Tag: Pancreatic Cancer

Reassessing First-Line Chemotherapy Selection in Metastatic PDAC: Insights from the PASS-01 Trial

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SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 people will die of the disease. Pancreatic Ductal AdenoCarcinoma (PDAC) remains one of the most lethal malignancies, with most cases diagnosed at advanced stages and few modifiable risk factors identified to date.

Pancreatic ductal adenocarcinoma is characterized by marked biological heterogeneity and limited therapeutic durability. While combination chemotherapy regimens have modestly extended survival in the metastatic setting, outcomes remain poor for the majority of patients, underscoring the urgent need for better treatment selection strategies. Molecular stratification has emerged as a promising approach in PDAC, supported by well-established predictive biomarkers such as germline BRCA2 and PALB2 alterations, which identify a subset of patients more likely to benefit from platinum-based chemotherapy and PARP inhibition. Beyond DNA damage repair defects, transcriptomic profiling has further refined the molecular landscape of PDAC, consistently identifying two dominant expression subtypes-Classical and Basal-like, with important prognostic and potentially predictive implications.

The Classical subtype is generally associated with a more differentiated epithelial phenotype and improved survival, whereas Basal-like tumors exhibit stem-like features, relative chemoresistance, and inferior outcomes. Prior nonrandomized and prospective studies have suggested differential chemotherapy sensitivity between these subtypes, raising the question of whether transcriptional classification could inform first-line regimen selection. The Pancreatic Adenocarcinoma Signature Stratification for Treatment-01 (PASS-01) trial was designed to address this gap by prospectively comparing two commonly used first-line chemotherapy regimens, modified FOLFIRINOX (mFOLFIRINOX) and Gemcitabine plus nab-Paclitaxel (GnP), while embedding comprehensive molecular and translational analyses.

PASS-01 Trial Design and Study Objectives

PASS-01 was a randomized, open-label, multinational Phase II study conducted across centers in Canada and the United States. The trial enrolled patients with de novo metastatic PDAC who were chemotherapy-naïve between October 2020 and January 2024, and excluded individuals harboring germline pathogenic variants in BRCA1, BRCA2, or PALB2, thereby removing a population with known platinum sensitivity. Patients were randomized 1:1 to receive either mFOLFIRINOX (N=80) or GnP (N=80. The Primary endpoint was Progression-Free Survival (PFS) in the intention-to-treat population, using a relaxed significance threshold appropriate for a signal-seeking Phase II design. Key Secondary objectives included Overall Survival (OS), Safety, Objective Response Rates (ORR), and exploratory analyses evaluating outcomes according to RNA expression subtype, GATA6 expression, Patient-Derived Organoid (PDO) data, and other molecular correlatives.

Importantly, PASS-01 incorporated mandatory pretreatment tumor biopsies whenever feasible. These samples underwent whole-genome and transcriptome sequencing, RNA-based subtype classification, and PDO generation, with results reviewed in a molecular tumor board to inform later-line treatment decisions. This design allowed for a real-world assessment of the feasibility and clinical relevance of upfront molecular profiling in metastatic PDAC.

First-Line Efficacy Outcomes in the Overall Study Population

With a median follow-up of 8.3 months, PFS was numerically longer with GnP compared with mFOLFIRINOX, although the difference did not reach conventional statistical significance. Median PFS in the intention-to-treat population was 5.3 months with GnP versus 4.0 months with mFOLFIRINOX. Similar trends were observed in the per-protocol analysis.

Overall Survival outcomes favored GnP more clearly. Median OS approached 10 months with GnP and was under 9 months with mFOLFIRINOX, translating into a statistically significant hazard ratio favoring the Gemcitabine-based regimen. Notably, these differences persisted after adjustment for key clinical covariates, including performance status, liver metastases, and KRAS mutation status. While absolute survival gains were modest, these findings are clinically relevant given the lack of head-to-head randomized data comparing these regimens in Western populations. Objective Response Rates were comparable between treatment arms. However, Disease Control Rate and Durability of Response favored GnP. Patients treated with GnP experienced a higher Disease Control Rate and a longer Duration of Response, suggesting more sustained benefit in a subset of patients.

Safety Profile and Treatment Tolerability

Treatment-related toxicity differed meaningfully between regimens. Hospitalizations due to adverse events were more frequent in the mFOLFIRINOX arm, driven primarily by gastrointestinal complications, febrile neutropenia, and serious infections. In contrast, severe toxicities with GnP were less common and more limited in scope. These safety differences are particularly relevant in a population with aggressive disease biology and limited physiologic reserve, where treatment tolerability may influence both quality of life and the ability to receive subsequent therapy.

Impact of Transcriptional Subtypes on Clinical Outcomes

One of the most informative aspects of PASS-01 was its prospective evaluation of RNA expression subtypes. Among patients with adequate tissue for analysis, approximately 75% were classified as Classical and 25% as Basal-like, consistent with prior reports. Across the entire cohort, Basal-like tumors were associated with numerically shorter PFS and OS compared with Classical tumors, reinforcing their adverse prognostic significance.

When outcomes were examined by treatment arm within each subtype, important patterns emerged. In patients with Classical PDAC, PFS was similar between regimens, but OS was notably longer with GnP compared with mFOLFIRINOX. Conversely, in Basal-like disease, outcomes were uniformly poor regardless of regimen, though trends consistently favored GnP across PFS, Response Rate, and Duration of Response. These findings suggest that Basal-like tumors may derive limited benefit from intensified multi-agent chemotherapy and may be particularly resistant to Fluorouracil and Irinotecan-based approaches.

GATA6 Expression as a Pragmatic Surrogate Biomarker

Given prior evidence linking GATA6 expression with the Classical subtype, PASS-01 also evaluated GATA6 RNA in situ hybridization as a pragmatic surrogate biomarker. High GATA6 expression correlated strongly with Classical transcriptional identity. While patients with high GATA6 expression demonstrated a trend toward longer PFS, GATA6 status alone did not reliably predict differential benefit from mFOLFIRINOX versus GnP. These findings suggest that while GATA6 may serve as a useful prognostic marker, its role as a standalone predictive tool for chemotherapy selection remains limited and may require integration into broader multiplex or composite biomarker platforms.

