Triple meeting 2025 – Zai discloses pivotal DLL3 plans

Details of a pivotal trial of Zai Lab’s DLL3-targeting ADC zocilurtatug pelitecan have been revealed on clinicaltrials.gov, and notably the study will include Amgen’s Imdelltra as an option in the control arm.

ApexOnco understands that 1.2mg/kg and 1.6mg/kg doses will be taken into the phase 3 study, in relapsed small-cell lung cancer; Zai had once hoped to focus solely on 1.6mg/kg. The company announced the start of its pivotal trial during the Triple (EORTC-NCI-AACR) symposium, where it also presented updated results from its phase 1 study of the agent.

The headline finding is a 68% overall response rate among 19 second-line patients given 1.6mg/kg. This number, which includes confirmed and unconfirmed responses, represents a deterioration from the 79% ORR reported at ASCO among 14 patients in the same cohort. However, if it holds up it still could give zoci-P an edge over Imdelltra, which gained FDA accelerated approval based on a 40% ORR in the uncontrolled Dellphi-301 trial.

But other DLL3-targeting agents are coming, including Ideaya/Jiangsu HengRui’s rival ADC IDE849, which recently looked potentially even more efficacious in relapsed SCLC, and Roche’s RG6810, licensed from Innovent. Suzhou Zelgen, meanwhile, is developing a DLL3 x DLL3 T-cell engager, alveltamig, which has just gone into a Chinese phase 3.

Pivotal details

Zai will therefore hope to keep ahead of the chasing pack, and investors have finally got the phase 3 details they’ve been waiting for. The new trial, known as ZL-1310-003 and slated to begin at the end of November, will enrol 665 patients globally, including in North America, Asia and Europe.

Subjects can either be second line, following platinum-based chemo, or third line, following Imdelltra. The study will compare zoci-P versus investigator’s choice of Imdelltra, Zepzelca, topotecan or amrubicin. Zai Lab previously played down the importance of Imdelltra’s potential inclusion here, saying that even if this was an option Imdelltra use in the study probably wouldn’t be high, given that it’s not available in many countries.

However, the FDA might want to see how zoci-P fares against Imdelltra, with Amgen’s drug looking likely to gain full approval soon, based on the Dellphi-304 trial.

Full approval of Imdelltra could also hit Zai’s plans to seek accelerated approval of zoci-P; as previously indicated, the phase 3 trial has co-primary endpoints of ORR and overall survival.

Triple data

At least on a cross-trial basis, the signs look good for Zai. As well as the 68% ORR with the 1.6mg/kg dose of zoci-P, at the Triple meeting Zai also disclosed a median duration of response of 6.1 months, and a median PFS of 5.4 months across all doses and all lines of therapy. In Dellphi-304, Imdelltra produced mPFS of 4.2 months.

Zai Lab has also long claimed that zoci-P, which it licensed from Medilink, could be safer than Imdelltra; the Amgen drug has a black box warning for cytokine release syndrome and neurologic toxicity including ICANS.

In Zai’s phase 1 study, grade 3 or higher treatment-related adverse events were seen in 13% of patients receiving the 1.6mg/kg dose, and serious TRAEs in 9%. No patients discontinued this dose because of toxicity; however, there were five discontinuations at higher dose levels.

There were also two cases of pneumonitis and interstitial lung disease in patients receiving 1.2mg/kg or 1.6mg/kg; however, both were grade 1.

Zai also plans to start pivotal trials of zoci-P in first-line SCLC and neuroendocrine carcinoma next year, and more details on these will be eagerly awaited.