Category: Precision Oncology

Late Breaking Abstract – ASCO 2025: Redefining the First-Line Standard: DESTINY-Breast09 Highlights T-DXd Plus Pertuzumab as a Potential New Benchmark in HER2+ Metastatic Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15%-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Trastuzumab (HERCEPTIN®) is a humanized monoclonal antibody targeting HER2. Trastuzumab binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). Pertuzumab (PERJETA®) is a recombinant humanized monoclonal antibody that binds to the HER2 at a different epitope of the HER2 extracellular domain (subdomain II) compared to Trastuzumab, and prevents the dimerization of HER2 with HER3 receptor. Pertuzumab stimulates ADCC similar to Trastuzumab. By combining Trastuzumab and Pertuzumab, a more comprehensive blockade of HER2 signaling can be accomplished, as these two agents bind to different HER2 epitopes and may complement each other and improve efficacy.

Trastuzumab deruxtecan (T-DXd) (ENHERTU®) is a next-generation Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). T-DXd has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike  ado-Trastuzumab emtansine, another ADC targeting HER2, T-DXd has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

Background and Clinical Rationale
Trastuzumab deruxtecan (T-DXd) has demonstrated potent antitumor activity in HER2-positive breast cancer across multiple treatment lines. However, prior to the DESTINY-Breast09 study, all approved indications for T-DXd required patients to have received prior systemic therapy in either the metastatic or adjuvant setting. With the longstanding CLEOPATRA regimen, Docetaxel, Trastuzumab, and Pertuzumab (THP) established over a decade ago as the first-line standard of care, the oncology community has been eager to evaluate whether T-DXd could improve frontline outcomes.

Study Design and Patient Population
DESTINY-Breast09 (NCT04784715) is a randomized, global Phase 3 study designed to evaluate the efficacy and safety of first-line T-DXd with or without Pertuzumab, versus Taxane plusTrastuzumab plus Pertuzumab (THP), in patients with HER2-positive advanced/metastatic breast cancer. A total of 1,157 patients were enrolled across 283 sites worldwide. Eligible patients had centrally confirmed HER2-positive disease (IHC 3+ or ISH+), no prior chemotherapy or HER2-targeted therapy in the metastatic setting, and ≤1 prior line of endocrine therapy. Patients were stratified by Hormone Receptor (HR) status, PIK3CA mutation status, and de novo vs recurrent disease, and randomized 1:1:1 to:

  • T-DXd + placebo – N=387
  • T-DXd + pertuzumab (T-DXd + P) – N=383
  • THP (control arm) – N=387

The interim analysis presented at ASCO 2025 focused on the comparison between T-DXd + P and THP. The T-DXd monotherapy arm remains blinded until the final PFS analysis.

The Primary endpoint was Progression-Free Survival (PFS) by Blinded Independent Central Review (BICR) in the intent-to-treat population. Secondary endpoints included Overall Survival (OS), PFS by investigator (INV), Objective Response Rate (ORR), Duration of Response (DOR), and Safety

Efficacy Outcomes: Progression-Free Survival and Response
At a median follow-up of 29 months, T-DXd + P demonstrated a statistically significant and clinically meaningful improvement in PFS compared to THP:

  • Median PFS by BICR:
    • T-DXd + P: 40.7 months
    • THP: 26.9 months
    • HR: 0.56; P <0.00001
  • PFS by Investigator Assessment:
    • Median: 40.7 months vs 20.7 months
    • HR: 0.49 (95% CI: 0.39–0.61)
  • Overall Response Rate (ORR):
    • T-DXd + P: 85.1%
    • THP: 78.6%
  • Complete Response Rate:
    • T-DXd + P: 15.1%
    • THP: 8.5%
  • Median Duration of Response:
    • T-DXd + P: 39.2 months
    • THP: 26.4 months

The PFS benefit was consistent across all patient subgroups, including HR status and PIK3CA mutation.

Safety Profile and Adverse Events
The safety profile of T-DXd + P in the frontline setting was consistent with known toxicities of T-DXd, with no new safety signals. Adjudicated drug-related Interstitial Lung Disease/pneumonitis occurred in 12.1% of patients receiving T-DXd + P (mostly grade 1 and 2) in contrast to only 1.0% among patients receiving THP. Other treatment-related toxicities such as nausea, vomiting, and constipation were more common with T-DXd + P, possibly due to longer median treatment exposure (~3.5 years).

Clinical Implications and Emerging Questions
The marked 13.8-month PFS improvement positions T-DXd + P as a strong candidate to replace THP as the first-line standard for HER2-positive advanced metastatic breast cancer. These results mirror the transformative impact of T-DXd seen in the second-line DESTINY-Breast03 trial comparing T-DXd with ado-Trastuzumab emtansine, where it yielded a median PFS of 28.8 months.

However, while efficacy is unquestionable, questions remain around treatment sequencing, duration, and long-term quality of life:

  • Could T-DXd be reserved for second-line therapy in select patients with less aggressive disease?
  • Might a strategy of T-DXd + P induction followed by de-escalation to maintenance Trastuzumab/Pertuzumab reduce toxicity?
  • Can biomarker-driven personalization refine who should receive first-line T-DXd?

The researchers of this study emphasized that these results represent a paradigm shift in first-line treatment of advanced HER2-positive breast cancer.