Early CA 19-9 Dynamics as a Biomarker of Treatment Response

PASS-01 also provided important insights into the utility of early CA 19-9 changes as a biomarker of treatment response. Among patients with evaluable markers, a decline in CA 19-9 within four weeks of therapy initiation was associated with significantly prolonged PFS, whereas early increases were linked to inferior outcomes. However, a subset of patients with early CA 19-9 rises subsequently achieved radiographic disease control, underscoring that CA 19-9 kinetics should not be used in isolation to prompt premature treatment discontinuation. These findings support the potential role of early biomarker dynamics, particularly when combined with emerging tools such as circulating tumor DNA, in adaptive treatment strategies.

Translational Findings and the Challenge of Second-Line Therapy

Despite the extensive molecular profiling and use of correlate-guided recommendations, outcomes in the second-line setting were uniformly poor. Only about half of patients were able to receive subsequent therapy, and survival following progression was measured in months. Correlate-guided treatment selection did not meaningfully improve outcomes compared with standard approaches, highlighting the clinical reality that opportunities for precision intervention in PDAC are often lost once patients progress beyond first-line therapy.

Clinical Implications for First-Line Treatment Selection

PASS-01 confirms that outcomes with standard first-line combination chemotherapy for metastatic PDAC remain disappointing, even in carefully selected clinical trial populations. Within this context, the modest but consistent efficacy and safety advantages observed with GnP over mFOLFIRINOX are practice-informing, particularly for patients without known DNA repair defects. More importantly, the trial reinforces the prognostic importance of transcriptional subtypes and supports the concept that molecular features should be assessed early, when they are most likely to influence meaningful treatment decisions.

As novel therapeutic strategies, including KRAS-targeted agents and rational combination approaches, move into earlier lines of therapy, transcriptional subtype may prove critical in guiding regimen selection and trial design. PASS-01 demonstrates that comprehensive upfront molecular profiling is feasible in multicenter settings and provides a framework for future biomarker-driven trials aimed at improving first-line outcomes in this highly lethal disease.

Key Takeaways and Conclusions

In the Phase II PASS-01 trial, Progression-Free Survival was similar between mFOLFIRINOX and Gemcitabine plus nab-Paclitaxel. However, Overall Survival, treatment durability, and safety trends favored the Gemcitabine-based regimen. Molecular analyses confirmed the adverse prognosis associated with Basal-like PDAC and suggested limited benefit from intensified chemotherapy in this subgroup. Collectively, these findings emphasize the critical importance of optimizing first-line treatment strategies and integrating molecular stratification early in the disease course, as opportunities for effective intervention rapidly diminish after progression.

PASS-01: Randomized Phase II Trial of Modified FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel and Molecular Correlatives for Previously Untreated Metastatic Pancreatic Cancer. Knox JJ, O’Kane G, King D, et al. J Clin Oncol. 2025;43:3355-3368.

Chronic Hepatitis C as a Modifiable Risk Factor for Pancreatic Cancer: Insights from a National VA Cohort

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SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 people will die of the disease. Pancreatic Ductal AdenoCarcinoma (PDAC) remains one of the most lethal malignancies, with most cases diagnosed at advanced stages and few modifiable risk factors identified to date. Detecting cancer at early stages can significantly increase survival rates and outcomes.

A large population–based cohort study from the US Veterans Health Administration (VA) provides compelling new evidence that chronic hepatitis C virus (HCV) infection independently increases PDAC risk, strengthening the rationale for broad HCV screening and antiviral treatment initiatives.

Study Design

This retrospective cohort study evaluated 6.3 million veterans with documented HCV testing between 2001 and 2020, leveraging two decades of integrated VA electronic health records and linked Medicare data. Veterans were classified into three groups:

  • Chronic HCV infection (confirmed via viral load, genotype, or treatment history)
  • HCV exposure only (positive antibody or diagnostic code without RNA confirmation)
  • No HCV infection

More than 5.6 million individuals comprised the final analytic cohort. Individuals were followed for a median 5.1 years, with adjustment for key PDAC risk factors such as smoking, alcohol use, pancreatitis, diabetes, liver disease, and demographic variables.

Key Findings

  1. HCV infection significantly increases PDAC risk.
    Compared with veterans without HCV, the risk of PDAC was higher among those with:
  • Chronic HCV Infection: adjusted HR=1.76 (95% CI, 1.67–1.86)
  • HCV exposure: adjusted HR=1.18 (95% CI, 1.11–1.25)

Veterans with chronic HCV infection developed PDAC at markedly younger ages (median 65 years vs 72 years in non-HCV patients), suggesting accelerated carcinogenesis.

  1. PDAC incidence rates were substantially higher with chronic HCV.
  • 107.7 per 100,000 person-years (chronic HCV infection)
  • 68.0 per 100,000 person-years (HCV exposure)
  • 51.9 per 100,000 person-years (non-HCV)
  1. HCV genotype influences PDAC risk.
    Among individuals with chronic HCV infection, risk varied significantly compared with no HCV infection:
  • Genotype 3: adjusted HR=2.02
  • Genotype 1: adjusted HR=1.75
  • Genotype 2: adjusted HR=1.35

Higher-risk genotypes (1 and 3) parallel patterns previously observed in HCV-associated hepatocellular carcinoma.

Biological Context

The study supports earlier observations linking HCV to pancreatic injury and inflammation. Proposed mechanisms include:

  • Chronic inflammation induced by persistent viral infection may create a tumor-promoting microenvironment similar to that seen in HCV-associated hepatocellular carcinoma.
  • Viral antigens identified in pancreatic acinar cells suggest the possibility of direct infection, with potential for genomic injury and local inflammation.
  • Activation of pancreatic stellate cells, analogous to hepatic stellate cell activation in liver fibrosis and cirrhosis, may facilitate desmoplasia and tumor progression

These pathways align with known inflammatory drivers of PDAC, including tobacco use, alcohol-associated disease, and metabolic dysfunction.

