Category: Precision Oncology

Precision Approaches in Stage III NSCLC: A New Standard of Care

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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.

Stage III NSCLC represents a diverse and complex clinical scenario, historically guided by resectability and nodal involvement. Approximately one third of all patients with NSCLC have Stage III, locally advanced disease at the time of initial presentation and 60 to 90% of these patients have unresectable disease. However, recent ASCO guideline updates emphasize the integration of biomarker testing and precision medicine to improve outcomes across both resectable and unresectable disease.

Unresectable Stage III NSCLC with EGFR Mutation: Osimertinib Now Preferred

The Phase III LAURA trial established a new benchmark for patients with unresectable Stage III NSCLC harboring common EGFR mutations (exon 19 deletion or exon 21 L858R mutation). Osimertinib (TAGRISSO®), administered after completion of definitive chemoradiotherapy, led to a nearly 7-fold improvement in median Progression-Free Survival (39.1 vs 5.6 months; HR 0.16, P<0.001) compared with placebo. The incidence of brain metastases was also significantly reduced (8% vs 29%).

Given this magnitude of benefit and the modest toxicity profile (Grade ≥3 adverse events in 35%, including low rates of severe pneumonitis), Osimertinib is now considered the preferred consolidation therapy in this setting. Immune checkpoint inhibitors (ICIs), commonly used in other NSCLC populations, should be avoided in EGFR-mutated cases due to lack of efficacy and potential toxicity with sequential therapy.

Resected Stage III NSCLC: Targeted Adjuvant Therapies Lead the Way

EGFR-Mutated Disease – Adjuvant Osimertinib

Updated results from the Phase III ADAURA trial confirmed that adjuvant Osimertinib for 3 years significantly improves both Disease-Free Survival (DFS) and Overall Survival (OS) in patients with completely resected Stage IB–IIIA EGFR-mutated (exon 19 deletion or exon 21 L858R mutation) NSCLC. For patients with Stage IIIA, the DFS was extended to 55.1 months vs 14.4 months (HR=0.22), and 5-year OS rates reached 85% with Osimertinib compared to 67% with placebo (HR=0.37). There was greater DFS and OS benefit with adjuvant Osimertinib among patients with Stage III disease than that observed for Stage II or IB.

Platinum-based chemotherapy remains recommended before initiating Osimertinib, despite its non-mandatory use in ADAURA trial. Clinicians should counsel patients on the 3-year treatment duration plan with Osimertinib, cost considerations, and manageable toxicity profile.

ALK-Positive Disease – Adjuvant Alectinib

The Phase III ALINA trial established that 2 years of adjuvant Alectinib (ALECENSA®) as a superior alternative to chemotherapy in completely resected stage II–IIIA ALK-rearranged NSCLC. Two-year DFS was 93.8% with alectinib versus 63.0% with chemotherapy (HR=0.24; P<0.001). Alectinib also significantly reduced CNS relapse risk. While the trial did not include chemotherapy in the Alectinib arm, many experts still recommend preceding adjuvant Alectinib with four cycles of platinum–Pemetrexed doublet chemotherapy, based on known chemosensitivity in ALK-positive tumors.

Targeted Therapy for Rare Driver Mutations: Proceed with Caution

Although actionable mutations like ROS1 and RET are increasingly identified, there is limited evidence to guide adjuvant or consolidation therapy in Stage III NSCLC for these alterations. Clinicians should be cautious when extrapolating data from EGFR or ALK trials, given the lack of prospective data in this setting.

Immunotherapy in the Perioperative Setting: Expanding Options for Resectable Stage III NSCLC

Emerging data support the use of neoadjuvant and perioperative chemoimmunotherapy in resectable Stage III NSCLC without EGFR or ALK alterations. Trials such as CheckMate-816 (Nivolumab), KEYNOTE-671 (Pembrolizumab), AEGEAN (Durvalumab), and CheckMate-77T showed improvements in pathological Complete Response and Event-Free Survival when Immune Checkpoint Inhibitors (ICIs) were added to neoadjuvant chemotherapy.

These studies typically continued ICI therapy for up to one year post-surgery. Although overall survival data remain immature, perioperative immunotherapy has become a viable treatment paradigm in patients with PD-L1-positive, driver mutation-negative disease. Conversely, patients with EGFR or ALK alterations should not be offered ICIs in the adjuvant or consolidation setting.

