials producing similar results, I think they are clearly showing the potential of DLL3 T-cell engagers in SCLC, regarding large cell neuroendocrine carcinoma of the lung, which is a rare subtype and is as aggressive as SCLC,” said Wermke.

Notably, adverse effects of DLL3 T-cell engagers include neutropenia, taste abnormalities, cytokine release syndrome, and rare cases of immune-related adverse events.

“I hope it could convince you that DLL3 remains a valid therapeutic target in small cell and large cell neuroendocrine carcinoma of the lung. I think we are already in a stage where we can witness how DLL3 T-cell engagers are transforming our current treatment options in these diseases. The side effects are generally different from chemotherapy, but they're manageable. DLL3 targeting cell therapy, although it's still in its early days, has some promising results,” Wermke said.

REFERENCE

Wermke M. Novel Immunotherapy Options for Patients With Neuroendocrine Tumors, Targeting DLL3 in Lung NETs: TCE, ADCs and Beyond. 2024 World Conference on Lung Cancer, San Diego, California. Presented September 9, 2024. Accessed online September 11, 2024.