Clinical and Public Health Implications

This analysis, the largest of its kind, suggests that chronic untreated HCV is a modifiable PDAC risk factor, independent of other established contributors. With direct-acting antiviral (DAA) therapies achieving >95% cure rates, improving HCV screening and treatment uptake may hold downstream benefits for PDAC prevention.

Key implications include:

  • Risk stratification: Incorporating HCV status into PDAC prediction models may enhance early detection strategies.
  • Genotype-specific counseling: Patients with genotype 1 or 3 may represent a higher-risk subgroup requiring closer surveillance.
  • Therapeutic impact: Future research is needed to clarify whether DAA-mediated HCV eradication attenuates long-term PDAC risk.

Conclusion

In a nationwide cohort of more than 6 million veterans, chronic HCV infection was associated with a 1.8-fold increase in PDAC risk, with particularly elevated risk among those with HCV genotypes 1 and 3. These findings underscore the importance of early HCV identification and treatment, not only to prevent liver disease, but potentially to reduce the burden of pancreatic cancer.

Pancreatic Ductal Adenocarcinoma After Hepatitis C Infection. Levinson RN, Bushman R, Tate JP, et al. JAMA Netw Open. Published online:November 14, 2025;8;(11):e2543701. doi:10.1001/jamanetworkopen.2025.43701.

Late Breaking Abstract – ASCO 2025: CASSANDRA Phase 3 Trial: Neoadjuvant PAXG Improves Event-Free Survival in Resectable and Borderline-Resectable PDAC

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SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 people will die of the disease. Detecting cancer at early stages can significantly increase survival rates and outcomes. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies, ranking among the leading causes of cancer-related mortality globally. A significant challenge in improving PDAC outcomes is its frequent diagnosis at an advanced stage, when therapeutic options are limited and prognosis is poor, with a 5-year survival rate of approximately 10%.

For patients with resectable or borderline-resectable Pancreatic Ductal AdenoCarcinoma (PDAC), the ideal perioperative treatment regimen remains an area of active investigation. Existing strategies vary in chemotherapy combinations, timing and duration of neoadjuvant therapy, and the use of radiation. Modified FOLFIRINOX (mFOLFIRINOX) has emerged as a standard neoadjuvant approach; however, whether more intensified or differently structured regimens can yield better outcomes is a crucial question.

The CASSANDRA trial (NCT04793932) was designed to evaluate this, comparing two chemotherapy regimens, PAXG and mFOLFIRINOX, as neoadjuvant treatment in patients with resectable or borderline-resectable PDAC.

Trial Design: A 2×2 Factorial Randomization
CASSANDRA is a multicenter, randomized, Phase 3 superiority trial enrolling 260 patients 75 years or younger with resectable/borderline resectable PDAC. Patients were stratified by site and CA19.9 level, then randomized in a 2-by-2 factorial design:

First Randomization:

    • Arm A (PAXG) N=132: Capecitabine 1250 mg/m2 PO, daily,  along with Cisplatin 30 mg/m2, nab-Paclitaxel 150 mg/m2, and Gemcitabine 800 mg/m2, given biweekly.
    • Arm B (mFOLFIRINOX) N=128: 5-Fluorouracil (5-FU) 2400 mg/m2, Irinotecan 150 mg/m2, Oxaliplatin 85 mg/m2, and Leucovorin 400 mg/m2 given biweekly.

Second Randomization:
After 4 months of therapy, patients without disease progression or unacceptable toxicity were re-randomized to receive 2 additional months of the same regimen either before or after surgery.

The median age was 64 yrs and both treatment groups were well balanced.

Study Endpoints

  • Primary Endpoint: Event-Free Survival (EFS), defined as the absence of disease progression, recurrence, two consecutive CA19.9 increases 20% or more (separated by 4 weeks or more), unresectability, intraoperative metastasis, or death.
  • Secondary Endpoints: Overall survival (OS), radiographic response, CA19.9 response, pathological response, resection rate, toxicity, and Quality of Life (QoL).

Key Findings: PAXG Demonstrates Significant EFS Benefit

  • At the data cutoff of March 1, 2025, with a median follow-up of 23.9 months, PAXG significantly improved EFS compared to mFOLFIRINOX
  • The 3-year EFS rate more than doubled with PAXG and was 31% compared to 13% with mFOLFIRINOX (HR=0.64; P=0.003), and the median EFS was 16 months and 10.2 months, respectively.
  • The Disease Control Rate was 98% with PAXG and 91% with mFOLFIRINOX (P=0.009)
  • PAXG yielded greater CA19.9 responses and pathologic downstaging compared to mFOLFIRINOX. CA19.9 reduction more than 50% was 88% versus 64% (P<0.001), resection rate was 75% versus 67% (P=0.165), and pathologic stage less than II 35% versus 23% (P=0.03), respectively.
  • Notably, trends in OS also favored PAXG, though data are immature (median OS ~37 vs 26 months; HR ~0.70; P≈0.07)

The overall, toxicity profiles were similar between the two treatment groups. Patients who received PAXG did have a higher rate of grade 3-4 neutropenia, at 42% versus 29%.

Conclusion:
Neoadjuvant treatment with PAXG significantly improved EFS compared to mFOLFIRINOX in patients with resectable/borderline resectable PDAC. While PAXG shows potential as a new neoadjuvant standard, its role must be confirmed through long-term OS analysis from CASSANDRA and results from ongoing trials such as PREOPANC-3 and Alliance A021806 trials. If confirmed, neoadjuvant PAXG could become a preferred regimen for resectable or borderline-resectable PDAC, especially in patients with elevated CA19.9 or more aggressive disease phenotypes. Oncology teams should remain attentive to the evolving perioperative landscape, as long-term data and trial results continue to inform best practices.

