Partner Therapeutics, Inc. has unveiled new post hoc data from the eNRGy trial indicating that zenocutuzumab, a bispecific antibody targeting HER2 and HER3, may offer continued clinical benefit in patients with NRG1 fusion–positive pancreatic adenocarcinoma and cholangiocarcinoma, even after conventional disease progression. Presented at the 2026 ASCO Gastrointestinal Cancers Symposium, the findings suggest a sustained therapeutic role for zenocutuzumab beyond radiographic progression in this biomarker-defined subgroup of gastrointestinal cancers

This new analysis underscores a broader clinical challenge: standard progression metrics may not fully capture the benefit of targeted therapies in rare, genomically driven cancers. In a field where survival gains are typically measured in months, any evidence of prolonged disease control post-progression is clinically and biologically noteworthy.

What this reveals about HER3 signaling as a therapeutic vulnerability in fusion-driven GI tumors

The eNRGy trial evaluated zenocutuzumab in a small subset of 17 patients with advanced NRG1+ GI malignancies — 12 with pancreatic adenocarcinoma and 5 with cholangiocarcinoma — who continued receiving therapy despite disease progression. Progression patterns included oligoprogression, mixed responses, or otherwise indolent disease biology. Patients received at least three additional doses of therapy beyond progression.

The post-progression overall response rate (ORR) was 35%, including one complete response and five partial responses. Eight patients achieved stable disease, and the clinical benefit rate — defined as complete/partial response or stable disease lasting ≥24 weeks — was 65%. Median post-progression treatment duration was two months, with some patients exceeding one or even two years of continued therapy

These results strengthen the case for HER3 inhibition as a biologically relevant strategy in NRG1-driven tumors. Unlike more common fusion-driven cancers (e.g., ALK or ROS1), NRG1 fusions encode chimeric ligands, not receptors. These ligands hyperactivate HER3 through HER2/HER3 heterodimerization, fueling tumor growth via downstream PI3K and MAPK signaling. Zenocutuzumab is designed to disrupt this interaction directly, suggesting that even in the face of initial radiographic progression, HER3 blockade may suppress residual oncogenic signaling in indolent or heterogeneous disease.

Industry analysts tracking the HER family receptor space view this as a mechanistically consistent outcome, drawing parallels with other contexts where suppression of a key signaling axis may delay progression despite partial resistance or clonal evolution. In pancreatic cancer, where actionable mutations are rare and systemic therapies offer limited durable control, HER3 remains one of the few viable targets in genomically enriched subpopulations.

Why treatment beyond progression could matter in biomarker-defined populations

The practice of continuing therapy after progression — known as treatment beyond progression (TBP) — is not without precedent. In NSCLC, breast cancer, and even certain colorectal cancer subtypes, TBP is often pursued in the setting of targeted agents when progression is localized or indolent. In the case of zenocutuzumab, the new eNRGy data extend this logic into previously underexplored territory: pancreatic and biliary tract cancers with NRG1 fusions.

Clinicians watching the ASCO GI 2026 presentation noted the rarity of durable disease control in these indications, especially after prior lines of therapy. Pancreatic cancer has a five-year survival rate under 12%, and options beyond first-line FOLFIRINOX or gemcitabine-nab-paclitaxel are often palliative rather than disease-modifying. Biliary tract cancers fare little better, with high resistance to systemic chemotherapy and limited availability of targeted treatments outside FGFR2 and IDH1 fusions.

The durability of zenocutuzumab in a post-progression context suggests a potential role for the drug as functional maintenance — where it may hold disease in check even if RECIST criteria indicate technical progression. That distinction is increasingly relevant in molecular oncology, where volumetric imaging may not always capture dynamic or spatial heterogeneity in treatment response.

Still, this strategy may not apply universally. The data were drawn from a subset of patients deemed clinically appropriate to continue therapy, introducing selection bias. Moreover, the study did not define a molecular signature for resistance, and longitudinal biopsies were not reported, leaving the underlying biology of post-progression benefit unclear.