Conclusion
DESTINY-Breast09 demonstrates that T-DXd + Pertuzumab significantly improves PFS compared to THP, with durable responses and manageable toxicity. The findings suggest a potential new first-line standard for HER2-positive metastatic breast cancer. While overall survival and long-term safety data are still maturing, the study sets a new benchmark in the frontline treatment landscape and invites critical dialogue on optimizing sequencing, duration, and patient-centered outcomes.

Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): Interim results from DESTINY-Breast09. Tolaney S, Jiang Z, Zhang Q, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA1008)

Late Breaking Abstract – ASCO 2025: SERENA-6: A ctDNA-Guided Switch to Camizestrant Improves PFS in HR-Positive/HER2-Negative Advanced Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.

Background
The SERENA-6 trial is the first global registrational Phase 3 study to evaluate a ctDNA-guided approach for the early detection and treatment of ESR1 mutations in HR+, HER2-negative advanced breast cancer. ESR1 mutations, which promote ligand independent Estrogen Receptor activation, are a common mechanism of acquired resistance to estrogen deprivation therapies such as Aromatase Inhibitors (AIs) plus CDK4/6 inhibitors (CDK4/6i). ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, has been associated with shorter Overall Survival. ESR1 mutations are typically absent at diagnosis but emerge during AI therapy. Detecting ESR1 mutations through circulating tumor DNA (ctDNA) provides a non-invasive method to identify molecular progression prior to radiographic evidence.

Camizestrant is an oral, next-generation Selective Estrogen Receptor Degrader (SERD) with antagonist activity against both wild-type and mutant estrogen receptors. SERENA-6 evaluated whether switching to Camizestrant plus continued CDK4/6i upon ctDNA detection of ESR1 mutations, but before radiographic progression, can improve outcomes, compared to continuing the standard AI-based regimen.

Study Design and Results
SERENA-6 is a randomized, double-blind, Phase 3 trial in which 3,256 patients with HR+/HER2-negative advanced breast cancer who had received 6 or more  months of first-line AI + CDK4/6 inhibitor (Palbociclib, Ribociclib, or Abemaciclib) were surveilled for ESR1 mutations using ctDNA performed every 2-3 months alongside routine imaging. Upon ESR1 mutations detection without clinical progression, 315 eligible patients (N=315) who were found to have an ESR1 mutation during ctDNA surveillance were randomized were randomized 1:1 to Switch to Camizestrant (75 mg daily) + continued CDK4/6i + placebo for AI (N=157) or continue AI + CDK4/6i + placebo for Camizestrant (N=158). Both treatment groups were well balanced. Stratification included visceral disease status, timing of ESR1 mutation detection, prior duration of therapy, and CDK4/6 inhibitor type. The Primary endpoint was Investigator-assessed Progression-Free Survival (PFS).

At the prespecified interim analysis, about 50% had ESR1mutations detected on the first ctDNA test. The median PFS was significantly longer with Camizestrant – 16.0 vs 9.2 months; HR=0.44, P<0.00001. This PFS benefit was consistent across all subgroups. The 12-month PFS rates were 60.7% in the Camizestrant group vs 33.4% in the control group. The 24-month PFS rates: 29.7% vs 5.4%. Overall survival (OS) data remains immature. Patients in the Camizestrant arm had a quality of life that was maintained longer than the AI group.

Treatment discontinuation due to adverse events were low at 1.3% for the Camizestrant, and 1.9% for the Aromatase Inhibitor group.

Clinical Implications
SERENA-6 demonstrated that early, ctDNA-guided switching from AI to Camizestrant in patients with emergent ESR1 mutations significantly prolonged PFS without added toxicity. This trial is the first to validate a molecular response–guided treatment strategy in HR+/HER2-negative advanced breast cancer, potentially redefining first-line management.

However, questions remain regarding long-term Overall Survival benefits and the cost-effectiveness and logistical feasibility of serial ctDNA monitoring. Additional follow-up and Real-World Data will be crucial to determine the broader clinical utility of this approach.

Conclusion
Camizestrant in combination with CDK4/6 inhibition, guided by ctDNA detected ESR1 mutations emergence, offers a promising new treatment paradigm for HR+/HER2-negative advanced breast cancer. SERENA-6 paves the way for incorporating precision molecular monitoring into routine first-line management.

Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial. Turner N, Mayer E, Park YH, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA4).

FDA Grants Accelerated Approval to EMRELIS® for NSCLC with High c-Met Overexpression

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SUMMARY: The FDA on May 14, 2025, granted accelerated approval to Telisotuzumab vedotin-tllv (EMRELIS®), a c-Met-directed antibody and microtubule inhibitor conjugate, for adults with locally advanced or metastatic, non-squamous Non-Small Cell Lung Cancer (NSCLC) with high c-Met protein overexpression [≥50% of tumor cells with strong (3+) staining], as determined by an FDA-approved test, who have received a prior systemic therapy. FDA also approved the VENTANA MET (SP44) RxDx Assay as a companion diagnostic test to aid in detecting c-Met protein overexpression in patients with non-squamous NSCLC who may be eligible for treatment with Telisotuzumab vedotin.

The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

The MET proto-oncogene encodes c-Met, a receptor tyrosine kinase also known as the Hepatocyte Growth Factor (HGF) receptor, that plays a central role in regulating cellular processes such as proliferation, survival, and angiogenesis. Aberrations in the MET pathway, including gene amplification or exon 14 skipping mutations, are implicated in a subset of non–small cell lung cancer (NSCLC) cases. Approximately 5% of patients harbor MET amplification and 2-4% carry MET mutations, making this an increasingly relevant therapeutic target. While MET tyrosine kinase inhibitors (TKIs) are approved for MET exon 14 skipping mutations and are under investigation for amplification, no targeted therapies are currently available for MET protein overexpression, a phenomenon observed in roughly 25-39% of NSCLCs and associated with poor prognosis.