Results of a randomized phase III trial of pre-operative chemotherapy with mFOLFIRINOX or PAXG regimen for stage I-III pancreatic ductal adenocarcinoma. Reni M, Macchini M, Orsi G, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA4004)

Rising Incidence of Pancreatic and Colorectal Adenocarcinoma among Younger Populations

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SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 people will die of the disease. Detecting cancer at early stages can significantly increase survival rates and outcomes. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies, ranking among the leading causes of cancer-related mortality globally. A significant challenge in improving PDAC outcomes is its frequent diagnosis at an advanced stage, when therapeutic options are limited and prognosis is poor, with a 5-year survival rate of approximately 10%. Early detection is critical to expanding treatment possibilities and enhancing survival rates. Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. Even though the diagnosis of colorectal cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of colorectal cancer cases diagnosed in people under age 50, leading to revisions in screening guidelines.

Study Objective
To provide an updated analysis of Annual Percentage Changes (APCs) in the incidence of pancreatic and colorectal adenocarcinoma across different age groups, focusing on younger populations, using data from the SEER database (2000–2021).

Methods
Data Source

  • SEER (Surveillance, Epidemiology, and End Results) database (22 registries, ~47.9% of US population)
  • Data updated through April 17, 2024

Study Design

  • Retrospective cohort study
  • Inclusion: Pancreatic and colorectal adenocarcinoma only
  • Exclusion: Rare pancreatic cancer subtypes (e.g., neuroendocrine tumors, mucinous cystadenocarcinoma)
  • The Rutgers University IRB exempted the study, and informed consent was not needed owing to the deidentified nature of the data.

Analysis

  • Yearly incidence rates per 100,000 population
  • Annual Percentage Changes (APCs) and 95% confidence intervals calculated for three age groups:
    • 15–34 years
    • 35–54 years
    • 55+ years

Results
Pancreatic Adenocarcinoma

  • Total cases (2000–2021): 275,273
    • 51.8% male, 87.1% aged ≥55 years
  • APC in 15–34 years: 4.35% (95% CI, 2.03–6.73)
  • APC in 35–54 years: 1.54% (95% CI, 1.18–1.90)
  • APC in 55+ years: 1.74% (95% CI, 1.59–1.89)

The APC for pancreatic adenocarcinoma in the group aged 15 to 34 year was statistically significantly higher than the APCs of 1.74 (P =0.007) for the group aged 55 years and older and 1.54 (P =0.004) for the group aged 35 to 54 years. The authors commented that the dramatic increase in the APC in the younger population suggests that close attention should be paid to this trend.

Colorectal Adenocarcinoma

  • Total cases: 1,215,200
    • 52.8% male, 80.4% aged ≥55 years
  • APC in 15–34 years: 1.75% (95% CI, 1.08–2.42)
  • APC in 35–54 years: 0.78% (95% CI, 0.51–1.06)
  • APC in 55+ years: -3.31% (95% CI, -3.54 to -3.08)

The APC for colorectal adenocarcinoma for the group aged 55 years and older was statistically significantly lower than the APCs for the group aged 15 to 34 years (P =0.001) and for the group aged 35 to 54 years (P =0.002). Most declines in colorectal cancer incidence was attributed to increased screening in older adults. Screening age was lowered from 50 to 45 years and may likely reduce future incidence in those aged 35–54.

Interpretation & Implications

Pancreatic Cancer

  • Though rare, pancreatic adenocarcinoma in young adults (15–34 years) is rising at an alarming rate.
  • Potential contributors: Smoking, alcohol, environmental exposures, though definitive causes remain unclear.
  • Clinician awareness is critical when evaluating younger patients with:
    • Abdominal pain
    • Weight loss
    • Anemia
    • Family history of pancreatic cancer

Clinical Insight: Historically, the above findings are not investigated in a young individual. It is therefore important to make sure a serious condition is not missed.

Colorectal Cancer

  • Increasing in younger groups, despite an overall declining trend.
  • This supports recent screening age revisions and highlights the need for vigilance in symptomatic young patients.

Limitations

  • SEER data covers ~47.9% of the U.S. population.
  • However, SEER is designed for accurate trend analysis and has reliable coding for common cancers like pancreatic and colorectal adenocarcinoma.
  • Restricting to adenocarcinoma improves the homogeneity and accuracy of the study.

Conclusions

  • Pancreatic adenocarcinoma incidence is rising in all age groups, especially in the youngest cohort (15–34 years).
  • Colorectal adenocarcinoma is increasing among younger individuals, while declining among those 55 and older.
  • Clinicians must heighten awareness of these trends and consider appropriate workups in symptomatic younger patients.

Key Takeaways

  • Pancreatic adenocarcinoma incidence rose >4% annually in individuals aged 15–34 years.
  • Colorectal adenocarcinoma also increased among patients aged 15–34 years.
  • Consider early imaging and endoscopic evaluations in symptomatic young adults.
  • Continue to support early screening efforts, especially for high-risk individuals.

Incidence of Pancreas and Colorectal Adenocarcinoma in the US. Bussetty A, Shen J, Benias PC, et al. JAMA Netw Open. 2025;8(4):e254682. doi:10.1001/jamanetworkopen.2025.4682

 

 

 

 

 

BIZENGRI® for Non Small Cell Lung Cancer and Pancreatic Adenocarcinoma

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SUMMARY: The FDA granted accelerated approval to Zenocutuzumab-zbco (BIZENGRI®) for adults with advanced, unresectable, or metastatic Non-Small Cell Lung Cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy, or advanced, unresectable, or metastatic pancreatic adenocarcinoma harboring a NRG1 gene fusion with disease progression on or after prior systemic therapy. This represents the first FDA approval of a systemic therapy for patients with NSCLC or pancreatic adenocarcinoma harboring an NRG1 gene fusion.

Genomic rearrangements involving the neuregulin 1 (NRG1) gene have been implicated in a variety of solid tumors, including lung, breast, pancreas, ovarian, and prostate cancers. NRG1 fusions are rare oncogenic drivers occurring in less than 1% of solid tumors, highly enriched in KRAS-wild-type pancreatic adenocarcinoma and invasive mucinous adenocarcinoma of the lung. NRG1 fusions produce chimeric ligands that activate the ERBB Receptor Tyrosine Kinase (RTK) family, a group of proteins frequently exploited by cancer cells to promote tumor growth. In lung cancer, NRG1 fusions are associated with poor prognosis in patients with lung cancer, with low Response Rates to standard chemotherapy and immunotherapy, and a short Overall Survival.

