Triple meeting 2024 – Zai Lab impresses in small cell

DLL3 is back in vogue as a target, and Zai Lab just unveiled data that appear to trump the only approved therapy, Amgen’s T-cell engager Imdelltra. Zai Lab’s ADC ZL-1310 produced an ORR of 74%, according to phase 1 results presented at the Triple meeting on Thursday – which stacks up well against the 40% that supported Imdelltra’s US accelerated green light.

However, a closer look shows that nearly two thirds of the responses with ZL-1310 were unconfirmed, and the ORR sinks to a much less impressive 26% if only confirmed responses are counted.

74% or 26%

The phase 1 study, in second-line or later small-cell lung cancer not preselected for DLL3 expression, initially tested ZL-1310 monotherapy at 0.8mg/kg 1.6mg/kg, 2.0mg/kg and 2.4mg/kg. Among 19 evaluable patients there were 14 partial responses, Zai Lab said today.

However, the presentation at the Triple (EORTC-NCI-AACR) symposium showed that only five of these had been confirmed.

There’s still hope that ZL-1310 could outdo Imdelltra, as well as Merck & Co/Daiichi’s T-cell engager MK-6070: it seems that confirmed ORR could improve, with the nine unconfirmed responses ongoing at the 10 October cutoff date.

And, interestingly, there was a partial response in one patient who previously received Imdelltra and went on to get ZL-1310. Zai Lab shares traded up 15% on Thursday.

Cross-trial comparison of DLL3-targeting agents in SCLC

Note: all trials uncontrolled; *includes unconfirmed responses; **efficacy & safety data for 10mg (approved) dose only; ^SCLC pts only; ^^across all cohorts. Source: OncologyPipeline & Imdelltra label.

It’s also worth noting that the latest results with ZL-1310 come across all dose-escalation cohorts, so the response rate could improve further once the go-forward dose(s) are selected. Zai Lab also plans to test the project in combination with Roche’s PD-L1 blocker Tecentriq.

As for safety, ZL-1310 looks slightly better than both Imdelltra and MK-6070, with the caveat of low patient numbers. 20% of patients receiving ZL-1310 had grade 3 or higher treatment-related adverse events, with neutropenia most common. There were no treatment-emergent discontinuations or deaths. There was one dose-limiting toxicity of grade 4 transient neutropenia/thrombocytopenia in the 2.4mg/kg cohort.

Combos

Another SCLC contender is Merck & Daiichi’s B7-H3-targeting ADC ifinatamab deruxtecan, which recently produced an ORR of 55% in the high-dose cohort of the phase 2 Ideate-Lung01 trial. The companies are now testing a combination of MK-6070 with ifinatamab-dxd in phase 1/2.

Amgen also plans to evaluate Imdelltra alongside MediLink’s B7-H3-targeting ADC YL201. One question is whether such combinations could improve efficacy while avoiding unacceptable toxicity.

Options could soon be increasing for SCLC, which was for a long time a poorly served cancer. Still, ZL-1310 is one of only three clinical-stage DLL3-targeted ADCs, according to OncologyPipeline, the others being Systimmune’s BL-M14D1 and Shanghai Fudan-Zhangjiang's FZ-AD005 (both in phase 1 in China).

ADCs, and DLL3 in general, fell out of favour when AbbVie discontinued rova-T after failing to find a therapeutic window. The latest results support the idea that it was the poor design of rova-T that was the problem, although Zai Lab will have to prove this in more patients.