Telisotuzumab vedotin is a first-in-class Antibody-Drug Conjugate directed against c-Met. It combines a monoclonal antibody targeting c-Met with the cytotoxic agent MonoMethyl Auristatin E (MMAE). Telisotuzumab uses c-Met protein overexpression as a biomarker to deliver its cytotoxic payload selectively to tumor cells, distinguishing it from therapies that rely on genomic alterations alone. In early-phase studies, it demonstrated encouraging antitumor activity and manageable toxicity in c-Met–overexpressing NSCLC.

LUMINOSITY Trial Design
The Phase II LUMINOSITY trial evaluated Telisotuzumab in patients with locally advanced or metastatic c-Met–overexpressing NSCLC who had received ≤2 prior lines of systemic therapy. Stage I of this study enrolled three cohorts based on tumor histology and EGFR status:

  1. Nonsquamous EGFR-wildtype
  2. Nonsquamous EGFR-mutant
  3. Squamous NSCLC

Stage II of this trial focused on the nonsquamous EGFR-wildtype cohort, which showed the most promise in Stage I part of the study. c-Met overexpression was determined by immunohistochemistry (IHC), with high expression defined as ≥50% of tumor cells showing 3+ membrane staining, and intermediate expression as ≥25% to <50%. Telisotuzumab was administered at a dose of 1.9 mg/kg IV every two weeks. The Primary endpoint was Overall Response Rate (ORR) as assessed by Independent Central Review using RECIST v1.1 criteria. Secondary endpoints included Duration of Response (DOR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS).

Efficacy Outcomes
Among 172 patients with nonsquamous EGFR wild-type NSCLC treated at the 1.9 mg/kg dose, 161 were evaluable for efficacy. This group included 84 patients with high c-Met expression and 84 with intermediate expression. The ORR in the total c-Met overexpression group was 28.6% (95% CI, 21.7–36.2). When stratified, ORRs were higher in the c-Met high group at 34.6% (95% CI, 24.2–46.2) compared to 22.9% (95% CI, 14.4–33.4) in the intermediate group.

The median time to response was 1.41 months. Duration of response was also encouraging, with medians of 9.0 months in the high-expression group and 7.2 months in the intermediate group. Median PFS across all c-Met–overexpressing patients was 5.7 months, with similar figures for the high and intermediate groups. Median OS was 14.5 months overall and nearly identical across subgroups.

Safety Profile
Telisotuzumab was generally well tolerated. The most common treatment-related Adverse Events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%). Grade ≥3 AEs were infrequent, with peripheral sensory neuropathy being the most common (7%).

Conclusion
Telisotuzumab demonstrated durable antitumor activity and manageable toxicity in patients with c-Met protein–overexpressing, nonsquamous EGFR-wildtype NSCLC, especially those with high c-Met expression. Although the LUMINOSITY trial lacked a comparator arm, the results support further evaluation of Telisotuzumab in this population. A randomized phase III trial is ongoing and will compare Telisotuzumab monotherapy with Docetaxel in previously treated patients. Given the unmet need and lack of approved therapies targeting c-Met protein overexpression, Telisotuzumab represents a promising therapeutic advance in NSCLC.

 Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein–Overexpressing Advanced Nonsquamous EGFR-Wildtype Non–Small Cell Lung Cancer in the Phase II LUMINOSITY Trial. Camidge DR, Bar J, Horinouchi H, et al.  J Clin Oncol 42:3000-3011, 2024

 

Zongertinib Shows Promising Efficacy and Safety in HER2-Mutant NSCLC: Insights from the Beamion LUNG-1 Trial

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SUMMARY: The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including Breast, Gastric, Lung and Colorectal cancers. It is a growth-promoting protein, and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types.

HER2 mutations unlike HER2 overexpression and gene amplification are oncogenic drivers and are detected in 2 to 4% of NSCLCs. They are more often detected in younger, female and never-smokers, and almost exclusively in Adenocarcinomas. Next-generation sequencing is used to identify HER2 mutations. Majority of HER2 mutations (80-90%) occur in exon 20, as either a duplication or an insertion of 12 nucleotides, resulting in the addition of four amino acids (YVMA) at codon 775 in the kinase domain. This distinct molecular entity is characterized by specific pathological and clinical behavior. These acquired HER2 gene mutations have been independently associated with cancer cell growth, aggressive form of disease and poor prognosis, and with an increased incidence of brain metastases.

The FDA in 2022 granted accelerated approval to ENHERTU&reg; (Trastuzumab deruxtecan), for adult patients with unresectable or metastatic NSCLC whose tumors have HER2 (ERBB2) mutations. This is the first drug approved for HER2-mutant NSCLC. Trastuzumab deruxtecan however can be associated with toxicities including Interstitial Lung Disease (ILD). Similarly, pan-HER TKIs such as Poziotinib and Pyrotinib have shown limited efficacy and are frequently associated with EGFR-related adverse events, underscoring the urgent need for more targeted, better-tolerated therapies.

Zongertinib is a novel, oral, irreversible Tyrosine Kinase Inhibitor designed to selectively target HER2 while sparing EGFR, thus minimizing common toxicities such as rash and diarrhea.

