ZL-1310 Receives Orphan Drug Designation in Small Cell Lung Cancer

A phase 1a/1b trial showed that ZL-1310 elicited an ORR of 74%, all of which were PRs, in patients with SCLC who received prior chemotherapy.

ZL-1310, a first-in-class DLL3 antibody-drug conjugate, has been granted orphan drug designation by the FDA for the treatment of patients with small cell lung cancer (SCLC), according to a press release from the developer, Zai Lab.¹

Supporting data come from the monotherapy, dose-escalation portion of the ongoing open-label phase 1a/1b trial (NCT06179069)that evaluated the pharmacokinetics, safety, and tolerability of ZL-1310 with and without atezolizumab (Tecentriq) in patients with SCLC. Findings were presented at the EORTC-NCI-AACR (ENA) Symposium 2024 in October 2024.²

“Receiving an orphan drug designation for ZL-1310 recognizes its potential to treat patients with SCLC. These patients have an urgent need for innovative treatment options with improved efficacy, safety and ready access in tertiary care and community settings,” Rafael G. Amado, MD, president and head of Global Research and Development at Zai Lab, stated in the press release.¹ “ZL-1310 has demonstrated promising objective response rates [ORRs] and a favorable safety profile from the ongoing phase 1 trial in patients with recurrent SCLC recently disclosed. We look forward to continuing to advance the clinical development of this promising asset across lines of therapy in SCLC and other DLL3-expressing tumors.”

At a median follow-up of 2.4 months (range, 0.3-6.5), the ORR, including patients with unconfirmed responses, was 74% (95% CI, 48.8%-90.9%); 0 patients experienced complete responses, 74% (n = 14) of patients had partial responses (PRs), 16% (n = 3) had stable disease, and 10% (n = 2) had progressive disease. The median time to response was 1.38 months (range, 1.2-2.8). Of 6 evaluable patients with brain metastases at baseline, PRs were observed in all.

Additionally, 13 of the 14 patients to experience a response remained on study treatment at data cut-off: 2 of 3 patients in the 0.8 mg/kg cohort, 6 of 6 patients in the 1.6 mg/kg cohort, 1 of 1 in the 2.0 mg/kg cohort, and 4 of 4 in the 2.4 mg/kg cohort.

Duration of response (DOR) and progression-free survival (PFS) data were not mature at the time of data cut-off.

Median H-score at baseline was 92.5 (range, 0-260). In patients with a PR, the range was 5 to 260; a clinical tumor reduction was experienced by 1 patient who had an H-score of 2; and 1 patient treated with prior tarlatamab-dlle (Imdelltra) experienced a PR and had an H-score of 170.

A total of 25 patients with metastatic or extensive-stage SCLC who received at least 1 prior platinum-based chemotherapy regimen but less than 3 total prior regimens were enrolled into the trial. During part 1A, the dose-escalation phase, patients received 0.8 mg/kg (n = 4), 1.6 mg/kg (n = 8), 2.0 mg/kg (n = 6), or 2.4 mg/kg (n = 7) of intravenous ZL-1310 once every 3 weeks.

The overall median age was 67 years (range, 36-79); 72% of patients had an ECOG performance status of 1; 44% received 1 prior line of therapy, 36% received 2, and 20% received 3; and 92% received a prior anti–PD-L1 therapy.

Regarding safety, 96% of patients experienced any treatment-emergent adverse event (TEAE), and 84% experienced TEAEs related to ZL-1310. Of grade 3 or higher TEAEs, 40% of patients experienced at least 1, and 20% experienced toxicity related to ZL-1310. Serious TEAEs were experienced by 24% of patients, and 8% of those were related to ZL-1310.

TEAEs related to ZL-1310 lead to dose interruption, dose reduction, drug withdrawal, and death in 8%, 12%, 0%, and 0% of patients, respectively. There was 1 transient dose-limiting toxicity (DLT) reported in the 2.4 mg/kg cohort.

Overall, the most common TEAEs of any grade were nausea (48%), anemia (44%), neutrophil count decreased (40%), white blood cell count decreased (36%), and decreased appetite (28%). TEAEs of grade 3 or higher were anemia (4%), neutrophil count decreased (12%), white blood cell count decreased (4%), hyponatremia (4%), and platelet count decreased (4%).

Primary trial end points were DLTs, TEAEs, and serious TEAEs. Secondary end points included ORR, DOR, PFS, disease control rate, and overall survival, as well as pharmacokinetic parameters of ZL-1310, total antibody, and unconjugated payload.

References

1. Zai Lab receives orphan drug designation from the U.S. FDA for ZL-1310 (DLL3 ADC) for the Treatment of small cell lung cancer (SCLC). News release. Zai Lab. January 22, 2025. Accessed January 23, 2025. https://tinyurl.com/yc4tehn5
2. Spira A, Dowlati A, Zhao J, et al. Preliminary results from a phase Ia/Ib, open-label, multicenter study of ZL-1310, a DLL3-targeted ADC, to evaluate the safety, tolerability, and pharmacokinetics in subjects with small cell lung cancer - NCT06179069. EJC. 2024;211(suppl 1):114534. doi:10.1016/j.ejca.2024.114534