Take-Home Message

ASCO’s guideline update underscores a paradigm shift in Stage III NSCLC, integrating molecular profiling and personalized treatment strategies. Key recommendations include:

  • Osimertinib for unresectable EGFR-mutant NSCLC post-chemoradiotherapy
  • Adjuvant Osimertinib or Alectinib in resected Stage III disease with EGFR or ALK alterations, respectively
  • Chemoimmunotherapy in resectable, driver mutation-negative Stage III NSCLC

As the treatment landscape rapidly evolves, multidisciplinary collaboration and upfront biomarker testing are essential to optimize outcomes.

Management of Stage III Non–Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update Clinical Insights. Singh N, Früh M, Gubens MA, et al. JCO Oncol Pract. 2024;21:463-466

DESTINY-Gastric04: Trastuzumab Deruxtecan Improves Survival Over Ramucirumab Plus Paclitaxel in HER2-Positive Gastric and GEJ Cancers

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SUMMARY: The American Cancer Society estimates that in the US, about 30,300 new cases of Gastric cancer will be diagnosed in 2025 and about 10,780 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of advanced Gastric and GastroEsophageal (GE) junction cancers, overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody, Trastuzumab, as there is Overall Survival (OS) benefit with this combination regimen. Upon progression, Paclitaxel plus Ramucirumab (CYRAMZA®), an anti-VEGFR-2 antibody is recommended as second-line therapy, regardless of HER2 expression, based on OS and Progression Free Survival (PFS) data for this combination regimen. 

Trastuzumab Deruxtecan (T-DXd) (ENHERTU®) is an 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 (KADCYLA®), 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, minimizing systemic exposure.

The DESTINY-Gastric04 study represents the first confirmatory Phase 3 trial evaluating T-DXd as second-line therapy against the current standard, Ramucirumab plus Paclitaxel, in patients with Trastuzumab-pretreated HER2-positive metastatic disease.

Study Design

DESTINY-Gastric04 is a global, randomized, open-label, Phase 3 trial in which 494 patients (N=494) with HER2-positive metastatic gastric or GEJ adenocarcinoma were randomly assigned in a 1:1 ratio to receive T-DXd 6.4 mg/kg IV every 3 weeks (N=246) or Ramucirumab 8 mg/kg IV days 1 and 15 every 28 days along with Paclitaxel 80 mg/m² IV days 1, 8, 15 every 28 days (N=248). Treatment continued until progression or unacceptable toxicity. No crossover was allowed during the trial. The median patient age was 64 yrs, randomized patients had an ECOG performance status of 0–1, documented HER2 positivity on post-trastuzumab tumor biopsy (IHC 3+ or IHC 2+/ISH+) and no prior history of interstitial lung disease (ILD) or pneumonitis. Approximately, two thirds of the patients had the primary tumor location in the stomach whereas one third had tumors at the GE junction. Patients were stratified based on HER2 status (IHC 3+ vs. 2+/ISH+), geographic region, and time to progression on prior therapy. The Primary end point was Overall Survival (OS). Secondary end points included Progression-Free Survival (PFS), Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), and safety.

Efficacy Outcomes

Overall Survival (OS):
The Overall Survival was significantly longer with T-DXd than with Ramucirumab plus Paclitaxel with a 30% reduction in the risk of death. The median OS was 14.7 months with T-DXd versus 11.4 months with Ramucirumab–Paclitaxel (HR=0.70; P=0.004). The 24-month OS rate was 29.0% with T-DXd versus 13.9% with Ramucirumab–Paclitaxel

Progression-Free Survival (PFS):
The median PFS was 6.7 months versus 5.6 months (HR=0.74; P=0.007) and 12-month PFS rate was 22.9% versus 13.6%, favoring T-DXd

Objective Response Rate (ORR):
The confirmed ORR was 44.3% with T-DXd versus 29.1% with Ramucirumab–Paclitaxel (P<0.001) and the median duration of response was 7.4 months versus 5.3 months and higher Disease Control Rate was observed in T-DXd group, reflecting both improved response and stable disease.

Safety Profile

Overall Safety:
Grade 3 or more drug-related Adverse Events were 50.0% in the T-DXd group versus 54.1% in the Ramucirumab–Paclitaxel group. Drug discontinuation due to AEs was 11.5% versus 13.3% respectively.