Beamion LUNG-1 is an ongoing Phase 1a/1b trial evaluating Zongertinib in previously treated patients with HER2-altered advanced or metastatic solid tumors (Phase 1a) and those with HER2-mutant advanced or metastatic NSCLC across multiple clinically relevant patient cohorts (Phase 1b). In the Phase 1a dose-escalation trial, Zongertinib showed encouraging preliminary activity at the recommended expansion doses of 120 mg and 240 mg once daily, with a low incidence of Grade 3 or higher adverse events.

The Phase 1b portion of the study evaluated Zongertinib in three key populations:

  • Cohort 1: Patients with tumors harboring HER2 mutations in the TKD (Tyrosine Kinase Domain), the most common category of HER2 mutations encountered in the clinic.
  • Cohort 5: Patients whose tumors had HER2 mutations within the TKD and had previously received HER2-directed ADCs, including Trastuzumab deruxtecan.
  • Cohort 3: Patients whose tumor had HER2 mutations outside the TKD.

Patients were initially treated at 120 mg or 240 mg daily and following interim analysis, 120 mg was selected as the optimal dose based on a favorable efficacy and safety balance. The median age in Cohort 1 was 62 yrs. The Primary end point was an Objective Response Rate (ORR) assessed by Blinded Independent Central Review (Cohorts 1 and 5) or by Investigator Review (Cohort 3). Secondary end points included the Duration of Response and Progression-Free Survival (PFS).

Efficacy Outcomes
The median follow-up was 11.3 months at the data-cutoff date. Zongertinib demonstrated robust and durable activity, particularly in Cohort 1:

  • Cohort 1 (N=75 at 120 mg daily dose):
    • Objective response rate (ORR): 71% (P<0.001)
    • Median Duration of Response (DoR): 14.1 months
    • Median progression-free survival (PFS): 12.4 months

Importantly, responses were consistent across subgroups, including patients with brain metastases (ORR: 64%) and common TKD insertion subtypes such as A775_G776insYVMA (ORR: 81%).

  • Cohort 5 (N=31):
    • ORR: 48%, including patients previously treated with Trastuzumab deruxtecan (ORR: 42%)
  • Cohort 3 (N=20):
    • ORR: 30%
    • Activity observed across several non-TKD mutations (e.g., S310X, V659E)

These findings suggest that Zongertinib may offer a viable treatment option even in patients who have progressed on ADCs or harbor atypical HER2 alterations.

Safety and Tolerability
Zongertinib was well tolerated across all cohorts:

  • Grade ≥3 drug-related adverse events occurred in:
    • 17% of patients in Cohort 1
    • 3% in Cohort 5
    • 25% in Cohort 3
  • No cases of drug-related interstitial lung disease were observed
  • Most common adverse event was diarrhea (any grade: 56%; grade ≥3: 1%), followed by rash (all grade ≤2)

The safety profile compares favorably with existing HER2-targeted agents, including Trastuzumab deruxtecan, which has reported interstitial lung disease rates of up to 26% in earlier trials.

Clinical Context and Future Directions
Compared with other HER2-targeted agents including Trastuzumab deruxtecan and investigational pan-HER TKIs, Zongertinib stands out for its high response rates, durability, and manageable toxicity. While cross-study comparisons have inherent limitations, these results support Zongertinib as a promising, HER2-selective oral agent for patients with HER2-mutant NSCLC. The ongoing Phase 3 Beamion LUNG-2 trial (NCT06151574) will further assess Zongertinib in the first-line setting, providing critical data on its role relative to current standard-of-care therapies.

Conclusion
Zongertinib has emerged as a strong candidate in the evolving landscape of HER2-mutant NSCLC. With high response rates, durable outcomes, and a favorable safety profile, it may soon offer oncologists a powerful new tool for treating this difficult-to-manage patient population.

Zongertinib in Previously Treated HER2-Mutant Non–Small-Cell Lung Cancer. Heymach JV, Ruiter G, Ahn M-J, et al. for the Beamion LUNG-1 Investigators. Published April 28, 2025. DOI: 10.1056/NEJMoa2503704

Prostate Cancer Screening with Polygenic Risk Score

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease

PSA is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. PSA-based screening is widely debated due to false positives, overdiagnosis, and overtreatment.

The researchers in the present study hypothesized that Polygenic Risk Scores (PRS) based on aggregation of common genetic variants offer a promising way to stratify individual risk, independent of PSA or family history. Following completion of a pilot study, the BARCODE1 study was designed to prospectively test whether using a Polygenic Risk Score (PRS) could improve targeted screening effectiveness.

STUDY DESIGN:
BARCODE1 is a prospective, population-based, genetic risk-stratified screening study which included 6,393 men aged 55-69 yrs, with their Polygenic Risk Score calculated and recruited from 130 UK general practices. Germline DNA from saliva was used to calculate Polygenic Risk Score based on 130 known prostate cancer SNPs (Single Nucleotide Polymorphisms). Single Nucleotide Polymorphisms (SNPs “snips”) are variations in certain genes of a person’s DNA that can increase or decrease an individual’s risk of susceptibility to the disease. Men in the top 10% of the Polygenic Risk Score distribution (N=745) were invited for further screening with multiparametric MRI (mpMRI) and transperineal biopsy, regardless of PSA level.

KEY RESULTS:
MRI/biopsy was performed in 468 of these 745 men and 40% (N=187) were diagnosed with prostate cancer. Of the 187 participants, 103 men (55.1%) had clinically significant (Grade Group ≥2) cancer.

High-risk (Grade Group 3-5) cancer was found in 21.4% (N=40) of diagnosed men. These cancers typically qualify for radical therapy.

