LBL-024 Receives Breakthrough Therapy Designation in China for Extrapulmonary Neuroendocrine Carcinoma

The Center for Drug Evaluation of China’s National Medical Products Administration has granted breakthrough therapy designation to LBL-024 for the treatment of the patients with advanced extrapulmonary neuroendocrine carcinoma (EP-NEC) that has progressed after 2 or more lines of chemotherapy.¹

LBL-024 is an anti–PD-L1/4-1BB bispecific antibody that is currently being investigated in a phase 1/2 trial (NCT05170958) in patients with advanced malignant tumors and NEC.^1,2

“According to historical data from the China Drug Review Annual Report, only a few products are eligible for breakthrough therapy designation, and even fewer have been approved,” Charles Cai, MD, PhD, chief medical officer of Leads Biolabs, stated in a news release.¹ “The designation for LBL-024 is another proof of the robust research and development capabilities of Leads Biolabs, and it is also a major victory for Leads Biolabs’ insistence on focusing on the first-in-class product research and development strategy for the global market. Leads Biolabs will vigorously pursue the global clinical development of LBL-024, with the anticipation of offering more effective treatment options for patients with EP-NEC at the earliest opportunity.”

Findings from the phase 1/2 trial presented at the 2024 ASCO Annual Meeting showed that among patients with EP-NEC who underwent at least 1 tumor assessment (n = 45), the overall response rate (ORR) was 33.3%, with all responders achieving a partial response (PR).² The disease control rate (DCR) was 51.1%. In the overall population (n = 47), the PR, stable disease, and progressive disease rates were 31.9%, 17.0%, and 46.8%, respectively; 4.3% of patients were not evaluable.

At the recommended phase 2 dose (RP2D) of 15 mg/kg, LBL-024 elicited an ORR of 33.3% and a DCR of 48.5%.

The study enrolled patients at least 18 years of age with advanced malignant tumors who had progressed on prior standard-of-care therapy, had an ECOG performance status of 0 or 1, and had adequate organ function. In the phase 2b portion, patients were required to have EP-NEC as confirmed by central laboratory assessment and have received at least 2 prior lines of chemotherapy.

Phase 1 of the study utilized a 3+3 design where patients received LBL-024 once every 3 weeks at escalating doses ranging from 0.2 mg/kg to 25 mg/kg. The primary end points of this portion of the study were safety, tolerability, and determining the RP2D. Secondary end points included pharmacokinetics, immunogenicity, and efficacy.

Phase 2a included 4 arms, which enrolled patients with previously treated EP-NEC (arm 1); patients with biliary tract cancer previously treated with chemotherapy (arm 2); patients with pretreated non–small cell lung cancer with or without actionable alterations (arm 3); and those with malignancies previously treated with anti–PD-(L)1 therapy, such as hepatocellular carcinoma or esophageal squamous cell carcinoma (arm 4). The primary end point for phase 2a was ORR; secondary end points included safety, immunogenicity, duration of response (DOR), and progression-free survival (PFS).

Phase 2b specifically included patients with pretreated EP-NEC. ORR per independent review committee assessment served as the primary end point, and second end points consisted of DOR, PFS, DCR, and safety.

Additional data showed that for patients with EP-NEC treated across the study, the median DOR was 5.3 months. For those treated in the second line and in the third line or later, the median DOR was 4 months and 7 months, respectively. The overall median PFS was 2.8 months; the median PFS for those treated in the second line and those treated in the third line or later was 4.1 months and 2.7 months, respectively.

The median overall survival (OS) was not reached at a median follow-up of 8.5 months. The respective 6-month OS rates for the overall population, the second-line population, and the third-or-later-line population were 61.7%, 72.7%, and 52.0%.

Regarding safety for all treated patients (n = 175), the rates of any-grade treatment-emergent adverse effects (TEAEs), treatment-relates AEs (TRAEs), serious AEs, and serious TRAEs were 92.0%, 77.1%, 33.1%, and 16.6%, respectively. Grade 3 or higher AEs occurred in 39.4% of patients, and the rate of grade 3 or higher TRAEs was 20.6%. TRAEs led to dose interruptions and treatment discontinuation in 22.3% and 4.0% of patients, respectively. No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached in phase 1.

The most common TEAEs included anemia (any-grade, 33.1%; grade ≥ 3, 5.1%), increased aspartate aminotransferase (32.6%; 1.1%), increased alanine aminotransferase (27.4%; 0.6%), leukopenia (20.0%; 3.4%), hypoalbuminemia (16.6%; 0%), hyponatremia (16.0%; 1.7%), thrombocytopenia (14.3%; 2.3%), hypertriglyceridemia (14.3%; 0%), neutropenia (13.7%; 2.9%), hypokalemia (13.1%; 2.9%), asthenia (13.1%; 1.1%), proteinuria (13.1%; 0%), increased blood bilirubin (12.6%; 1.7%), decreased appetite (10.9%; 1.1%), and pyrexia (10.9%; 0.6%).

References

1. The CDE has granted breakthrough therapy designation to LBL-024, a bispecific antibody that targets PD-L1 and 4-1BB, developed by Leads Biolabs, for the treatment of extrapulmonary neuroendocrine carcinoma. News release. Leads Biolabs. October 9, 2024. Accessed October 9, 2024. https://en.leadsbiolabs.com/The-CDE-has-Granted-Breakthrough-Therapy-Designation-to-LBL-024-a-Bispecific-Antibody-that-Targets-PD-L1-and-4-1BB-Developed-by-Leads-Biolabs-for-the-Treatment-of-Extrapulmonary-Neuroendocrine-Carc-id48602756.html
2. Lu M, Zhang P, Luo S, et al. A novel and uniquely designed bispecific antibody (LBL-024) against PD-L1 and 4-1BB in patients with advanced malignant tumors and neuroendocrine carcinoma: a report of safety and robust efficacy of LBL-024 monotherapy in phase I/II, first-in-human, open-label, multicenter, dose escalation/expansion study. J Clin Oncol. 2024;42(suppl 16):4010. doi:10.1200/JCO.2024.42.16_suppl.4010