Interstitial Lung Disease (ILD)/Pneumonitis:
ILD occurred in 13.9% of T-DXd recipients (mostly grade 1–2) and 0.4% experienced grade 3 events versus 1.3% in the Ramucirumab–Paclitaxel group (one grade 5 event)

Clinical Interpretation

The DESTINY-Gastric04 trial reinforces the clinical value of Trastuzumab deruxtecan as a second-line option in HER2-positive gastric and GEJ cancers, demonstrating superior survival outcomes and deeper, more durable responses compared to Ramucirumab plus Paclitaxel. Notably, this benefit was achieved even in the absence of protocol-defined crossover, and despite access to post-trial HER2-targeted agents in some regions. ILD remains a recognized risk associated with T-DXd and mandates proactive monitoring and prompt intervention. Nonetheless, the overall safety profile was manageable and consistent with prior studies.

Key Takeaways for Practice

  • Trastuzumab deruxtecan offers a statistically and clinically significant OS advantage over Ramucirumab plus Paclitaxel in the second-line setting for HER2-positive gastric/GEJ cancer.
  • HER2 re-testing after progression on Trastuzumab is crucial, as HER2 loss is documented and impacts therapeutic eligibility.
  • Safety profiles of both regimens are acceptable, though clinicians must remain vigilant for ILD with T-DXd.
  • These results support the positioning of T-DXd as the preferred second-line therapy in eligible patients who retain HER2 positivity.

Future Directions

Given the survival gains observed in this trial, ongoing studies are evaluating T-DXd in earlier lines of therapy and in combination with immunotherapy. Longer follow-up and Real-World Data will further clarify optimal sequencing strategies and management of T-DXd–associated toxicities.

Precision Medicine in Practice: Timely Use of Tumor NGS Remains Suboptimal in Common Cancers

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SUMMARY: Next-generation sequencing (NGS) has revolutionized the management of advanced cancers by enabling identification of tumor-specific genomic alterations for which targeted therapies are now available. National guidelines recommend early and routine NGS testing for patients with advanced or metastatic solid tumors to inform treatment decisions. In the United States, the five most prevalent advanced or metastatic solid tumors include advanced Non-Small Cell Lung Cancer (aNSCLC), metastatic Breast Cancer (mBC), metastatic Prostate Cancer (mPC), advanced Colorectal Cancer (aCRC), and metastatic Pancreatic Cancer (mPanC). For these malignancies, the integration of NGS has become increasingly critical in guiding targeted therapy selection and improving survival outcomes. Despite the approval of multiple targeted therapies for these malignancies, real-world utilization of NGS remains inconsistent.

In this study presented at the 2025 ASCO Annual Meeting, Chehade and colleagues,  evaluated patterns in NGS testing and its timing, relative to patient mortality.

Study Overview: This retrospective analysis leveraged the Flatiron Health EHR-derived de-identified database across 280 cancer clinics, spanning data from 2011 onward. The study included patients with a diagnosis of aNSCLC, mBC, mPC, aCRC, or mPanC, all of whom had records of NGS testing and a documented date of death. The researchers identified 86,536 patients with advanced non-small cell lung cancer, 36,000 with metastatic breast cancer, 35,702 with advanced colorectal cancer, 24,105 with metastatic prostate cancer and 14,964 with metastatic pancreatic cancer. About a third of patients from each cancer group received NGS testing (NSCLC, 36.3%; breast cancer, 32.1%; colorectal cancer, 41%; prostate cancer, 30.9%; and pancreatic cancer, 35.4%).

Patients were categorized based on the interval between receipt of NGS results and death:

  • More than 3 months before death
  • Within 3 months of death
  • After death

Key Findings Across cancer types, only 30% to 40% of patients received NGS testing. Among those who were tested and had a recorded date of death, the timing of NGS was as follows:

Timing of First NGS aNSCLC (N=19,958) mBC (N=5,689) mPC (N=3,397) aCRC (N=8,553) mPanC (N=3,957)
>3 mo before death          72.3%        81.6%        85.4%        85.0%         71.1%
Within 3 mo of death          25.6%        16.9%        13.5%        13.7%         26.5%
After death          2.1%        1.5%        1.1%        1.3%         2.4%

Notably, up to one in four patients with NSCLC or pancreatic cancer received their first NGS results within 3 months of death, a timeframe often too late for actionable therapeutic intervention.