Current UK PSA thresholds (PSA >3.0 ng/mL) would have missed 71.8% of clinically significant cancers found through Polygenic Risk Score-based screening. Notably, 52% of all clinically significant cases had PSA <3.0 ng/mL, reinforcing the inadequacy of PSA-alone screening.

Estimated overdiagnosis (Grade Group 1 tumors) was 15.6–20.8%, comparable to, or lower than rates seen in PSA-based screening.

mpMRI-negative but Polygenic Risk Score-positive men still had a 6.4% clinically significant prostate cancer detection rate, underscoring Polygenic Risk Score value beyond imaging.

CONCLUSION:
Polygenic Risk Score-based screening detected more clinically significant prostate cancers than PSA or mpMRI alone. Combining Polygenic Risk Score with age and family history may help optimize risk-based screening strategies. One important limitation of this study is that participants were mostly educated men of European ancestry. These results may therefore not generalize to other ethnic groups or broader populations. Further research is needed to assess cost-effectiveness, utility across ancestries, and integration of genomics into national screening programs.

Polygenic Risk Score for Prostate Cancer Screening. McHugh JK, Bancroft EK, Saunders E, et al. for the BARCODE1 Steering Committee and Collaborators. N Engl J Med 2025;392:1406-1417

Emerging Biomarker Insights in Esophageal Squamous Cell Carcinoma: NOTCH1 Mutations as a Predictor of Anti–PD-1 Benefit

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SUMMARY: The American Cancer Society estimates that in 2025, about 22,070 new cases of esophageal cancer will be diagnosed in the US and about 16,250 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in Caucasians. Squamous Cell Carcinoma (SCC) accounts for approximately 85% of cases. Majority of esophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually will relapse, and only about 20% of patients will survive at least 5 years following diagnosis. Patients with advanced esophageal cancer have a median survival of less than a year when treated with the standard Fluoropyrimidine plus Platinum based chemotherapy. For those patients progressing on first line chemotherapy, treatment options are limited, with a 5-year relative survival rate of 8% or less.

Recent advancements in the treatment of advanced or metastatic Esophageal Squamous Cell Carcinoma (ESCC) have firmly positioned Immune Checkpoint Inhibitors (ICIs) as a cornerstone of second-line therapy. Numerous agents targeting PD-1 have demonstrated superior clinical outcomes compared to chemotherapy.

Tislelizumab (TEVIMBRA&reg;)  is a humanized immunoglobulin G4 (IgG4) anti-Programmed cell Death protein- 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is uniquely designed to minimize binding to Fc-gamma receptors on macrophages, helping to aid immune cells of the body to detect and fight tumors, while minimizing off-target effects. The FDA in 2024 approved Tislelizumab in combination with platinum-containing chemotherapy for the first-line treatment of adults with unresectable or metastatic ESCC whose tumors express PD-L1 (≥1) and also as a single agent in adults with unresectable or metastatic ESCC after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor.

RATIONALE-302 is a randomized, open-label, multicenter, Phase 3 study in which 512 patients with advanced or metastatic ESCC whose tumor progressed after first-line systemic treatment, were randomly assigned (1:1) to receive Tislelizumab 200 mg IV every 3 weeks or chemotherapy (investigators choice of Paclitaxel, Docetaxel, or Irinotecan). The trial met its Primary endpoint, demonstrating a significant improvement in Overall Survival (OS) with Tislelizumab over chemotherapy.

A comprehensive biomarker analysis stemming from the pivotal RATIONALE-302 trial has shed light on a promising genomic signal that could shape future treatment pathways. Researchers conducted extensive tumor profiling using PD-L1 ImmunoHistoChemistry (N=359), Gene Expression Profiling (N=346), and Mutation analysis (N=209) on tumor samples from patients enrolled in the RATIONALE-302 trial. The aim of this study was to uncover molecular determinants of response to Tislelizumab.

Clinical Findings: NOTCH1 as a Predictive Biomarker
Among the 209 patients with available mutation data, 22% harbored NOTCH1 mutations. This subgroup demonstrated a markedly improved Overall Survival (OS) with Tislelizumab, compared to chemotherapy:

  • Median OS with tislelizumab: 18.4 months
  • Median OS with chemotherapy: 5.3 months
  • Hazard Ratio: 0.35 (95% CI, 0.17–0.71)

In contrast, patients with wild-type NOTCH1 derived minimal OS benefit from tislelizumab (6.0 vs 6.9 months; HR 0.81), underscoring the potential of NOTCH1 status to guide therapeutic decisions.

Mechanistic Insights: An Immunologically Favorable TME
Transcriptomic data linked NOTCH1 mutations to increased expression of Type I interferon (IFN-I) and Toll-Like Receptor (TLR) signatures—hallmarks of an activated Tumor MicroEnvironment (TME). Concurrently, these tumors exhibited reduced infiltration by B cells and neutrophils, which have been associated with resistance to immunotherapy.

Further validation using murine models showed that NOTCH1 deficiency promotes a TME, more permissive to anti–PD-1 activity, supporting a biological rationale for these clinical findings.

Independent of PD-L1 and TMB
Importantly, the survival benefit associated with NOTCH1 mutations was independent of PD-L1 expression levels and Tumor Mutational Burden (TMB). Even among patients with low PD-L1 tumor positivity (<10%), those with NOTCH1 mutations showed a trend toward improved OS with Tislelizumab over chemotherapy.

