Zenocutuzumab Addresses High Unmet Need in NRG1-Positive NSCLC and Pancreatic Cancer

Alison Schram, MD

Patients with non–small cell lung cancer (NSCLC) and pancreatic adenocarcinoma who harbor rare NRG1 fusions now have an efficacious option after progression on standard-of-care (SOC) therapies following the December 4, 2024, FDA accelerated approval of zenocutuzumab-zbco (Bizengri), according to Alison Schram, MD.¹

The bispecific antibody became the first FDA-approved systemic therapy for patients with NRG1 fusion–positive pancreatic adenocarcinoma or NSCLC,¹ and it is the first and only agent to receive an indication from the FDA for the treatment of adults with advanced, unresectable, or metastatic NRG1 fusion–positive pancreatic adenocarcinoma or NSCLC who experienced disease progression on or after prior systemic therapy.²

“This is an exciting approval in a patient population that truly has a high unmet need, and I hope that many patients will benefit from this therapy,” Schram said in an interview with OncLive®. “Zenocutuzumab is extremely well tolerated with [few] grade 3 or greater toxicities occurring in patients. Infusion-related reactions can occur, but typically these are grade 1, manageable, and patients are able to continue treatment.”

Findings from the phase 2, multicenter, open-label, multicohort eNRGy study (NCT02912949), which supported the approval, showed that the agent was well tolerated as only 3% of patients in the NSCLC cohort (n = 99) discontinued zenocutuzumab due to adverse effects (AEs); dyspnea, pneumonitis and sepsis led to discontinuation in 3 patients.³ In the NSCLC and pancreatic cancer cohorts, AEs led to dose interruptions (29% and 33%) and serious AEs occurred (25% and 23%), respectively. The most common any-grade AEs in the NSCLC cohort were diarrhea (25%) and musculoskeletal pain (23%), and the most common AEs in the pancreatic cancer cohort were diarrhea (36%), musculoskeletal pain (28%), nausea (23%), vomiting (23%), and fatigue (21%).

Furthermore, zenocutuzumab yielded encouraging efficacy in patients. The overall response rate (ORR) was 33% (95% CI, 22%-46%) in patients with NSCLC who previously received systemic therapy (n = 64), which was comprised of a 1.6% complete response (CR) rate and 31% partial response (PR) rate. The median duration of response (DOR) was 7.4 months (95% CI, 4.0-16.6) and 43% of patients experienced a response for at least 6 months. In the pancreatic cancer cohort, patients treated with zenocutuzumab (n = 30) achieved an ORR of 40% (95% CI, 23%-59%) comprised of a 3.3% CR rate and 37% PR rate. The DOR ranged from 3.7 months to 16.6 months, and 67% of patients experienced a response for at least 6 months.

In the interview, Schram detailed the significance of findings with zenocutuzumab from eNRGy. Schram is an assistant attending physician, gynecologic medical oncologist, and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: How does the approval of zenocutuzumab address an unmet need for patients with NRG1-positive cancers?

Schram: NRG1 fusions are oncogenic drivers found across solid tumors, most commonly in KRAS wild-type pancreatic cancer and driver-negative NSCLC. In NSCLC, patients with NRG1 fusions have a poor prognosis and respond poorly to SOC chemoimmunotherapy. In pancreatic cancer, effective treatment options are very limited after first- and second-line chemotherapy. Zenocutuzumab is a bispecific HER2/HER3 antibody that is the first targeted therapy approved for patients with NRG1-positive [pancreatic and non–small cell lung] cancers, a group of patients [who are] in dire need of better therapies with improved outcomes.

What were the key findings from the pancreatic cancer cohort of the eNRGy trial?

In the pancreatic cancer cohort, among the [30] evaluable patients, [40%] had an ORR by RECIST version 1.1 criteria. The median DOR [ranged from 3.7 to 16.6 months], and [most] patients had a CA 19-9 [level] decline of greater than 50% from baseline.

There are currently no approved therapies after first- and second-line chemotherapy for patients with pancreatic cancer. The durability [of responses seen] in this heavily pretreated population are very clinically meaningful and compare favorably to chemotherapy and supportive care. Zenocutuzumab offers an efficacious and well tolerated option for patients.

What findings are important to note from the lung cancer cohort of eNRGy?

In the [64] patients with driver-negative NSCLC, the ORR was [33]% and the median DOR was [7.4] months. The clinical trial required that patients must have been treated with prior chemotherapy [or] be ineligible for or declined standard chemoimmunotherapy. Therefore, this is the appropriate context for zenocutuzumab [to be given in]. That being said, retrospective studies showed that these patients respond very poorly to standard therapy. Further research is needed to optimize the sequence of treatments in this patient population.

What is the importance of expanding the practice of RNA-based testing to identify patients with NRG1 fusions?

This is a very important point. NRG1 fusions are typically only detected on DNA-based panels when the fusion partner is tiled on the panel. RNA-based testing is superior for detecting these fusions, which can be often missed on DNA-based testing, so it’s very important to get RNA testing done, particularly in patients who are more likely to have NRG1 fusions like [those with] driver-negative lung cancers and KRAS wild-type pancreatic cancers.

References

1. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma. FDA. December 4, 2024. Accessed January 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic
2. 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. News release. Merus. December 4, 2024. Accessed January 15, 2025. https://ir.merus.nl/news-releases/news-release-details/merus-announces-fda-approval-bizengrir-zenocutuzumab-zbco-nrg1
3. Bizengri. Prescribing information. Merus; 2024. Accessed January 14, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761352s001lbl.pdf