Category: Hem/Onc Updates

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® (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

Perioperative KEYTRUDA® Reshapes the Treatment Landscape for Resectable Locally Advanced HNSCC

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SUMMARY: The American Cancer Society estimates that 59,660 new cases of cancer involving the oral cavity and pharynx will be diagnosed in the US in 2025 and 12,770 will die of the disease. The head and neck region includes the oral cavity, oropharynx, hypopharynx and larynx. Squamous Cell Carcinoma (SCC) of the Head and Neck accounts for about 3-5% of all cancers in the United States. Common risk factors include tobacco and alcohol use and Human PapillomaVirus (HPV) infection. Even though tobacco has long been associated with head and neck cancer development, cannabis has similar carcinogens.

The Standard of Care for patients with Stage III–IVA Head and Neck Squamous Cell Carcinoma (HNSCC) has remained largely static for nearly 2 decades: surgery followed by risk-adapted adjuvant radiotherapy, with or without concurrent chemotherapy. Despite refinements in technique and supportive care, relapse rates remain high, particularly among patients with adverse pathological features such as extranodal extension and positive margins.

The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. Checkpoint inhibitors administered in a neoadjuvant setting activates both the priming phase of immunity within tumor tissue, and the effector phase within the tumor microenvironment. It has been shown that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. Preclinical models have also demonstrated that both radiation therapy and Cisplatin chemotherapy increase the PD-L1 expression on the tumor, suggesting that combining radiotherapy with anti-PD-1 therapy could improve the outcomes.

Pembrolizumab (KEYTRUDA&reg;) is a fully humanized, Immunoglobulin G4, monoclonal antibody and checkpoint inhibitor, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. Pembrolizumab has been shown to improve Overall Survival in patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

KEYNOTE-689, a landmark Phase 3 trial, has provided the most compelling evidence to date that perioperative immunotherapy, specifically Pembrolizumab, can significantly improve clinical outcomes for patients with resectable, locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC). This international, randomized, placebo-controlled study enrolled 714 patients (N=714) with newly diagnosed, resectable, Stage III–IVA HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx.

Patients were randomized 1:1 to receive:

  • Investigational arm (N=356):
    • 2 cycles of neoadjuvant Pembrolizumab (200 mg IV Q3W) starting about 3 weeks before surgery.
    • Standard-of-care surgery.
    • Up to 3 doses of Pembrolizumab administered concurrently with adjuvant chemoradiotherapy (depending on pathologic risk).
    • 12 additional adjuvant doses of Pembrolizumab Q3W (total treatment duration: about 1 year).
  • Control arm (N=358):
    • Identical treatment structure, substituting placebo for Pembrolizumab.

PD-L1 expression was assessed via Combined Positive Score (CPS), and stratification included CPS ≥1 and CPS ≥10 subgroups, recognizing the prognostic and potentially predictive value of PD-L1 expression. The Primary endpoint was Event-Free Survival (EFS), defined as time from randomization to disease progression, local/regional recurrence, distant metastasis, or death from any cause. Secondary endpoints included Overall Survival (OS) and Major Pathological Response.

The trial met its Primary endpoint of EFS. At median follow-up of 38.3 months, patients in the investigational arm had significantly improved EFS compared with the Standard of Care arm (median 51.8 months vs. 30.4 months; HR=0.73; P=0.0041). Patients who received Pembrolizumab who had a CPS score ≥10 derived the greatest benefit (median 59.7 months vs. 26.9 months; HR = 0.66; P=0.002) whereas the median EFS in the CPS ≥1 subgroup was 59.7 vs. 29.6 months (HR, 0.70; P = .0014).

Major pathological response defined as 90% or more tumor regression was also notably improved. Among all patients, the major pathological response rate was 9.4% with Pembrolizumab vs. 0% with Standard of Care (P < 0.00001). In the CPS ≥10 subgroup, the major pathological response rate reached 13.7%.