The ERBB RTK family includes EGFR (ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). These proteins mediate crucial cell signaling pathways that regulate growth and survival. They can be oncogenically activated by ligand stimulation such as NRG1 fusion proteins binding to HER3 or HER4, mutations and translocations that may confer constitutive enzymatic activity, such as EGFR kinase domain mutations, the EGFRvIII variant (where the extracellular region of EGFR is deleted), EGFR fusions or gene amplification, or protein overexpression resulting in increasing receptor abundance on cell surfaces to amplify signaling.

NRG1 preferentially binds to HER3 and HER4, promoting their heterodimerization with other ERBB family members like HER2 and EGFR. This interaction is critical because HER3, a pseudokinase, lacks intrinsic enzymatic activity and depends on phosphorylation by its heterodimer partners. The activated HER3 forms docking sites for SH2-domain proteins, triggering multiple downstream signal transduction pathways like the PI3K pathway, which drive proliferation and survival.

Zenocutuzumab is a bispecific humanized immunoglobulin G1 (IgG1) containing two different Fab arms targeting the extracellular domains of HER2 and HER3. The HER2-targeting arm binds HER2, concentrating the antibody locally and positioning it (Dock) to block NRG1 binding to HER3 (Dock-and-block mechanism). The HER3-targeting arm prevents HER3 from undergoing the conformational changes necessary for heterodimerization with HER2 and EGFR. This dual targeting halts HER3 phosphorylation, disrupting downstream oncogenic signaling. Moreover, the glycoengineered IgG1 backbone of Zenocutuzumab enhances its affinity for Fc receptors, boosting Antibody-Dependent Cellular Cytotoxicity (ADCC)-a mechanism by which immune cells destroy antibody-coated tumor cells.

eNRGy is a Phase 2 part of an open-label, multicenter, multicohort, registrational, Phase 1–2 clinical study of Zenocutuzumab, in patients with solid tumors with a NRG1 fusion. A total of 204 patients (N=204) with 12 tumor types were enrolled and patients had a median of one prior line of therapy, including platinum chemotherapy (72%) and Afatinib (11%). The median patient age was 62 years and most were female (60%), and 35% were Asian. The most common NRG1 fusion partners were CD74 (35%), SLC3A2 (14%), ATP1B1 (11%), SDC4/7 (7%), and CDH1/2 (3%). The most common fusion partners among patients with NSCLC were CD74 (in 56%) and SLC3A2 (in 23%), and the most common fusion partner among those with pancreatic cancer was ATP1B1 (in 44%). Most NRG1 fusions were identified by RNA sequencing (81%), followed by DNA sequencing (14%). Patients received Zenocutuzumab 750 mg IV every 2 weeks until disease progression. The Primary efficacy outcome measure was confirmed Overall Response Rate (ORR) and Secondary end points included Duration of Response (DOR), Progression Free Survival (PFS) and Safety. 

Among 158 patients who had measurable disease, the ORR among patients with NSCLC was 29% and median DOR was 12.7 months. The ORR among pancreatic adenocarcinoma patients was 42% and the DOR was 7.4 months. Responses were noted across multiple NRG1 fusion partners. In the pooled safety population, the most common adverse reactions were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. The most common Grade 3 or 4 laboratory abnormalities were increased gamma-glutamyl transferase, anemia, thrombocytopenia and hyponatremia.

It was concluded from this analysis that Zenocutuzumab provided robust and durable efficacy in advanced NRG1 positive NSCLC and pancreatic adenocarcinoma, with a well-tolerated safety profile, and represents a potential first and best-in-class therapy for patients with NRG1 fusion solid tumors.

Efficacy of Zenocutuzumab in NRG1 Fusion–Positive Cancer. Schram AM, Goto K,  Kim D-W, et al. for the eNRGy Investigators. N Engl J Med 2025;392:566-576

Development of PAC-MANN Assay for Early Detection of Pancreatic Ductal Adenocarcinoma

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SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 people will die of the disease. Detecting cancer at early stages can significantly increase survival rates and outcomes. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies, ranking among the leading causes of cancer-related mortality globally. A significant challenge in improving PDAC outcomes is its frequent diagnosis at an advanced stage, when therapeutic options are limited and prognosis is poor. Early detection is critical to expanding treatment possibilities and enhancing survival rates. Currently, CA 19-9 is the only FDA-approved biomarker for PDAC; however, it is sanctioned solely for monitoring therapeutic response and not for diagnostic purposes.

Protease Activity in Cancer Detection
Protease production is a hallmark of tumor progression. In PDAC, as in many cancers, elevated circulating protease activity is observed. Proteases contribute to cancer metastasis by degrading extracellular matrices, facilitating tumor invasion. This biological activity presents a diagnostic opportunity: measuring protease activity in peripheral blood could provide a noninvasive means of detecting malignancy.

Assay Development: PAC-MANN
Montoya Mira, Fischer, and colleagues developed a novel, noninvasive diagnostic assay named PAC-MANN (Protease Activity Characterization via Magnetic Nanosensor), aimed at detecting PDAC via serum protease activity. The method utilizes a magnetic nanosensor coupled to a fluorescently labeled, protease-sensitive peptide probe. When exposed to a blood sample, if PDAC-associated proteases are active, they cleave the peptide substrate, releasing a fluorescent signal. The intensity of fluorescence correlates with protease activity, allowing for rapid and quantifiable detection.

Key Features of PAC-MANN Assay:

  • Sample Volume: Requires only 8 µL of blood.
  • Turnaround Time: Results available within 45 minutes.
  • Cost Efficiency: Material cost estimated at less than one cent per test.
  • Throughput: Capable of analyzing 300–500 samples per day with minimal personnel and equipment.

