Continued zenocutuzumab treatment beyond progression in patients with <i>NRG1+</i> pancreatic cancer and cholangiocarcinoma: Analysis from the phase 2 eNRGy trial.

703 Background: While progressive disease (PD) is often considered a surrogate for treatment failure, continued therapy beyond progression may offer clinical benefit, particularly in cancers with limited effective treatment options. This approach may be justified in cases of mixed response, indolent progression, or isolated progression amenable to local intervention. Zenocutuzumab, a HER2×HER3 bispecific antibody that blocks HER3-mediated NRG1 signaling and HER2/HER3 dimerization, is the first and only targeted therapy for NRG1+ cancers (FDA approved for previously treated, advanced NRG1+ NSCLC and pancreatic adenocarcinoma [PDAC]). We report an analysis of patients with advanced NRG1+ PDAC and cholangiocarcinoma (CCA) who continued zenocutuzumab beyond progression. Methods: eNRGy is an ongoing, open-label, single-arm, phase 2 trial of zenocutuzumab in advanced NRG1+ cancers. Patients are ≥18 y, previously treated with or not a candidate for other therapy, ECOG PS ≤2, and have measurable or evaluable disease per RECIST v1.1. Zenocutuzumab (750 mg IV every 2 weeks) is administered until PD or unacceptable toxicity. Treatment can continue beyond PD when clinical benefit is considered possible based on investigator assessment. In this post hoc analysis, we report data from patients with gastrointestinal (GI) tumors who received ≥3 doses of zenocutuzumab post-PD. Results: As of June 2025, 17 patients with advanced NRG1+ GI tumors (PDAC n=12, CCA n=5) continued zenocutuzumab after initial PD. Treatment is ongoing in 1 patient. Median age was 53 y, 41% male, median time since metastatic diagnosis of 15.7 mo, and median of 2 prior systemic therapies (range 0–5). The ORR was 35% (1 CR, 5 PR, 8 SD, 3 PD). Patients remained on zenocutuzumab for a median total exposure duration of 11.0 mo (range 2.8–47.8 mo). Median exposure duration before and after PD was 9.1 mo (range 1.3–22.5 mo) and 2 mo (range 1.4–35.1 mo), respectively. Three patients remained on zenocutuzumab for &gt;1 y post-PD for 1.2 y (CCA; best objective response [BOR]: SD), 1.5+ y (CCA; ongoing; BOR: PR), and 2.9 y (PDAC; BOR: PR). Two patients received local radiotherapy to a focal lesion(s) after PD, allowing sustained benefit from ongoing zenocutuzumab for 2.5+ y (CCA; ongoing; 1.5+ y after PD) and 4.0 y (PDAC; 2.9 y after PD). Zenocutuzumab was well tolerated as monotherapy and with localized radiotherapy. Most common Grade 3–4 AEs were anemia and GGT increase (both 12%). Serious treatment-emergent AEs occurred in 35% of patients. No discontinuations were due to AEs. Conclusions: Continued treatment with zenocutuzumab beyond progression in select cases of NRG1+ PDAC and CCA was well tolerated and provided a clinically meaningful benefit, especially adjunct to local therapy for progressing lesions. This meaningful extension of therapy is important for patients with limited treatment options. Clinical trial information: NCT02912949 .