World Lung 2025 – Ideaya challenges Zai Lab

Zai Lab is leading the increasingly crowded anti-DLL3 ADC field, but now it has a new challenger in Ideaya. A late-breaking presentation at the World Conference on Lung Cancer on Sunday shows Ideaya’s IDE849, licensed from Jiangsu HengRui, producing early data in relapsed small-cell lung cancer that look in line with results with Zai’s zocilurtatug pelitecan.

There are the usual caveats about cross-trial comparisons, and both assets have much to prove as they chase down Imdelltra, Amgen’s approved DLL3-targeting T-cell engager. But there now look to be two legitimate ADC contenders – and Roche is also jostling for position here, via a deal with Innovent over IBI3009 (now known as RG6810).

Safety first

There are a few reasons to be caution about IDE849, previously known as SHR-4849, which Ideaya licensed outside China for $75m up front. First, the HengRui-sponsored phase 1 trial presented at World Lung only enrolled Chinese patients, so it can be questioned whether the findings are applicable to a global population.

Second, the incidence of grade 3 or higher adverse events looked relatively high, at 37%, the most common being reductions in white blood cells. There was also a dose-limiting toxicity of grade 4 decreased platelet count at 4.2mg/kg, the highest of five doses tested.

On the positive side, there were no treatment-related discontinuations or deaths.

As for efficacy, at a cutoff date of 28 February there were 25 partial responses among 42 evaluable SCLC patients, giving an ORR of 60% (the trial also included a handful of patients with neuroendocrine carcinoma).

However, only 14 of these responses were confirmed. Still, more than a third of patients had less than 12 weeks’ follow-up, making it possible that some unconfirmed responses could later be confirmed.

The results are less impressive than the 73% ORR that HengRui reported among 11 SCLC patients last year; however, that's probably to be expected with greater patient numbers. 

The data also echo those seen with Zai’s zoci-P, most recently at ASCO. In that project’s global phase 1 study there was a 51% ORR across doses – but this dropped to 37% if only confirmed responses were counted. That company is focused on a 1.6mg/kg dose, which produced a confirmed ORR of 57%, but among a small sample of 14 second-line patients.

Cross-trial comparison of DLL3-targeting ADCs in relapsed SCLC

Notes: both trials uncontrolled, both datasets across various doses; *confirmed + unconfirmed responses. Source: OncologyPipeline, ASCO & WCLC.

Zai has previously said that zoci-P, previously known as ZL-1310 and which it licensed from MediLink, could be safer and at least as efficacious, if not better than Imdelltra – and Ideaya likely hopes to show this with IDE849, too.

Imdelltra has produced a 35-40% ORR, but its label carries warnings of cytopenias, infections and hepatotoxicity. Furthermore, patients must be closely monitored because of the risk of cytokine release syndrome. 

Still, Amgen’s confirmatory Dellphi-304 trial shifted from monitoring patients for 48 hours in hospital, to outpatient monitoring over six to eight hours. And the ADCs don’t seem immune from cytopenias either.

There are also questions about whether Zai will be able to file for accelerated approval of zoci-P, as planned, with Imdelltra now seemingly headed for full approval following strong results from Dellphi-304.

Ideaya has said it's started a US phase 1 trial of IDE849 in SCLC, although this doesn't yet appear to have been listed on clinicaltrials.gov. With the ideal dose of the project still being nailed down, the group has a way to go – but for a relatively modest outlay it looks to have secured a decent DLL3 contender.