BIZENGRI Solution for injection Ref.[113877] Active ingredients: Zenocutuzumab

Zenocutuzumab-zbco is a bispecific antibody that binds to the extracellular domains of HER2 and HER3 expressed on the surface of cells, including tumor cells, inhibiting HER2:HER3 dimerization and preventing NRG1 binding to HER3. Zenocutuzumab-zbco decreased cell proliferation and signaling through the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. In addition, zenocutuzumab-zbco mediates antibody-dependent cellular cytotoxicity (ADCC). Zenocutuzumab-zbco showed antitumor activity in mouse models of NRG1 fusion-positive lung and pancreatic cancers.

The exposure-response relationship and time-course of pharmacodynamic response for zenocutuzumab-zbco have not been fully characterized.

Zenocutuzumab-zbco pharmacokinetic parameters are expressed as mean unless otherwise specified. Zenocutuzumab-zbco exposure increases proportionally over a dose range from 480 mg (0.6 times the approved recommended dosage) to 900 mg (1.2 times the approved recommended dosage). The median time to steady state of zenocutuzumab-zbco concentrations is 8 weeks and the median accumulation ratio is 1.6-fold at the approved recommended dosage.

Distribution

Zenocutuzumab-zbco volume of distribution is 6 L (CV 18%).

Elimination

The steady state zenocutuzumab-zbco half-life is 8 days (SD ±1.3 days) with a clearance of 22 mL/h (CV 37%).

Metabolism

Zenocutuzumab-zbco is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations

No clinically significant differences in the pharmacokinetics of zenocutuzumab-zbco were observed based on age (22 to 88 years), sex, race [White or Asian], body weight (38 to 126 kg), albumin level (20 to 49 g/L), mild or moderate renal impairment (creatinine clearance (CLcr) 30 to 89 mL/min), and mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN).

The pharmacokinetics of zenocutuzumab-zbco in patients with moderate to severe hepatic impairment (total bilirubin >1.5 to 3 times ULN with any AST) or severe renal impairment (CLcr <30 mL/min) is unknown

No studies have been performed to assess the carcinogenic or mutagenic potential of zenocutuzumab-zbco.

Animal fertility studies have not been conducted with zenocutuzumab-zbco.

14.1 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Non-Small Cell Lung Cancer

The efficacy of BIZENGRI was evaluated in the eNRGy study (NCT02912949) a multicenter, open-label, multi-cohort clinical study. The study enrolled adult patients with advanced or metastatic NRG1 fusion-positive NSCLC who had disease progression following standard of care treatment for their disease. Identification of positive NRG1 gene fusion status was prospectively determined based on next generation sequencing (NGS) assays performed at local laboratories or central laboratories. Patients received BIZENGRI as an intravenous infusion, 750 mg every 2 weeks, until unacceptable toxicity or disease progression. Tumor assessments were performed every 8 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) as determined by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Efficacy was evaluated in 64 patients with NRG1 fusion-positive NSCLC previously treated with systemic therapy enrolled in eNRGy.

The trial population characteristics were: median age 63.5 years (range: 32 to 86) with 10% of patients ≥65 years of age; 64% female; 56% Asian, 33% White, 3.4% Black or African American, and 11% other races or not reported; none were Hispanic or Latino; baseline ECOG performance status of 0 or 1 (97%) or 2 (3%) and 98% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1 to 6); 95% had prior platinum chemotherapy and 64% had prior anti-PD-1/PD-L1 therapy. A total of 54 patients (84%) had an NRG1 gene fusion detected by RNA-based NGS that may include DNA sequencing and 9 (14%) had an NRG1 gene fusion detected by DNA-based NGS.

Efficacy results are summarized in Table 7 and Table 8.

Table 7. Efficacy Results for Advanced Unresectable or Metastatic NRG1 Fusion-Positive NSCLC in the eNRGy Study:

¹ Confirmed overall response rate assessed by BICR
² Based on observed duration of response

Table 8. Efficacy Results by NRG1 Gene Fusion Partner in NRG1 Fusion-Positive NSCLC Patients in the eNRGy Study:

¹ Fusion partners identified in this primary analysis set (n=64) may not represent all potential fusion partners.
PR=partial response; PD=progressive disease; NA=not applicable; “+” indicates ongoing response-

14.2 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Pancreatic Adenocarcinoma

The efficacy of BIZENGRI was evaluated in the eNRGy study (NCT02912949), a multicenter, open-label, multi-cohort clinical study. The study enrolled 30 adult patients with advanced or metastatic NRG1 fusion-positive pancreatic adenocarcinoma who had disease progression following standard of care treatment. Identification of an NRG1 gene fusion was prospectively determined in local laboratories using next generation sequencing (NGS). Patients received BIZENGRI as an intravenous infusion, 750 mg every 2 weeks, until unacceptable toxicity or disease progression. Tumor assessments were performed every 8 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) as determined by a blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

The trial population characteristics were: median age 49 years (range: 21 to 72) with 10% of patients ≥65 years of age; 43% female; 87% White, 7% Asian, 3.3% Black or African American, and 3.3% other races or not reported; 3.3% were Hispanic or Latino; baseline ECOG performance status of 0 (53%) or 1 (47%) and all patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 0 to 5); 97% had prior systemic therapy with FOLFIRINOX, gemcitabine/taxane-based therapy, or both. A total of 27 patients (90%) had an NRG1 gene fusion detected by RNA-based NGS that may include DNA sequencing and 3 (10%) had an NRG1 gene fusion detected by DNA-based NGS.

Efficacy results are summarized in Table 9 and Table 10.

Table 9. Efficacy Results for Advanced Unresectable or Metastatic NRG1 Fusion-Positive Pancreatic Adenocarcinoma in the eNRGy Study:

¹ Confirmed overall response rate assessed by BICR.
² Based on observed duration of response

Table 10. Efficacy Results by NRG1 Gene Fusion Partner in NRG1 Fusion-Positive Pancreatic Adenocarcinoma Patients in the eNRGy Study:

¹ Fusion partners identified in this primary analysis set (n=30) may not represent all potential fusion partners.
PR=partial response; PD=progressive disease; SD=stable disease; NA=not applicable; “+” indicates ongoing response