Clinical Performance

Validation Studies:

  • Sample Cohort: 110 pre-treatment PDAC samples (mean age 65.6 years; 57% male) and 246 noncancerous controls (mean age 63.2 years; 59% male), including cases of pancreatitis and pancreatic neoplasia.
  • Assay Accuracy:
    • Standalone PAC-MANN assay demonstrated 98% specificity and 73% sensitivity across all PDAC stages.
    • PAC-MANN combined with CA 19-9 achieved 85% sensitivity and 96% specificity for detecting stage I PDAC.
    • The assay accurately differentiated PDAC from noncancerous pancreatic conditions with 100% specificity.

Surgical Cohort Findings:
In patients undergoing tumor resection, post-surgical evaluation showed a 16 ± 24% reduction in probe cleavage signal, indicating potential utility in monitoring treatment efficacy.

Future Directions and Clinical Implications

Researchers emphasize that PAC-MANN is an initial step toward improved cancer diagnostics. Planned next steps include:

  • Prospective Clinical Trials: Targeting high-risk patient populations.
  • Global Sample Analysis: Expanding validation to diverse healthcare settings.
  • Technological Refinement: Enhancing assay sensitivity via engineering modifications (e.g., nanoparticle composition, probe architecture).
  • Multiplexing Potential: Early data suggest improved performance when multiple probes are used concurrently.
  • Broader Application: Initial results indicate potential use in detecting other gastrointestinal and possibly non-GI cancers through the measurement of protease activity.

Limitations and Considerations

While promising, the assay is not intended to replace imaging modalities. A positive test would necessitate further localization via advanced imaging techniques. As part of a multi-modal diagnostic strategy, PAC-MANN may significantly improve early PDAC detection and patient outcomes.

Conclusion

The PAC-MANN assay offers a rapid, low-cost, and highly specific method for detecting PDAC at early stages, especially when used in combination with CA 19-9. Its minimal sample requirement and ease of use make it a viable candidate for widespread clinical implementation. Further research and trials will ascertain its role in routine screening, particularly among high-risk populations, and its potential extension to other cancer types.

Early detection of pancreatic cancer by a high-throughput protease-activated nanosensor assay. Montoya Mira JL, Quentel A, Patel RK, et al. Science Translational Medicine.12 Feb 2025.Vol 17, Issue 785.

FDA Grants Accelerated Approval to BIZENGRI® for Non Small Cell Lung Cancer and Pancreatic Adenocarcinoma

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SUMMARY: The FDA on December 4, 2024, granted accelerated approval to Zenocutuzumab-zbco (BIZENGRI®) for adults with advanced, unresectable, or metastatic Non-Small Cell Lung Cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy, or advanced, unresectable, or metastatic pancreatic adenocarcinoma harboring a NRG1 gene fusion with disease progression on or after prior systemic therapy. This represents the first FDA approval of a systemic therapy for patients with NSCLC or pancreatic adenocarcinoma harboring an NRG1 gene fusion.

Genomic rearrangements involving the neuregulin 1 (NRG1) gene have been implicated in a variety of solid tumors, including lung, breast, pancreas, ovarian, and prostate cancers. NRG1 fusions are rare oncogenic drivers occurring in less than 1% of solid tumors, highly enriched in KRAS-wild-type pancreatic adenocarcinoma and invasive mucinous adenocarcinoma of the lung. NRG1 fusions produce chimeric ligands that activate the ERBB Receptor Tyrosine Kinase (RTK) family, a group of proteins frequently exploited by cancer cells to promote tumor growth. In lung cancer, NRG1 fusions are associated with poor prognosis in patients with lung cancer, with low Response Rates to standard chemotherapy and immunotherapy, and a short Overall Survival.

The ERBB RTK family includes EGFR (ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). These proteins mediate crucial cell signaling pathways that regulate growth and survival. They can be oncogenically activated by ligand stimulation such as NRG1 fusion proteins binding to HER3 or HER4, mutations and translocations that may confer constitutive enzymatic activity, such as EGFR kinase domain mutations, the EGFRvIII variant (where the extracellular region of EGFR is deleted), EGFR fusions or gene amplification, or protein overexpression resulting in increasing receptor abundance on cell surfaces to amplify signaling.

NRG1 preferentially binds to HER3 and HER4, promoting their heterodimerization with other ERBB family members like HER2 and EGFR. This interaction is critical because HER3, a pseudokinase, lacks intrinsic enzymatic activity and depends on phosphorylation by its heterodimer partners. The activated HER3 forms docking sites for SH2-domain proteins, triggering multiple downstream signal transduction pathways like the PI3K pathway, which drive proliferation and survival.

Zenocutuzumab is a bispecific humanized immunoglobulin G1 (IgG1) containing two different Fab arms targeting the extracellular domains of HER2 and HER3. The HER2-targeting arm binds HER2, concentrating the antibody locally and positioning it (Dock) to block NRG1 binding to HER3 (Dock-and-block mechanism). The HER3-targeting arm prevents HER3 from undergoing the conformational changes necessary for heterodimerization with HER2 and EGFR. This dual targeting halts HER3 phosphorylation, disrupting downstream oncogenic signaling. Moreover, the glycoengineered IgG1 backbone of Zenocutuzumab enhances its affinity for Fc receptors, boosting Antibody-Dependent Cellular Cytotoxicity (ADCC)-a mechanism by which immune cells destroy antibody-coated tumor cells.

The present approval is supported by the Phase 1/2 eNRGy ongoing trial, which is an open-label, multicenter, multicohort, dose-escalation study of Zenocutuzumab, in patients with solid tumors with a NRG1 fusion. Enrolled patients had a median of one prior line of therapy, including platinum chemotherapy (72%) and Afatinib (11%). The median patient age was 64 years and most were female (62%), and 51% were Asian. The most common NRG1 fusion partners were CD74 (57%), SLC3A2 (22%), SDC4/7 (9%), and CDH1/2 (3%). Most NRG1 fusions were identified by RNA sequencing (81%), followed by DNA sequencing (14%). Patients received Zenocutuzumab 750 mg IV every 2 weeks until disease progression. The major efficacy outcome measures were confirmed Overall Response Rate (ORR) and Duration of Response (DOR), determined by Blinded Independent Central Review.