While the interim analysis did not demonstrate a statistically significant OS benefit, trends were favorable, particularly in the CPS ≥10 group (HR, 0.72; P =0.02). Further OS follow-up is ongoing.

Adverse events were consistent with known profiles of checkpoint inhibitors. Grade 3 or more  Treatment-Related Adverse Events (TRAEs) occurred in 44.6% of the Pembrolizumab group and 42.9% in the Standard of Care group. Immune-mediated adverse events were observed in 43.2% of the Pembrolizumab arm, with hypothyroidism being the most common (24.7%). Mortality attributable to treatment was slightly higher with Pembrolizumab (1.1% vs. 0.3%).

The researchers concluded that perioperative Pembrolizumab is now emerging as a new standard of care in the treatment of resectable locally advanced HNSCC. The findings from this study underscore the importance of harnessing the immune system both before and after surgery. Neoadjuvant administration may prime the immune response when tumor antigen burden is highest, while adjuvant therapy may help eliminate residual microscopic disease.

Neoadjuvant and adjuvant pembrolizumab plus standard of care in resectable locally advanced head and neck squamous cell carcinoma: phase 3 KEYNOTE-689 study. Uppaluri R, et al. Abstract CT001. Presented at: American Association for Cancer Research Annual Meeting; April 25-30, 2025; Chicago.

 

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

FDA Approves OPDIVO® Plus YERVOY® for Unresectable or Metastatic MSI-H/MMR Deficient Colorectal Cancer

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SUMMARY: The FDA on April 8, 2025, approved Nivolumab (OPDIVO®) with Ipilimumab (YERVOY®) for adult and pediatric patients 12 years of age and older with unresectable or metastatic MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) colorectal cancer (CRC). The FDA also converted the accelerated approval to regular approval for single agent Nivolumab for adult and pediatric patients 12 years of age and older with MSI-H or dMMR metastatic CRC, that has progressed following Fluoropyrimidine, Oxaliplatin, and Irinotecan.

Colorectal cancer 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. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI high colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors.

MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

Nivolumab is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas Ipilimumab is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.

The present FDA approval is based on CheckMate 8HW, which is an ongoing Phase III, multinational, open-label, randomized trial evaluating Nivolumab plus Ipilimumab as compared with Nivolumab alone or chemotherapy, in patients with MSI-H or dMMR metastatic CRC. In this study, patients with unresectable or mCRC and MSI-H/dMMR status by local testing who had received 0-1 prior line of therapy were randomly assigned in a 2:2:1 ratio to receive either Nivolumab monotherapy (N=353), Nivolumab plus Ipilimumab combination therapy (N=354), or the investigator’s choice of chemotherapy (mFOLFOX6 or FOLFIRI with or without Bevacizumab or Cetuximab (N=132). Patients who had previously received two or more prior lines of therapy for unresectable or metastatic disease were randomly assigned, in a 1:1 ratio, to receive Nivolumab plus Ipilimumab or Nivolumab alone. In the Nivolumab monotherapy arm, patients received Nivolumab 240 mg IV once every two weeks for six doses, followed by 480 mg IV every four weeks. In the Nivolumab plus Ipilimumab arm, patients were given Nivolumab 240 mg IV plus Ipilimumab 1mg/kg IV every three weeks for four doses, followed by Nivolumab 480 mg IV every four weeks. The median patient age was 64 years and tumor location was in the right colon in two thirds of the patients. Treatments continued until disease progression or unacceptable toxicity in all treatment groups or a maximum of 2 years. The dual Primary end points were Progression-Free Survival (PFS) as determined by Blinded Independent Central Review (BICR) comparing Nivolumab plus Ipilimumab to chemotherapy in the first-line therapy setting, and PFS comparing Nivolumab monotherapy to Nivolumab plus Ipilimumab across all lines of therapy, in patients with centrally confirmed MSI-H/dMMR metastatic CRC. At a median follow-up of 31.5 months the results from the prespecified interim analysis (the primary analysis) showed that the PFS outcomes were significantly better with Nivolumab plus Ipilimumab than with chemotherapy (HR=0.21; P<0.001).

