FDA Approves First and Only Systemic Therapy for NRG1+ Lung, Pancreatic Cancers

The FDA granted accelerated approval to zenocutuzumab-zbco (Bizengri) as the first systemic therapy for patients with non-small cell lung cancer (NSCLC) or pancreatic adenocarcinoma (PDAC) harboring an NRG1 gene fusion.¹

The FDA granted accelerated approval to zenocutuzumab-zbco as the first systemic therapy for patients with lung or pancreatic cancers harboring an NRG1 gene fusion.

Previously, the biologics license application of zenocutuzumab was granted priority review in May 2024, and the agent was granted breakthrough therapy designation in July 2023.

Trial Support for Approval

The phase 1/2 eNRGy trial investigating the safety and antitumor activity of zenocutuzumab supports this approval. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), determined by blinded independent central review according to RECIST v1.1. For patients with NSCLC, the ORR was 33% (95% CI, 22%-46%). The median DOR was 7.4 months in these patients (95% CI, 4.0 -16.6). For those with pancreatic adenocarcinoma, the ORR was 40% (95% CI, 23%-59%) and the DOR was 3.7 months to 16.6 months.

For safety, the most common adverse events (≥10%) included diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities (≥10%) most commonly seen were increased gamma-glutamyl transferase, decreased hemoglobin, decreased sodium, and decreased platelets.

eNRGy Trial Data Readouts

Data from this trial were also presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2021 and 2022, as well as at the European Society for Medical Oncology (ESMO) 2023 Congress.

According to data presented at ASCO, zenocutuzumab led to an objective response rate (ORR) of 34% (95% CI, 24%-46%) by investigator assessment and RECIST v1.1 criteria at a median follow-up of 6.3 months in 79 patients with previously treated advanced NRG1+ cancers.2 Additionally, the median time to response (TTR) was 1.8 months, and the median duration of response (DOR) was 9.1 months (95% CI, 7.4-not reached).

“Zenocutuzumab is highly effective in pretreated NRG1 fusion-positive pancreatic cancer, with rapid and durable responses,” said Alison M. Schram, MD, lead study author and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, during a presentation of the data. “There is activity across multiple NRG1 fusion-positive cancer types and an extremely well-tolerated safety profile.”

Data presented at ESMO showed that zenocutuzumab delivered an ORR of 37.2% (95% CI, 26.5%-48.9%) and a clinical benefit rate (CBR) of 61.5% (95% CI, 49.8%-72.3%) in patients with NRG1+ NSCLC.

About the Phase 1/2 eNRGy Trial

eNRGy is an open-label, multicenter, dose-escalation study of zenocutuzumab in patients with solid tumors with a NRG1 fusion.3 The primary end points are ORR and DOR. Secondary end points include CBR, TTR, safety, tolerability, pharmacokinetics, overall survival, and progression-free survival.

Patients with at least 1 measurable lesion, an ECOG performance status of 0 to 2, an estimated life expectancy of at least 12 weeks, resolved toxicities from prior therapies, and adequate laboratory levels were eligible for participation in the trial. Patients who were pregnant or lactating, had a known HIV or hepatitis infection, had leptomeningeal metastases, or had a previous or concurrent malignancy were not eligible for enrollment in the study.

The recommended phase 2 dose is 750 mg, which was administered every 2 weeks in patients with both NSCLC and PDAC.

REFERENCES:

1. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma. News release. FDA. December 4, 2024. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic?utm_medium=email&utm_source=govdelivery

2. Schram AM, Goto K, Kim DW, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol. 2022;40(suppl 16):105. doi:10.1200/JCO.2022.40.16_suppl.105

3. A study of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy). ClinicalTrials.gov. Updated January 17, 2024. Accessed May 7, 2024. https://clinicaltrials.gov/study/NCT02912949