The ORR for NSCLC was 33% and median DOR was 7.4 months. The ORR for pancreatic adenocarcinoma was 40% and the DOR was 3.7-16.6 months. In the pooled safety population, the most common adverse reactions were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. The most common Grade 3 or 4 laboratory abnormalities were increased gamma-glutamyl transferase, anemia, thrombocytopenia and hyponatremia.

It was concluded from this analysis that Zenocutuzumab provided robust and durable efficacy in advanced NRG1 positive NSCLC and pancreatic adenocarcinoma, with a well-tolerated safety profile, and represents a potential first and best-in-class therapy for patients with NRG1 fusion solid tumors.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic

BIZENGRI® (Zenocutuzumab-zbco)

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The FDA on December 4, 2024, granted accelerated approval to BIZENGRI® for adults with the following:

Advanced, unresectable, or metastatic Non-Small Cell Lung Cancer (NSCLC) harboring a Neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy, or

Advanced, unresectable, or metastatic Pancreatic adenocarcinoma harboring a NRG1 gene fusion with disease progression on or after prior systemic therapy.

BIZENGRI® is a product of Merus N.V.

Early Detection of Pancreatic Cancer with an Exosome-Based Liquid Biopsy

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SUMMARY: The American Cancer Society estimates that in 2024, about 66,440 people will be diagnosed with pancreatic cancer and 51,750 people will die of the disease. Detecting cancer at early stages can significantly increase survival rates and outcomes.

Several multi-cancer early detection tests are being developed that involve blood-based circulating cell-free tumor DNA (cfDNA) in the plasma, to track hundreds of patient-specific mutations, to detect Minimal Residual Disease (MRD) , as well as detection of abnormal methylation patterns, followed by machine learning approaches, to differentiate between cancer and non-cancer for detecting clinically significant, late-stage (III and IV) cancers. Early detection of cancer, however, is the key to improving survival. This is particularly relevant for certain cancer types. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the deadliest cancers, and a leading cause of all cancer-related deaths in the United States and is typically detected when the disease is advanced. However, when detected at Stage I, survival rates can be as high as 80%. Even though serum CA19-9 is intended as an aid in the management of patients with confirmed pancreatic cancer for serial monitoring of their response to therapy and disease progression, it is NOT recommended by the FDA for screening, as it may be elevated in several benign conditions. Currently, there are no general screening strategies to detect asymptomatic, early-stage PDAC and there is therefore a significant unmet need in this patient group.

Exosomes are 30-150 nm-sized Extracellular Vesicles (EVs) secreted by multiple different cell types and released by tumors into the bloodstream. They mediate intercellular signaling by shuttling mRNAs and microRNAs between distant cells and tissues and therefore carry functional protein biomarkers representing the tumor proteome. MicroRNAs play a role in regulating gene expression and have been implicated in various cancer types due to their stability and specific expression patterns associated with tumor presence. Exosomes retain the cytoplasmic content of the cell from which they were shed, essentially replicating the biology of their tissue of origin. Exosomes represent one potential approach for more sensitive detection of cancer-related biomarkers from blood.

The researchers developed an exosome-based liquid biopsy signature as a diagnostic tool to detect pancreatic cancer through the analysis of circulating biomarkers in blood samples. This signature utilizes two primary types of biomarkers – Eight microRNAs unique to exosomes shed from pancreatic cancer cells, combined with five cell-free DNA (cfDNA) markers such as mutations or alterations in DNA methylation patterns found in the blood of patients with pancreatic cancer.

In previous work, researchers had tested an exosome-based liquid biopsy signature on a cohort of 95 individuals from either the United States or Japan. This initial study reported an impressive 98% detection rate for pancreatic cancer. Building on this success, the latest research aimed to validate this liquid biopsy approach in larger, more diverse populations across multiple institutions and countries.

The most recent study involved a comprehensive, multi-cohort evaluation to assess the performance of the exosome-based liquid biopsy signature. The study enrolled participants from four countries, each contributing both pancreatic cancer patients and healthy donors:
• Japan: 150 individuals with pancreatic cancer and 102 healthy donors
• United States: 139 individuals with pancreatic cancer and 193 healthy donors
• South Korea: 184 individuals with pancreatic cancer and 86 healthy donors
• China: 50 individuals with pancreatic cancer and 80 healthy donors

The research methodology involved training the liquid biopsy signature using data from the Japanese cohort. Machine learning algorithms were likely used to train and validate the diagnostic model, optimizing its sensitivity and specificity. After training the signature on the Japanese cohort, the researchers validated its performance using data from cohorts in the United States, South Korea, and China. Each of these cohorts included a mix of pancreatic cancer patients and healthy controls, allowing for an assessment of the signature’s performance across diverse populations.

The performance of the liquid biopsy signature across different cohorts was as follows:
• United States Cohort: The test detected 93% of pancreatic cancers.
• South Korean Cohort: The test detected 91% of pancreatic cancers.
• Chinese Cohort: The test detected 88% of pancreatic cancers.

These validation results demonstrated the signatures robustness and effectiveness in detecting pancreatic cancer across different ethnic and geographic backgrounds, although there was a noted decrease in detection rates with different cohorts.

To enhance the diagnostic accuracy, the researchers combined their exosome-based signature with the traditional pancreatic cancer marker CA 19-9, a carbohydrate antigen often elevated in pancreatic cancer but is less sensitive for detecting early-stage disease. The combination of the exosome-based signature with CA 19-9 improved the detection rate of early-stage pancreatic cancers (Stage I and II) to 97% in the U.S. cohort. This suggests that the combination approach offers a more comprehensive evaluation than CA 19-9 alone.