The researchers herein reported the first results from the other dual Primary endpoint of PFS for Nivolumab plus Ipilimumab versus Nivolumab monotherapy across all lines of therapy in patients with centrally confirmed MSI-H/dMMR metastatic CRC. Of all the randomized patients 296 in the Nivolumab plus Ipilimumab group and 286 in the Nivolumab monotherapy group had centrally confirmed MSI-H/dMMR status. With a median follow-up of 47.0 months, Nivolumab plus Ipilimumab demonstrated clinically meaningful and statistically significant improvement in PFS by BICR versus Nivolumab monotherapy, with a median PFS Not Reached (NR) in the Nivolumab plus Ipilimumab group, compared to 39.3 months for those on Nivolumab monotherapy (HR=0.62; P= 0.0003). The PFS rates at 12, 24, and 36 months were higher in the Nivolumab plus Ipilimumab group at 76%, 71%, 68% versus 63%, 56%, 51% for Nivolumab monotherapy. The Objective Response Rate (ORR) was significantly higher with Nivolumab plus Ipilimumab at 71%, compared to 58% with Nivolumab alone (P=0.0011). No new safety concerns were identified.

It was concluded that the CheckMate 8HW study met its dual Primary endpoints, with Nivolumab plus Ipilimumab demonstrating a statistically significant and clinically meaningful improvement in PFS compared to Nivolumab monotherapy across all lines of therapy in MSI-H/dMMR metastatic CRC. Moreover, Nivolumab plus Ipilimumab was associated with higher ORR, confirming its potential as a new standard of care for patients with MSI-H/dMMR metastatic CRC. The CheckMate 8HW study is a pivotal contribution to the treatment landscape of MSI-H/dMMR metastatic Colorectal cancer, providing compelling evidence for the use of Nivolumab plus Ipilimumab in the first-line and beyond.

Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Andre T, Elez E, Lenz H-J, et al. The Lancet. 2025; 405:383-395

Metabolic Syndrome and Breast Cancer Prognosis: A Comprehensive Meta-Analysis Highlights Urgent Need for Integrated Survivorship Strategies

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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.

Background and Rationale: As oncologists continue to shift from a purely disease-focused model to one that embraces survivorship, a growing body of evidence suggests that metabolic syndrome may play a crucial, underappreciated role in determining long-term outcomes for women diagnosed with breast cancer.
Metabolic syndrome—characterized by the presence of at least three of the following risk factors: hypertension, hyperglycemia, central obesity, hypertriglyceridemia, and low HDL cholesterol—is known to elevate the risk for cardiovascular and chronic metabolic diseases. More recently, it has also been implicated in breast cancer incidence and prognosis, potentially through inflammatory, hormonal, and metabolic pathways.

Study Objective: A recent systematic review and meta-analysis sought to quantify the impact of metabolic syndrome on breast cancer-specific outcomes, including recurrence, mortality, and disease-free survival (DFS). The goal: to assess whether metabolic syndrome at the time of breast cancer diagnosis correlates with a poorer prognosis, independent of other risk factors.

Methodology, Study Population and Demographics: The investigators performed systematic literature searches in PubMed and Embase, using combinations of search terms like breast neoplasms, metabolic syndrome, and survival and From an initial pool of 1,019 studies, 17 high-quality studies were selected for meta-analysis and data were drawn from 42,135 breast cancer survivors. Seven studies, which included 9029 women, provided data on breast cancer recurrence, another 7 studies involving 31,008 women reported on breast cancer mortality, and 8 studies with 17,235 women provided data on Overall Survival (OS). These studies were conducted across North America, Europe, and Asia, the average age was 53.2 years and average follow-up time was 94.8 months. Metabolic syndrome was defined consistently across studies based on AHA criteria: presence of ≥3 of the following—waist circumference >35 inches (women), elevated triglycerides, reduced HDL-C, high fasting glucose, and elevated blood pressure.

