LBL-024, a bispecific antibody targeting PD-L1 and 4-1BB, has received FDA orphan drug designation for neuroendocrine cancer treatment.
The FDA granted ODD to LBL-024, an anti-PD-L1/4-1BB bispecific antibody being evaluated for the treatment of patients with neuroendocrine cancer.1
LBL-024 is a novel tetravalent bispecific antibody made to simultaneously target 2 critical immune checkpoint pathways: PD-L1 and 4-1BB. The agent works through a dual mechanism of action to enhance anti-tumor immune responses. When used as monotherapy, LBL-024 has shown a favorable overall response rate (ORR) and duration of response (DOR) in patients with previously treated extrapulmonary neuroendocrine cancers (EP-NEC).
Breakthrough therapy designation was granted to the agent in October 2024 by the Center for Drug Evaluation (CDE) of National Medical Products Administration (NMPA) in China. Further, LBL-024 received IND approval from the FDA on July 30, 2021 and the NMPA on September 9, 2021, respectively.
"LBL-024 obtained breakthrough therapy designation from CDE in October this year for the treatment of advanced EP-NEC. Our clinical data to date has been very encouraging, suggesting that LBL-024 could meaningfully improve outcomes of patients living with this devastating disease. The grant of ODD from FDA further underscores the exceptional potential of LBL-024 to address a critical gap in this therapeutic area,” said Charles Cai, MD, PhD, chief medical officer of Leads Biolabs, in a press release.
LBL-024 blocks the immunosuppressive PD-1/PD-L1 pathway and selectively costimulates 4-1BB. By lifting the PD-1/PD-L1-mediated immune suppression and intensifying 4-1BB-driven T-cell activation, LBL-024 synergistically boosts the immune system's ability to recognize and destroy tumor cells.
As of July 2024, a single-arm pivotal trial of LBL-024 for EP-NEC is ongoing, marking the first 4-1BB-targeted drug candidate globally to have reached pivotal stage, the company stated in its press release. A phase 1b/2 trial (NCT06157827) in combination with etoposide plus cisplatin or carboplatin in first-line EP-NEC is also ongoing.
Findings from a phase 1/2 trial (NCT05170958) of the agent were previously presented at the 2024 American Society of Clinical Oncology Annual Meeting.2 The study evaluated the agent in patients aged 18 years and older with advanced malignant tumors whose disease had progressed on prior standard-of-care therapy, had an ECOG performance status of 0 or 1, and had adequate organ function. In phase 2b of the study, those included must have had EP-NEC as confirmed by central laboratory assessment and have received at least 2 prior lines of chemotherapy.
Results showed that the ORR among patients with advanced EP-NEC who underwent at least 1 tumor assessment (n = 45) was 33.3%.2 All responders had a partial response (PR) and the disease control rate (DCR) was 51.1%.
In the overall population, which consisted of 47 patients, the PR rate was 31.9%, the stable disease rate was 17.0%, and the progressive disease rate was 46.8%, respectively. A total of 4.3% of patients were not evaluable.
When evaluating the recommended phase 2 dose (RP2D) of 15 mg/kg, the ORR was 33.3% and the DCR was 48.5%. At median follow-up of 8.5 months, DOR was a median of 5.3 months. In 26 patients evaluated for PD-L1 expression, patients with negative and positive PD-L1 expression benefited similarly from LBL-024.
Looking at safety, the rates of any-grade treatment-emergent adverse events (TEAEs), treatment-related AEs (TRAEs), serious TEAEs, and serious TRAEs among all treated patients (n = 175) were 92.0%, 77.1%, 33.1%, and 16.6%, respectively. A total of 39.4% of patients had grade 3 or higher AEs, and the rate of grade 3 or higher TRAEs was 20.6%.
Dose interruptions and treatment discontinuation due to TRAEs were seen in 22.3% and 4.0% of patients, respectively. There were no dose-limiting toxicities reported, and the maximum tolerated dose was not reached in phase 1 of the study.
TEAEs that were most common consisted of 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%).
"The receipt of ODD for LBL-024 from FDA represents a pivotal milestone in our global strategy. This designation not only enables LBL-024 to receive additional policy support and resource allocation during its development, accelerating its path to market and positioning it as a potential first-in-class therapeutic antibody targeting 4-1BB worldwide, but also provides us with greater market opportunities and avenues for growth on a global scale," said Xiaoqiang Kang, MD, PhD, founder, chairman, and chief executive officer of Leads Biolabs, in a press release.1
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