Interpretation and Implications Despite advances in molecularly targeted therapies and growing guideline support for comprehensive genomic profiling, real-world testing patterns remain suboptimal:

  • Low uptake: Only about a third of eligible patients undergo NGS testing.
  • Late testing: A substantial proportion of tested patients receive results within 3 months of death.
  • Missed opportunities: Many patients are never tested—or are tested too late to benefit from life-extending therapies.

These findings highlight ongoing gaps in precision oncology implementation, especially in community-based settings.

Next Steps & Recommendations To improve the utility of NGS in oncology, efforts should focus on:

  • Earlier testing: At diagnosis or at first progression of advanced disease.
  • Workflow integration: Embedding NGS into routine clinical pathways.
  • Education: Raising awareness among clinicians and patients about the benefits of timely testing.
  • Health system support: Addressing barriers such as reimbursement, turnaround times, and tissue availability.

Conclusion: Real-World Data from this large retrospective analysis reveal late-stage testing and underutilization of life-prolonging genomic profiling. This study underscores an urgent need to optimize the timing and uptake of NGS testing in patients with advanced solid tumors. Earlier and broader testing is essential to ensure patients have access to the most effective, personalized treatment strategies, and to avoid the missed potential of life-extending therapies.

Utilization and timing of first tumor next-generation sequencing testing (NGS) in patients (pts) with five most common cancers in the USA. Chehade CH, Jo Y, Ozay ZI, et al. Doi: 10.1200/JCO.2025.43.16_suppl.11014. Abstract # 11014. Presented at: ASCO Annual Meeting; May 30-June 3, 2025; Chicago.

BREAKWATER Trial Establishes Encorafenib Combination with Cetuximab Plus mFOLFOX6 as a First-Line Standard for BRAF V600E–Mutated mCRC

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SUMMARY: 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. The lifetime risk of developing CRC is about 1 in 23.

Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as Panitumumab (VECTIBIX®) and Cetuximab (ERBITUX®), as well as anti VEGF agent Bevacizumab (AVASTIN®), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC) whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy.

BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. It should be noted that BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than Malignant Melanoma.

Encorafenib (BRAFTOVI®) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as Vemurafenib (ZELBORAF®) and Dabrafenib (TAFINLAR®), with a prolonged target dissociation half-life and higher potency. The FDA in 2020, approved Encorafenib in combination with Cetuximab for the treatment of adult patients with metastatic ColoRectal Cancer (mCRC) with a BRAF V600E mutation

Background and Unmet Need
BRAF V600E mutations are found in approximately 8-10% of metastatic CRC and are associated with aggressive tumor biology, poor prognosis, and limited response to conventional first-line therapies. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Historically, patients with these mutations experienced shorter survival when treated with chemotherapy with or without biologics such as Bevacizumab, compared to their BRAF wild-type counterparts. While the BEACON CRC trial established the Encorafenib plus Cetuximab (EC) doublet as standard in the previously treated setting, the optimal first-line strategy remained undefined.

Design of the BREAKWATER Study
The Phase 3 BREAKWATER trial addressed this gap by evaluating first-line treatment with Encorafenib and Cetuximab, with or without chemotherapy, in patients with previously untreated BRAF V600E-mutated mCRC. Initially designed with three arms (1:1:1), EC: Encorafenib (300 mg PO QD) + Cetuximab (500 mg/m² IV q2w), EC + mFOLFOX6: As above + Oxaliplatin, Leucovorin, and 5-FU and Control/Standard of Care: mFOLFOX6, FOLFOXIRI, or CAPOX with or without Bevacizumab, the protocol was later amended to focus on the EC+mFOLFOX6 (N=236) versus Standard of Care comparison (N=243). The median age was 61 yrs and stratification was based on ECOG performance status and geographic region. Eligible patients had metastatic colorectal adenocarcinoma with measurable disease and a confirmed BRAF V600E mutation, but no prior systemic therapy for metastatic disease. The Primary endpoints included Progression-Free Survival (PFS) and Objective Response Rate (ORR). Secondary endpoints included Overall Survival (OS), Duration of Response (DoR) and Time to Response.