What regulatory and confirmatory trial risks still exist for zenocutuzumab

Zenocutuzumab (BIZENGRI) received accelerated approval from the U.S. Food and Drug Administration in December 2024 for the treatment of adults with unresectable or metastatic NRG1 fusion-positive NSCLC and pancreatic adenocarcinoma, after progression on prior systemic therapy. This approval was based on ORR and duration of response, not survival endpoints, meaning continued approval remains conditional on confirmatory evidence

The eNRGy trial is not currently positioned as a confirmatory study for full approval. While the new post hoc analysis adds weight to zenocutuzumab’s long-term clinical value, regulators are unlikely to accept subgroup or post-progression data as substitutes for randomized evidence. Without a clear path to confirmatory trials — particularly in rare subpopulations — there is a risk that accelerated approval could be revoked if future trials underperform.

Industry observers note that one way to mitigate this risk is through basket or platform trials that capture multiple fusion-driven cancers with overlapping mechanisms, such as HER3 activation or NRG1 ligand overexpression. This approach could not only generate broader efficacy data but also support expanded indications in cholangiocarcinoma or other rare GI tumors.

Until then, the continued use of zenocutuzumab beyond progression will likely depend on physician discretion, payer support, and real-world evidence generation rather than formal label changes.

How tolerability and safety support long-term HER3 inhibition strategy

In high-morbidity cancers like PDAC and CCA, tolerability becomes as important as efficacy. The latest safety readouts from eNRGy support zenocutuzumab’s use over extended durations. No patients in the post-progression cohort discontinued due to adverse events. More broadly, across the eNRGy population, Grade 1–2 infusion reactions occurred in 13% of patients, with no Grade 3/4 anaphylaxis or hypersensitivity-related discontinuations reported

Interstitial lung disease (ILD) and pneumonitis occurred in just 1.1% of patients, with only one case prompting permanent discontinuation. Cardiac events — a concern with HER2 pathway inhibitors — were rare, with a 2% incidence of left ventricular dysfunction and one fatal case of cardiac failure not associated with decreased ejection fraction.

Common adverse reactions in NRG1+ pancreatic cancer patients included elevated liver enzymes, gastrointestinal symptoms, electrolyte imbalances, and hematologic changes. Importantly, these events were mostly manageable and consistent with chronic HER2/HER3 inhibition.

This favorable safety profile distinguishes zenocutuzumab from some HER2-directed antibody-drug conjugates or pan-HER TKIs, which often produce cumulative toxicities limiting long-term use. For patients receiving therapy beyond progression — often with compromised organ function or frailty — this profile becomes a crucial differentiator.

Clinicians believe zenocutuzumab’s safety record makes it a viable partner for future combination strategies, especially in GI tumors where chemotherapy remains standard. Dual inhibition approaches with immune checkpoint blockers, DNA damage repair agents, or newer HER3 ADCs may also become more feasible given this baseline tolerability.

Why zenocutuzumab’s next challenge is commercial and strategic, not just clinical

Despite the promising data, zenocutuzumab faces significant commercial headwinds. NRG1 fusions occur in just 0.2–0.5% of solid tumors, with even lower incidence in pancreatic cancer. Most community oncology centers do not routinely test for NRG1 rearrangements, and RNA-based sequencing panels — necessary to detect these fusions — remain underutilized.

This diagnostic bottleneck poses a major threat to market penetration. Without better integration of comprehensive genomic profiling into standard-of-care workflows, eligible patients may never be identified. Advocacy groups like PanCAN have urged broader adoption of biomarker testing, but reimbursement, turnaround time, and tissue limitations persist.

Moreover, competition is intensifying. Companies such as Elevation Oncology (EO-3021), GSK (GSK2849330), and Daiichi Sankyo (patritumab deruxtecan) are all pursuing HER3-directed therapies with broader target populations, including HER3-overexpressing tumors and EGFR-resistant NSCLC. These agents may eventually challenge zenocutuzumab not only on efficacy, but also on testing convenience and commercial footprint.

For Partner Therapeutics, a relatively small player, the strategic path forward may include partnerships, real-world evidence generation, and expanded access programs to build the case for adoption. The ability to secure post-approval trials and demonstrate survival or quality-of-life benefits will likely determine whether zenocutuzumab remains a niche therapy or expands into a broader HER3-directed franchise.

  ASCO GI 2026, BIZENGRI, cholangiocarcinoma, eNRGy trial, GI oncology, HER3 inhibition, NRG1 fusion, pancreatic cancer, Partner Therapeutics, zenocutuzumab