Broader Genomic Context
In addition to NOTCH1, alterations in genes such as KMT2D also correlated with improved response to Tislelizumab compared to investigator chosen chemotherapy, while EGFR alterations were associated with diminished benefit. The frequently mutated genes in the RATIONALE-302 cohort – TP53, CCND1, FGF3/4/19, CDKN2A, PIK3CA, KMT2D, NFE2L2, and TP63- fall into functional categories including cell cycle regulation, differentiation, PI3K signaling, and chromatin remodeling consistent with previous reports.

Clinical Implications
These findings strongly suggest that NOTCH1 mutation status should be evaluated in patients with advanced ESCC being considered for anti–PD-1 therapy. Routine integration of Next-Generation Sequencing (NGS) may enhance treatment personalization by identifying patients most likely to derive significant benefit from immunotherapy, beyond the current reliance on PD-L1 ImmunoHistoChemistry or TMB alone.

Next Steps
While these results are promising, prospective validation is needed. A clinical trial is currently being planned to assess whether patients with NOTCH1-mutated ESCC may be optimally treated with ICI monotherapy. Additional translational studies are underway to further clarify resistance mechanisms and inform future biomarker-driven strategies.

NOTCH1 Mutation and Survival Analysis of Tislelizumab in Advanced or Metastatic Esophageal Squamous Cell Carcinoma: A Biomarker Analysis From the Randomized, Phase III, RATIONALE-302 Trial. Lu Z, Du W, Jiao X, et al. J Clin Oncol. Published online April 3, 2025. https://doi.org/10.1200/JCO-24-01818

 

Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease.

The five year survival among patients first diagnosed with metastatic prostate cancer is approximately 30%. Early detection and treatment may improve outcomes. Risk factors for prostate cancer include age, ethnicity, and family history of prostate cancer. In individuals with a family history of prostate cancer in one or more first-degree relatives, the Relative Risk of prostate cancer increases approximately 2-3 fold, and the risk increases with an increasing number of affected relatives, and is inversely related to the age at time of diagnosis among those relatives.

It is estimated that approximately 40% of all diagnosed prostate cancers are inherited and prostate cancer risk also has been implicated in other familial cancer syndromes such as Hereditary Breast and Ovarian Cancer (HBOC) syndrome and Lynch Syndrome (LS). HBOC syndrome typically is found in families with early onset cancer and multiple cancer diagnoses such as, breast, ovarian and pancreatic cancer. Tumor suppressor DNA repair genes BRCA1 and BRCA2, has been implicated in prostate cancer, particularly in HBOC families. Patients with a BRCA1 mutation have a nearly 2-fold Relative Risk of prostate cancer among men less than 65 years, whereas those with BRCA2 mutations have a more than 7 fold Relative Risk. Further, patients with BRCA2 mutations are also associated with clinically aggressive disease, progression, and higher rates of cancer-specific mortality. It is estimated that the frequency of BRCA2 mutations ranges from 1-3%.

Somatic genomic testing in metastatic prostate cancer can offer insights into both prognosis and potential treatment responses, helping guide clinical decisions. Germline genetic testing can also yield similar insights, with the added benefit of revealing inherited cancer risks that may be relevant to patients relatives, including risks for cancers such as breast, pancreatic, colon, and endometrial. As a result, research has focused on determining which germline and somatic genetic tests deliver the most valuable information for individual patient cases.

The present ASCO guideline was developed by a multidisciplinary Expert Panel, following review of evidence on germline and somatic genomic testing for patients with metastatic prostate cancer. A total of 1,713 papers were identified in the literature search, and the recommendations are based on evidence from eight systematic reviews and six trials. This guideline is applicable to a patient who has a life expectancy of more than 6 months, is a candidate for systemic treatment, and for whom appropriate germline and somatic testing, including expertise in interpretation, is readily available.

This guideline addresses the following questions:
1) Why germline and somatic genomic testing should be offered?
2) The criteria for which patients should be offered testing?
3) Which test(s) to use?
4) When in the disease course testing should be considered?
5) Which biospecimens should be used for testing?

RECOMMENDATIONS

Clinical Question: Who should receive germline testing with NGS technologies?

Recommendation: All patients with metastatic prostate cancer should undergo germline genetic testing with next-generation sequencing technologies.

Clinical Question: Who should receive somatic testing with NGS technologies?

Recommendation: Those patients with metastatic prostate cancer (both Castrate Sensitive and Castrate Resistant Prostate Cancer) who are being considered for biomarker-directed systemic treatment should undergo somatic testing with next-generation sequencing technologies. While there are no current FDA-approved biomarker-directed treatments following somatic testing for metastatic Castrate Sensitive Prostate Cancer, somatic testing may be warranted in the presence of high-volume disease, or where there is a high likelihood the patient’s disease will progress to Castrate Resistant Prostate Cancer, where the patient is a candidate for future treatment with a biomarker-directed therapy (PARP inhibitor or checkpoint inhibitor).

Clinical Question: Who should receive sequential somatic testing with NGS technologies?

Recommendation: The panel recommends that sequential somatic testing may be offered when there has been a meaningful change in the patient’s status or treatment plan, especially in cases where prior tests were negative or uninformative (eg, insufficient or low tumor content).

Clinical Question: What are the strengths and weaknesses of primary tumor archival tissue versus fresh metastatic biopsy tissue versus ctDNA testing for somatic testing?

Recommendation: Archival tissue samples are preferred in initial testing. ctDNA is preferred when there is no accessible metastatic site to biopsy or for sequential testing. In the setting of minimal disease burden associated with low ctDNA fraction, metastatic biopsy is preferred.