In conclusion, the exosome-based liquid biopsy signature represents a significant advancement in the early detection of pancreatic cancer. By leveraging the unique properties of exosomal microRNAs and cfDNA, the researchers have developed a diagnostic tool with high sensitivity and specificity. The successful validation in multiple cohorts underscores its potential utility in clinical practice. This assay may be helpful for early detection of pancreatic cancer in certain groups with a high risk for pancreatic cancer such as a family history of pancreatic cancer, germline BRCA mutations, new-onset diabetes, chronic pancreatitis or pancreas precancer lesion such as intraductal papillary mucinous neoplasm. However, addressing the limitations and further optimizing the technology will be crucial for its widespread adoption and effectiveness in diverse populations.

An exosome-based liquid biopsy for non-invasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter and prospective study. Xu C, Xu Y, Han H, et al. AACR Annual Meeting 2024. Abstract 3899. Presented April 8, 2024.

Early Detection of Pancreatic Cancer with an Exosome-Based Liquid Biopsy

RR

SUMMARY: The American Cancer Society estimates that in 2024, about 66,440 people will be diagnosed with pancreatic cancer and 51,750 people will die of the disease. Detecting cancer at early stages can significantly increase survival rates and outcomes.

Several multi-cancer early detection tests are being developed that involve blood-based circulating cell-free tumor DNA (cfDNA) in the plasma, to track hundreds of patient-specific mutations, to detect Minimal Residual Disease (MRD) , as well as detection of abnormal methylation patterns, followed by machine learning approaches, to differentiate between cancer and non-cancer for detecting clinically significant, late-stage (III and IV) cancers. Early detection of cancer, however, is the key to improving survival. This is particularly relevant for certain cancer types. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the deadliest cancers, and a leading cause of all cancer-related deaths in the United States and is typically detected when the disease is advanced. However, when detected at Stage I, survival rates can be as high as 80%. Even though serum CA19-9 is intended as an aid in the management of patients with confirmed pancreatic cancer for serial monitoring of their response to therapy and disease progression, it is NOT recommended by the FDA for screening, as it may be elevated in several benign conditions. Currently, there are no general screening strategies to detect asymptomatic, early-stage PDAC and there is therefore a significant unmet need in this patient group.

Exosomes are 30-150 nm-sized Extracellular Vesicles (EVs) secreted by multiple different cell types and released by tumors into the bloodstream. They mediate intercellular signaling by shuttling mRNAs and microRNAs between distant cells and tissues and therefore carry functional protein biomarkers representing the tumor proteome. MicroRNAs play a role in regulating gene expression and have been implicated in various cancer types due to their stability and specific expression patterns associated with tumor presence. Exosomes retain the cytoplasmic content of the cell from which they were shed, essentially replicating the biology of their tissue of origin. Exosomes represent one potential approach for more sensitive detection of cancer-related biomarkers from blood.

The researchers developed an exosome-based liquid biopsy signature as a diagnostic tool to detect pancreatic cancer through the analysis of circulating biomarkers in blood samples. This signature utilizes two primary types of biomarkers – Eight microRNAs unique to exosomes shed from pancreatic cancer cells, combined with five cell-free DNA (cfDNA) markers such as mutations or alterations in DNA methylation patterns found in the blood of patients with pancreatic cancer.

In previous work, researchers had tested an exosome-based liquid biopsy signature on a cohort of 95 individuals from either the United States or Japan. This initial study reported an impressive 98% detection rate for pancreatic cancer. Building on this success, the latest research aimed to validate this liquid biopsy approach in larger, more diverse populations across multiple institutions and countries.

The most recent study involved a comprehensive, multi-cohort evaluation to assess the performance of the exosome-based liquid biopsy signature. The study enrolled participants from four countries, each contributing both pancreatic cancer patients and healthy donors:
• Japan: 150 individuals with pancreatic cancer and 102 healthy donors
• United States: 139 individuals with pancreatic cancer and 193 healthy donors
• South Korea: 184 individuals with pancreatic cancer and 86 healthy donors
• China: 50 individuals with pancreatic cancer and 80 healthy donors

The research methodology involved training the liquid biopsy signature using data from the Japanese cohort. Machine learning algorithms were likely used to train and validate the diagnostic model, optimizing its sensitivity and specificity. After training the signature on the Japanese cohort, the researchers validated its performance using data from cohorts in the United States, South Korea, and China. Each of these cohorts included a mix of pancreatic cancer patients and healthy controls, allowing for an assessment of the signature’s performance across diverse populations.

The performance of the liquid biopsy signature across different cohorts was as follows:
• United States Cohort: The test detected 93% of pancreatic cancers.
• South Korean Cohort: The test detected 91% of pancreatic cancers.
• Chinese Cohort: The test detected 88% of pancreatic cancers.

These validation results demonstrated the signatures robustness and effectiveness in detecting pancreatic cancer across different ethnic and geographic backgrounds, although there was a noted decrease in detection rates with different cohorts.

To enhance the diagnostic accuracy, the researchers combined their exosome-based signature with the traditional pancreatic cancer marker CA 19-9, a carbohydrate antigen often elevated in pancreatic cancer but is less sensitive for detecting early-stage disease. The combination of the exosome-based signature with CA 19-9 improved the detection rate of early-stage pancreatic cancers (Stage I and II) to 97% in the U.S. cohort. This suggests that the combination approach offers a more comprehensive evaluation than CA 19-9 alone.

In conclusion, the exosome-based liquid biopsy signature represents a significant advancement in the early detection of pancreatic cancer. By leveraging the unique properties of exosomal microRNAs and cfDNA, the researchers have developed a diagnostic tool with high sensitivity and specificity. The successful validation in multiple cohorts underscores its potential utility in clinical practice. This assay may be helpful for early detection of pancreatic cancer in certain groups with a high risk for pancreatic cancer such as a family history of pancreatic cancer, germline BRCA mutations, new-onset diabetes, chronic pancreatitis or pancreas precancer lesion such as intraductal papillary mucinous neoplasm. However, addressing the limitations and further optimizing the technology will be crucial for its widespread adoption and effectiveness in diverse populations.

An exosome-based liquid biopsy for non-invasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter and prospective study. Xu C, Xu Y, Han H, et al. AACR Annual Meeting 2024. Abstract 3899. Presented April 8, 2024.