Zenocutuzumab-zbco Granted Accelerated Approval for Patients With NSCLC, Pancreatic Ductal Adenocarcinoma

Zenocutuzumab-zbco (Bizengri; Merus NV) was granted accelerated approval by the FDA for adults with unresectable, or metastatic non-small cell lung cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy, or advanced, unresectable, or metastatic pancreatic ductal adenocarcinoma (PDAC) harboring a NRG1 gene fusion with disease progression on or after prior systemic therapy.

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The decision is based off results from the eNRGy study (NCT02912949) where the treatment demonstrated favorable objective response rate (ORR) and duration of response (DOR). This makes zenocutuzumab-zbco the first approved therapy for NSCLC or pancreatic adenocarcinoma with an NRG1 gene fusion.^1,2

Zenocutuzumab-zbco is a bispecific antibody that targets and binds to HER2 and HER3 on the surface of malignant cells and tumor cells to prevent NRG1 from binding to HER3. Preclinical mammalian studies showed that zenocutuzumab-zbco decreases cell proliferation and signaling through the phosphoinositide 3-kinase-AKT-mammalian targeted rapamycin pathway. Additionally, in mouse models with NRG1-positive (NRG1+) disease, investigators observed antitumor activity in lung and pancreatic cancers, as well as a mediation of antibody-dependent cellular cytotoxicity.³

The multicenter, open label, multi-national, dose escalation, single agent eNRGy clinical trial evaluated the safety, tolerability, pharmacokinetics, partial discharge, immunogenicity, and anti-tumor activity of zenocutuzumab-zbco.¹ The study population consisted of adults with advanced or metastatic NRG1+ NSCLC (n=64), or advanced or metastatic NRG1+ PDAC (n=30) who had disease progression following standard of care treatment. All patients received 750 mg of zenocutuzumab-zbco intravenously once every 2 weeks, the recommended dose for this therapy, until disease progression or unacceptable toxicity.^2-4

Next generation sequencing was used to identify positive NRG1 gene fusion status in patients. The primary end points were ORR and DOR, which were determined by blinded independent central review, according to Response Evaluation Criteria in Solid Tumors v1.1.³

Patients with NRG1+ PDAC (median age 49 years; 43% female; 87% White, 7% Asian, 3.3% Black or African American), achieved an ORR of 42.4% (95% CI, 25.5%-60.8%), which included complete response and partial responses of 3% and 39%, respectively. In the NRG1+ NSCLC group, patients demonstrated an ORR of 33% (95% CI, 22%-46%).^3,4

The median DOR was 9.1 months (95% CI, 5.5-12.0) with a 6-month DOR rate of 71% (95% CI, 41%-88%) in patients with PDAC. The median duration of treatment exposure and time to response were 9.4 months (range, 1.0-34.3) and 1.8 months (range, 1.6-5.4). Patients with NRG1+ NSCLC achieved a median DOR of 7.4 months (95% CI, 4.0-16.6).^3,4

The most common treatment-related adverse effects (≥10%) were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities (≥10%) included increased gamma-glutamyl transferase, decreased hemoglobin, decreased sodium, and decreased platelets. Zenocutuzumab-zbco has a box label warning disclosing risk of embryo-fetal toxicity.^2-4

“The FDA approval of [zenocutuzumab-zbco] marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion. I have seen firsthand how treatment with [zenocutuzumab-zbco] can deliver clinically meaningful outcomes for patients,” said Alison Schram, MD, an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and a principal investigator for the ongoing eNRGy trial, in a press release. “I am extraordinarily grateful for the patients and families who participated in the trial.”³

REFERENCES

1. A study of zenocutuzumab (mcla-128) in patients with solid tumors harboring an nrg1 fusion (enrgy). ClinicalTrials.gov Identifier: NCT02912949. Updated October 31, 2024. Accessed December 5, 2024. https://clinicaltrials.gov/study/NCT02912949

2. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma. FDA. December 4, 2024. Accessed December 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic

3. Merus announces fda approval of bizengri® (zenocutuzumab-zbco) for nrg1+ pancreatic adenocarcinoma and nrg1+ non–small cell lung cancer (nsclc) based on safety and efficacy data from the enrgy study. Merus. December 4, 2024. Accessed December 5, 2024. https://ir.merus.nl/news-releases/news-release-details/merus-announces-fda-approval-bizengrir-zenocutuzumab-zbco-nrg1

4. FDA grants accelerated approval to zenocutuzumab for nrg1+ nsclc and pancreatic adenocarcinoma. OncLive. December 4, 2024. Accessed December 5, 2024. https://www.onclive.com/view/fda-grants-accelerated-approval-to-zenocutuzumab-for-nrg1-nsclc-and-pancreatic-adenocarcinoma