Location
Philadelphia, PA
Start Date
17-4-2026 1:30 PM
End Date
17-4-2026 2:30 PM
Description
Background
Pancreatic adenocarcinoma is an aggressive malignancy with limited treatment options. In metastatic disease, first‑line regimens like FOLFIRINOX or gemcitabine plus nab‑paclitaxel provide modest survival benefits and are commonly limited by toxicity and disease progression.
Recent advances in precision oncology have identified genomic alterations in a subset of pancreatic cancers. Neuregulin‑1 (NRG1) gene fusions occur in < 1% of pancreatic adenocarcinomas and lead to activation of HER3 signaling through interaction with HER2, promoting tumor growth and survival.
Zenocutuzumab is a bispecific monoclonal antibody designed to target HER2 and HER3. By binding HER2 and preventing ligand-induced activation of HER3, zenocutuzumab disrupts NRG1-driven signaling while preserving HER2 receptor engagement for antibody-mediated targeting. In the eNRGy trial, zenocutuzumab achieved an objective response rate of approximately 42% in NRG1 fusion–positive pancreatic adenocarcinoma, with a median progression-free survival of 9.2 months and CA 19-9 decline in most patients.
Case Presentation
A 76-year-old woman with a history of GERD presented with progressive abdominal pain. MRI showed a 24×20mm pancreatic lesion and a 17mm lesion in the left hepatic lobe. Liver biopsy confirmed pancreatic adenocarcinoma. Molecular profiling showed microsatellite-stable disease. Next-generation sequencing identified APP–NRG1 pathogenic fusion, low tumor mutational burden, and low loss of heterozygosity.
First-line therapy with modified FOLFIRINOX was discontinued after one cycle due to toxicity. Imaging eight weeks later demonstrated enlargement of the pancreatic primary and hepatic metastasis, and new hepatic metastases. CA 19-9 rose from 24U/mL to 71U/mL.
Second-line treatment with gemcitabine plus nab-paclitaxel was initiated. After two cycles, imaging demonstrated stable disease. However, CA 19-9 increased to 119U/mL. Following five cycles, therapy was discontinued due to toxicity.
Restaging imaging seven weeks later demonstrated disease progression, with the pancreatic mass enlarging to 31×30×36mm and growth of hepatic metastases. CA 19-9 increased to 232U/mL. Given the presence of an NRG1 fusion and intolerance to cytotoxic therapy, zenocutuzumab was initiated.
Following zenocutuzumab initiation, the patient experienced rapid resolution of epigastric pain. CA 19-9 declined to 82U/mL after cycle one and 21U/mL after cycle two. Imaging after three cycles demonstrated reduction of the primary pancreatic tumor to 18×15mm and a decrease size in hepatic metastases. Adverse effects were limited to diarrhea and rash. The patient continues therapy with a sustained biochemical response and preserved performance status.
Discussion
This response is notable for several reasons. The patient had progression and rising tumor markers despite treatment with FOLFIRINOX and Gemcitabine plus nab-paclitaxel, yet experienced prompt and sustained response after initiation of zenocutuzumab. This occurred in a tumor with low mutational burden, low loss of heterozygosity, and microsatellite stability, supporting that clinical benefit was driven by inhibition of NRG1‑mediated HER2/HER3 signaling rather than nonspecific cytotoxic or immune mechanisms.
This case further supports that NRG1 fusion–positive pancreatic adenocarcinoma represents a biologically distinct subset with marked sensitivity to HER2/HER3-directed inhibition. It highlights the importance of molecular profiling in pancreatic adenocarcinoma, especially in patients with chemotherapy intolerance or rapid progression. Although NRG1 fusions are rare, their identification carries therapeutic implications and potential clinical benefit.
Embargo Period
6-3-2026
Included in
Significant response to third-line zenocutuzumab in metastatic NRG1 fusion–positive pancreatic adenocarcinoma: a case study
Philadelphia, PA
Background
Pancreatic adenocarcinoma is an aggressive malignancy with limited treatment options. In metastatic disease, first‑line regimens like FOLFIRINOX or gemcitabine plus nab‑paclitaxel provide modest survival benefits and are commonly limited by toxicity and disease progression.
Recent advances in precision oncology have identified genomic alterations in a subset of pancreatic cancers. Neuregulin‑1 (NRG1) gene fusions occur in < 1% of pancreatic adenocarcinomas and lead to activation of HER3 signaling through interaction with HER2, promoting tumor growth and survival.
Zenocutuzumab is a bispecific monoclonal antibody designed to target HER2 and HER3. By binding HER2 and preventing ligand-induced activation of HER3, zenocutuzumab disrupts NRG1-driven signaling while preserving HER2 receptor engagement for antibody-mediated targeting. In the eNRGy trial, zenocutuzumab achieved an objective response rate of approximately 42% in NRG1 fusion–positive pancreatic adenocarcinoma, with a median progression-free survival of 9.2 months and CA 19-9 decline in most patients.
Case Presentation
A 76-year-old woman with a history of GERD presented with progressive abdominal pain. MRI showed a 24×20mm pancreatic lesion and a 17mm lesion in the left hepatic lobe. Liver biopsy confirmed pancreatic adenocarcinoma. Molecular profiling showed microsatellite-stable disease. Next-generation sequencing identified APP–NRG1 pathogenic fusion, low tumor mutational burden, and low loss of heterozygosity.
First-line therapy with modified FOLFIRINOX was discontinued after one cycle due to toxicity. Imaging eight weeks later demonstrated enlargement of the pancreatic primary and hepatic metastasis, and new hepatic metastases. CA 19-9 rose from 24U/mL to 71U/mL.
Second-line treatment with gemcitabine plus nab-paclitaxel was initiated. After two cycles, imaging demonstrated stable disease. However, CA 19-9 increased to 119U/mL. Following five cycles, therapy was discontinued due to toxicity.
Restaging imaging seven weeks later demonstrated disease progression, with the pancreatic mass enlarging to 31×30×36mm and growth of hepatic metastases. CA 19-9 increased to 232U/mL. Given the presence of an NRG1 fusion and intolerance to cytotoxic therapy, zenocutuzumab was initiated.
Following zenocutuzumab initiation, the patient experienced rapid resolution of epigastric pain. CA 19-9 declined to 82U/mL after cycle one and 21U/mL after cycle two. Imaging after three cycles demonstrated reduction of the primary pancreatic tumor to 18×15mm and a decrease size in hepatic metastases. Adverse effects were limited to diarrhea and rash. The patient continues therapy with a sustained biochemical response and preserved performance status.
Discussion
This response is notable for several reasons. The patient had progression and rising tumor markers despite treatment with FOLFIRINOX and Gemcitabine plus nab-paclitaxel, yet experienced prompt and sustained response after initiation of zenocutuzumab. This occurred in a tumor with low mutational burden, low loss of heterozygosity, and microsatellite stability, supporting that clinical benefit was driven by inhibition of NRG1‑mediated HER2/HER3 signaling rather than nonspecific cytotoxic or immune mechanisms.
This case further supports that NRG1 fusion–positive pancreatic adenocarcinoma represents a biologically distinct subset with marked sensitivity to HER2/HER3-directed inhibition. It highlights the importance of molecular profiling in pancreatic adenocarcinoma, especially in patients with chemotherapy intolerance or rapid progression. Although NRG1 fusions are rare, their identification carries therapeutic implications and potential clinical benefit.