Efficacy Highlights
The results were compelling across both Primary endpoints (ORR and PFS), as well as key Secondary outcomes:

  • Objective Response Rate (ORR):
    EC+mFOLFOX6 achieved a confirmed ORR of 7%, compared with 37.4% in the Standard of Care arm (Odds Ratio, 2.44; P<0.001), with a median Time to Response of approximately 7 weeks. The median Duration of Response was 13.9 months and 10.8 months respectively
  • Progression-Free Survival (PFS):
    The median PFS was 8 months with EC+mFOLFOX6 versus 7.1 months with standard care (Hazard Ratio [HR] for progression or death, 0.53; P<0.001), representing a 47% reduction in risk.
  • Overall Survival (OS):
    Interim analysis demonstrated a median OS of 3 months with EC+mFOLFOX6, more than double the 15.1 months observed in the Standard of Care group (HR for death, 0.49; P<0.001). Twelve and 24 month survival rates favored the investigational arm (80.1% and 52.0%, respectively) over Standard of Care (66.0% and 29.0%).

Notably, survival outcomes with EC+mFOLFOX6 approached those historically seen in BRAF wild-type mCRC, underscoring the potential for targeted therapy to narrow the survival gap.

Subgroup and Secondary Analyses
Benefits of EC+mFOLFOX6 were consistent across prespecified subgroups, including patients with liver metastases or multi-organ involvement. Additionally, median second Progression-Free Survival was longer with EC+mFOLFOX6, reinforcing its value in delivering durable disease control.

Safety Profile
While the incidence of grade ≥3 adverse events was higher in the EC+mFOLFOX6 group (46.1%) compared to standard care (38.9%), toxicity was manageable, and treatment discontinuations remained relatively low. The safety profile was consistent with expectations for the individual agents, and chemotherapy dose reductions were not substantially increased.

Clinical Implications
These findings firmly establish EC+mFOLFOX6 as a new first-line standard for patients with BRAF V600E–mutated mCRC. The dual-targeted approach combined with chemotherapy offers significantly improved outcomes in a population long characterized by poor prognosis. The results also highlight the importance of early integration of targeted therapy, particularly encorafenib, into the treatment paradigm.

Next Steps in BRAF-Targeted Strategies
Although the EC doublet showed some activity, particularly in patients ineligible for chemotherapy, its efficacy was inferior to the triplet regimen. Enrollment into the EC-only arm was halted, and current exploration includes EC combined with FOLFIRI (ongoing in BREAKWATER cohort 3) and EC plus pembrolizumab in MSI-H/dMMR populations (SEAMARK trial).

Conclusion
The BREAKWATER trial demonstrated that first-line treatment with EC+mFOLFOX6 significantly improves Response Rates, Progression-Free Survival, and Overall Survival, compared to standard chemotherapy regimens, in BRAF V600E–mutated mCRC. This represents a transformative advance, closing the gap in outcomes between BRAF-mutated and wild-type mCRC, and setting a new benchmark in precision oncology.

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. Elez E,  Yoshino T,  Shen L, et al., for the BREAKWATER Trial Investigators. N Engl J Med 2025;392:2425-2437

Late Breaking Abstract – ASCO 2025: AMPLITUDE Trial: Defining a New Treatment Paradigm in HRR-Altered mCSPC

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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.

Metastatic Castration-Sensitive Prostate Cancer (mCSPC) is a heterogeneous disease. Despite therapeutic advances, outcomes vary significantly based on underlying tumor biology. Approximately 25% of patients with mCSPC harbor Homologous Recombination Repair (HRR) gene mutations, including BRCA1, BRCA2, CHEK2, CDK12, PALB2, and others. Among these, BRCA1/2 mutations account for nearly half of HRR alterations and are particularly associated with aggressive disease biology, resistance to Androgen Receptor Pathway Inhibitors (ARPIs), and shortened Progression-Free and Overall Survival. The integration of AR-pathway inhibitors such as Abiraterone Acetate plus Prednisone into first-line treatment has meaningfully improved outcomes in the general mCSPC population. However, patients with HRR mutations, especially those with BRCA1/2, derive significantly less benefit from these agents alone, highlighting a substantial unmet clinical need.

Rationale for PARP Inhibition in HRR-Altered Prostate Cancer
Cancer cells with HRR deficiencies are vulnerable to PARP (Poly ADP-Ribose Polymerase) inhibition, which blocks DNA repair pathways and induces synthetic lethality. Prior landmark trials, MAGNITUDE (Niraparib with Abiraterone Acetate plus Prednisone) and TALAPRO-2 (Talazoparib  plus Enzalutamide), demonstrated the value of combining PARP inhibitors with ARPIs in Castration-Resistant Prostate Cancer (mCRPC) with HRR mutations. However, whether such a combination could offer meaningful benefit earlier in the disease course, in the castration-sensitive setting, remained unknown, until now.