Clinical Question: What are the key therapeutic impacts of germline or somatic testing for single-gene genetic variants (eg, BRCA1, BRCA2)?

Recommendation: Patients with pathogenic germline variants or somatic alterations in BRCA1 and BRCA2 demonstrate poorer outcomes, but are candidates for treatment with PARP inhibitor monotherapy, PARP inhibitor with Androgen Receptor Pathway Inhibitor combination therapy, and platinum-based agents.

Clinical Question: What are the key prognostic impacts of germline or somatic testing?

Recommendation: Treatment recommendations should not be made based on prognostic only biomarkers. However, they may be considered for directing patients to clinical trials. Germline information may still be important for patient counseling, informing hereditary risk for patients and families.

Pre-Test Genetic Counseling for Germline Testing

Before conducting germline testing, clinicians should ensure patients understand the following essential aspects:

  • Purpose of Testing: Explain the goals and implications of germline genetic testing.
  • Hereditary Nature: Emphasize that the results can reveal inherited cancer risks.
  • Family Impact: Discuss how findings might indicate elevated cancer risks for relatives.
  • Testing Options: Inform patients about the availability of gene panel testing.
  • Possible Outcomes:
    • Pathogenic/Likely Pathogenic Variants (P/LPVs)
    • Variants of Uncertain Significance (VUS)
    • Negative or Inconclusive Results
  • Legal Protections: Outline patient protections under the Genetic Information Nondiscrimination Act (GINA).
  • Cascade Testing: Stress the importance of testing family members when a P/LPV is found.

Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline. Yu EY, Rumble RB, Agarwal N, et al. J Clin Oncol. 2025;43:748-758. DOI:10.1200/JCO-24-02608.

FDA Approves Radioligand Therapy with PLUVICTO® Before Chemotherapy in Castrate Resistant Prostate Cancer

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SUMMARY: The FDA on March 28, 2025, expanded the indication for Lutetium Lu 177 vipivotide tetraxetan (PLUVICTO&reg;) to include adults with Prostate-Specific Membrane Antigen (PSMA)-positive metastatic Castration-Resistant Prostate Cancer (mCRPC) who have been treated with Androgen Receptor Pathway Inhibitor (ARPI) therapy and are considered appropriate to delay taxane-based chemotherapy. Patients with previously treated mCRPC should be selected for PLUVICTO&reg; using LOCAMETZ&reg; (active ingredient Gallium Ga 68 gozetotide) or another approved PSMA Positron Emission Tomography (PET) product based on PSMA expression in tumors.

Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPI), which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). Approximately 10-20% of patients with advanced prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies. Patients who progress on Androgen Deprivation Therapy are often switched to second line hormonal treatments that block testosterone with a different mechanism of action, and upon further progression, offered taxane based chemotherapy.

Prostate-Specific Membrane Antigen (PSMA) is a Type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer.

Lutetium Lu 177 vipivotide tetraxetan (PLUVICTO®) is a radiopharmaceutical that targets PSMA. It is comprised of Lutetium-177, a cytotoxic radionuclide, linked to the ligand PSMA-617, a small molecule designed to bind with high affinity to PSMA. Radioligand therapy with PLUVICTO® targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell.

The FDA in March 2022, approved PLUVICTO® for the treatment of adult patients with Prostate-Specific Membrane Antigen (PSMA)-positive metastatic Castration-Resistant Prostate Cancer (mCRPC), who had been treated with Androgen-Receptor Pathway Inhibitors (ARPI) such as Enzalutamide or Abiraterone acetate and 1 or 2 taxane based chemotherapy regimens. This approval was based on the VISION Phase III study.

PSMAfore is a Phase III trial conducted to assess the benefit of PLUVICTO® in patients with metastatic Castration-Resistant Prostate Cancer who had progressed on ARPIs, but had NOT received taxane based chemotherapy, with the hope of making this promising therapy available to more patients earlier in the course of their treatment journey. This study enrolled 468 patients (N=468) with taxane-naive metastatic CRPC who had PSMA-positive disease on gallium-68–PSMA-11 PET/CT, and were candidates for an ARPI change after one progression on prior ARPI. Patients were randomized (1:1) to receive PLUVICTO® 7.4 GBq (200 mCi) IV every 6 weeks for 6 doses, or a change in ARPI (Abiraterone or Enzalutamide). The Primary endpoint was radiographic Progression Free Survival (rPFS). Secondary endpoints included Overall Survival (OS), Prostate-Specific Antigen (PSA) declines of 50% or more from baseline – known as a PSA50 response, Quality of Life measures, and Safety profiles.

At the Primary analysis conducted at 7.3 months, patients treated with PLUVICTO® demonstrated a median rPFS of 9.3 months compared to 5.6 months in the ARPI change group, showing a statistically significant and clinically meaningful benefit (HR=0.41; P<0.0001).

In the updated exploratory analysis, performed with a median follow-up of 24 months, PLUVICTO® more than doubled median rPFS versus ARPI change group (11.6 months versus 5.6 months, HR=0.49), with a 51% reduction in the risk of radiographic progression or death with PLUVICTO® versus a change in ARPI. At the preplanned final analysis, Overall Survival (OS) numerically favored PLUVICTO® but was not statistically significant. The median OS was 24.5 months with PLUVICTO® and 23.1 months with a change in ARPI (HR=0.91 (95% CI, 0.72-1.14). High crossover rate may have confounded OS analysis. Approximately 60% of patients randomized to the change in ARPI group subsequently crossed over to receive PLUVICTO® following confirmed radiographic progression. The Objective Response Rate (ORR) in the PLUVICTO® group was 49% versus 14% in the change in ARPI group, with Complete Response Rates of 21% versus 2.8%, respectively. PSA50 response was 51% with PLUVICTO® and 17% with change in ARPI.

