ASCO 2025 | DAREON-9: interim findings of obrixtamig and topotecan in pre-treated SCLC

DAREON-9 was a trial that tested the DLL3 bispecific T-cell engager, obrixtamig, in a population of pre-treated small cell lung cancer patients in combination with the chemotherapeutic topotecan. We relied on the fact that most small cell lung cancer patients do express DLL3 on the surface of their cells, while DLL3 is not expressed on healthy adult tissue and that’s why it’s an ideal immune target for T-cell engaging immunotherapy. Obrixtamig is an immunoglobulin-like novel T-cell engager that has been half-life prolonged. It has been already tested in a phase one monotherapy dose escalation trial. And now we tried whether it’s possible to combine it with topotecan, which is the standard chemotherapeutic used to treat small cell lung cancer patients failing platinum-based first-line therapy. We included a total of 25 patients, all of them being platinum-experienced, the vast majority also being progressive after PD-1, PD-L1 directed therapy. Patients received topotecan at the approved dose and obrixtamig as a step-in dose and then across three target dose levels which were increased from patient to patient. The good news was that the combination was pretty well tolerable. We did not see or we did not reach the maximum tolerated dose. Altogether there were three dose limiting toxicities, two in the dose escalation part and one at the target dose. Overall, we saw the expected cytopenias which are associated with topotecan. We saw a bit of cytokine release syndrome which is a known side effect of a bispecific T cell engager. However, this was somewhat lower than we expected from the monotherapy trials. Encouragingly, the response rate was quite high. So we saw an unconfirmed overall response rate of 70% with just one patient having progressive disease as primary response and even this patient had a shrinkage in its tumor lesions. For the 13 patients which already had a chance to confirm their response, the confirmed response rate remained stable at 69%. Given the short follow-up we currently have, we can’t say anything regarding the durability of these responses. I can only say from my experience we do have patients with durable responses for months ongoing at the time of this report.

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