AMPLITUDE Trial Design and Methods

Study Overview
The AMPLITUDE trial (NCT04497844) is a global, Phase 3, randomized, double-blind, placebo-controlled trial designed to evaluate whether combining the PARP inhibitor Niraparib with Abiraterone Acetate plus Prednisone improves clinical outcomes in patients with mCSPC (metastatic Castration-Sensitive Prostate Cancer) and HRR gene alterations.

Patient Population

  • Total enrolled: 696 men with mCSPC and at least one HRR gene mutation (germline or somatic)
  • Mutation profile: BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, RAD54L
  • BRCA1/2 prevalence: 55.6% of enrolled patients
  • Metastatic disease burden: 78% were high-volume M1disease, 87% had de novo M1disease and 16% had prior therapy with Docetaxel.
  • Prior therapies allowed:
    • 6 months or less of Androgen Deprivation Therapy (ADT)
    • 6 cycles or less of Docetaxel
    • 45 days or less of prior Abiraterone and Prednisone

Randomization and Treatment Arms

Patients were randomized 1:1 to:

  • Experimental arm: Niraparib 200 mg once daily plus Abiraterone acetate 1000 mg daily and Prednisone 5 mg daily (N=348)
  • Control arm: Placebo plus Abiraterone acetate 1000 mg along with Prednisone 5 mg daily (N=348)
    All patients continued on ADT.

Endpoints

  • Primary: Radiographic Progression-Free Survival (rPFS), assessed by investigator
  • Secondary: Time to Symptomatic Progression (TSP), Overall Survival (OS), Safety/tolerability

Key Results and Interpretation

Efficacy Outcomes

Radiographic Progression-Free Survival (Primary Endpoint)

  • Median rPFS:
    • Niraparib plus Abiraterone and Prednisone: Not reached
    • Abiraterone and Prednisone alone: 5 months (95% CI, 25.8–NR)
  • Hazard ratio: 0.63 (P=0.0001)
  • BRCA1/2 subgroup: HR =0.52 (P<0.0001)

This translates into a 37% relative risk reduction in progression or death in the overall population, and a 48% reduction in the BRCA1/2 subgroup, indicating a clear therapeutic effect in genetically defined populations.

Time to Symptomatic Progression

  • HR (overall): 0.50 (P<0.0001)
  • BRCA1/2 subgroup: HR 0.44 (P=0.0001)

This is clinically meaningful, and delaying symptom onset can preserve quality of life and extend time before additional therapies are needed.

Overall Survival (Interim Analysis)

  • HR (overall): 0.79 (95% CI, 0.59–1.04; P=0.10)
  • BRCA1/2 subgroup: HR 0.75 (95% CI, 0.51–1.11; P=0.15)

Although OS data are not yet mature, the trend suggests a potential survival benefit with longer follow-up.

Safety Profile
The safety of Niraparib plus Abiraterone and Prednisone was consistent with known profiles of both agents. Grade 3-4 AEs in the Niraparib plus Abiraterone and Prednisone was 75.2% versus 58.9% with Abiraterone and Prednisone alone, with the most common higher Grade 3-4 AEs  noted in the Niraparib plus Abiraterone and Prednisone group (Anemia: 29.1% vs 4.6% and Hypertension: 26.5% vs 18.4%). The discontinuation rates due to AEs in the Niraparib plus Abiraterone and Prednisone group was 11.0% vs 6.9% in the Abiraterone and Prednisone group. These AEs were manageable with appropriate monitoring. No new safety signals were identified.

Conclusion
The AMPLITUDE trial marks a milestone and provides robust evidence to support Niraparib plus Abiraterone and Prednisone as a new first-line option in mCSPC patients with BRCA1/2 or other HRR gene mutations. By demonstrating that Niraparib plus Abiraterone and Prednisone improves Progression-Free outcomes in HRR-altered mCSPC, especially those with BRCA mutations, it paves the way for a more personalized, biology-driven approach to therapy in this setting. Ongoing follow-up will determine whether this translates into improved survival, but the current data already support Niraparib plus Abiraterone and Prednisone as a new treatment benchmark for this high-risk subgroup.

Phase 3 AMPLITUDE trial: Niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. Attard G, Agarwal N, Graff J, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA5006)

 

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&reg;) 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&reg;) 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