The most frequently reported all-grade adverse events for PLUVICTO® included dry mouth, fatigue, nausea, and constipation, and were primarily Grade 1-2. Further, PLUVICTO® did not impair the ability of patients to be treated with subsequent chemotherapy.

It was concluded that in the updated analysis of the PSMAfore trial, PLUVICTO® more than doubled median rPFS versus a change in ARPI, with favorable safety profile and proven tolerability. The findings from the PSMAfore study suggest that PLUVICTO® could provide a viable therapeutic option earlier in the disease course, potentially delaying or obviating the need for more toxic chemotherapy regimens.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication

KADCYLA® Improves Overall Survival in Residual HER2-Positive Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive early stage, as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival (OS), when compared with TYKERB® (Lapatinib) plus XELODA® (Capecitabine), in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a Taxane.

It is well established that patients with HER2-positive early breast cancer, following HERCEPTIN® based neoadjuvant therapies, have a pathological Complete Response rate of 40-60%. Those without a pathological Complete Response tend to have significantly less favorable outcomes. These patients irrespective of pathological response status complete their standard adjuvant therapy which includes 12 months of HER2-targeted therapy.

KATHERINE trial was conducted to evaluate the benefit of switching from standard HER2-directed therapy to single-agent KADCYLA®, after neoadjuvant chemotherapy along with either single or dual HER2 targeted therapy, in patients with residual invasive cancer at surgery. This study was conducted to address the unmet need of patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2-targeted therapy.

The KATHERINE trial is an open-label, Phase III global study, which compared KADCYLA® with HERCEPTIN®, as an adjuvant treatment for patients with HER2-positive early breast cancer, who had residual invasive disease following neoadjuvant chemotherapy and HERCEPTIN®. This study included 1,486 patients with HER2-positive early stage breast cancer, who were found to have residual invasive disease in the breast or axillary lymph nodes at surgery, following at least six cycles (16 weeks) of neoadjuvant chemotherapy with a Taxane (with or without Anthracycline) and HERCEPTIN®. Within 12 weeks of surgery, patients (N=1486) were randomly assigned in a 1:1 ratio to KADCYLA® 3.6 mg/kg IV every 3 weeks or HERCEPTIN® 6 mg/kg IV every 3 weeks, for 14 cycles (743 patients in each group). Patients also received standard-of-care radiation and endocrine therapy as per institutional guidelines. Both treatment groups were well balanced and Hormone Receptor positive disease was present in 72% of the patients. The majority of the patients (77%) had received an Anthracycline-containing neoadjuvant chemotherapy regimen, and in 19% of the patients, another HER2-targeted agent in addition to HERCEPTIN® (dual HER2 blockade) had been administered as a component of neoadjuvant therapy. The Primary end point was invasive Disease Free Survival-iDFS (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). The Primary analysis showed that 3-year invasive DFS was significantly higher in the KADCYLA® group than in the HERCEPTIN® group (88.3% vs. 77.0%; HR=0.50; P<0.001), suggesting that KADCYLA® reduced the risk of developing an invasive breast cancer recurrence or death by 50%.

The researchers in this publication reported the prespecified final analysis of invasive DFS, and the second interim analysis of Overall Survival. With a median follow-up of 8.4 years, KADCYLA® sustained its superiority over HERCEPTIN® in improving invasive DFS and OS. The 7-year invasive DFS rate was 80.8% with KADCYLA® vs. 67.1% with HERCEPTIN® (unstratified HR=0.54, confirming a 46% reduction in risk. The 7-year OS was 89.1% with KADCYLA® vs. 84.4% with HERCEPTIN® (unstratified HR=0.66; P=0.003), demonstrating a 34% reduction in mortality risk.

Further analyses revealed consistent benefits across key subgroups which included patients with low tumor burden minimal residual disease (1 cm or less, node-negative), HER2-negative residual disease on retesting, both ER-positive and ER-negative patients, as well as HER2 expression level, with patients with IHC 3+ HER2 expression experiencing the most significant benefit (HR=0.47), whereas those with IHC 2+ ISH-amplified tumors had a smaller, though still positive, effect (HR=0.84).

The incidence of adverse events of Grade 3 or higher was noted in 26.1% of patients receiving KADCYLA® compared to 15.7% in the HERCEPTIN® group. The frequency of CNS metastases was comparable between the two cohorts, suggesting that while KADCYLA® enhances control of extracranial disease, it does not necessarily reduce CNS metastases.

In conclusion, the KATHERINE trial has established KADCYLA® as the new standard of care for patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant therapy. Long-term follow-up confirms sustained benefits in invasive DFS and OS, with an acceptable safety profile. While KADCYLA® significantly reduces recurrence and improves survival, certain high-risk subgroups may require additional therapeutic strategies, prompting the need for ongoing research. Future advancements in HER2-targeted therapies, including Tyrosine Kinase Inhibitors, Antibody Drug Conjugates, and immunotherapy combinations, will further refine treatment strategies and improve outcomes for this high-risk patient population.

Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. Geyer CE, Untch M, Huang C-S, et al. for the KATHERINE Study Group. N Engl J Med 2025;392:249-257

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