Results: The analysis revealed statistically significant associations between metabolic syndrome and adverse breast cancer outcomes. Patients with metabolic syndrome had a 69% increased risk of recurrence, 83% increased risk of breast cancer-related death (Breast Cancer Specific Mortality) and 57% higher likelihood of experiencing an adverse event (recurrence, new malignancy, or death) impacting Disease-Free Survival. Subgroup analyses showed geographically consistent associations across North America, Europe, and Asia, reinforcing the global applicability of the findings.

Limitations:

  • Lack of consistent reporting on ER status, preventing stratified analysis by tumor subtype
  • Inability to isolate effects of individual metabolic components
  • Missing data on pharmacological treatments (e.g., statins, antidiabetics)
  • Residual confounding factors (e.g., socioeconomic status, lifestyle, genetics)
  • Predominantly observational designs, limiting causal inference

Clinical Implications: This study sheds light on an often-overlooked factor in breast cancer prognosis: metabolic health at diagnosis. With over 40,000 survivors included, the findings make a compelling case for integrating metabolic screening and intervention into breast cancer care pathways. Cardiovascular disease is the second leading cause of death among breast cancer survivors. Managing metabolic syndrome could address both cancer and cardiovascular risk.

Opportunities for Oncologists:

  • Early metabolic screening for BC patients at diagnosis and during follow-up
  • Interdisciplinary care involving endocrinologists, dietitians, and cardiologists
  • Lifestyle counseling as a standard element of survivorship care
  • Pharmacologic management using statins, antihypertensives, and antidiabetic agents with potential antitumor effects

Conclusion: Metabolic syndrome is more than a cardiovascular risk factor—it’s a cancer prognostic marker. This meta-analysis, the most comprehensive to date, makes it clear: women diagnosed with both breast cancer and metabolic syndrome face significantly worse outcomes. Clinical guidelines should evolve to include routine metabolic screening and targeted interventions for breast cancer survivors. Addressing metabolic health may be one of the most cost-effective ways to improve survival and quality of life in this growing population.

Metabolic syndrome is associated with breast cancer mortality: A systematic review and meta-analysis. Harborg S, Larsen HB, Elsgaard S, et al. J Intern Med. 2025;297:262-275.

 

 

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

 

Optimizing Long-Term Anticoagulation in Cancer-Associated Thrombosis: Insights from the API-CAT Trial

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. There is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging. Traditionally, a six-month course of either Direct Oral AntiCoagulants (DOACs) or Low-Molecular-Weight Heparin (LMWH) has served as the standard initial treatment duration.

However, cancer is a chronic and often progressive condition, and the thrombotic risk doesn’t dissipate once the initial treatment window concludes. Clinical guidelines generally recommend the continuation of anticoagulation for as long as the malignancy remains active or systemic therapy is ongoing. Yet, this approach necessitates a careful balancing act – prolonged anticoagulation mitigates thrombotic recurrence but heightens the risk of bleeding, a risk that persists over time.

A major challenge in this domain has been the lack of robust evidence from randomized clinical trials to guide extended anticoagulation beyond six months, particularly regarding the optimal dose that maintains efficacy while minimizing harm. While reduced-dose anticoagulation has emerged as a promising strategy in non-cancer populations, its application to cancer-associated thrombosis had not been thoroughly evaluated until recently.

The Apixaban Cancer Associated Thrombosis (API-CAT) trial is a large, randomized, double-blind, noninferiority study aimed to determine whether a reduced dose of Apixaban (2.5 mg twice daily) could effectively prevent recurrent VTE in patients with active cancer, while also offering a safer bleeding profile, compared to the standard full dose (5 mg twice daily). All participants had previously completed a minimum of six months of anticoagulation for either proximal deep-vein thrombosis or pulmonary embolism. The trial enrolled 1,766 patients, randomly assigned to either the reduced-dose (N=866) or full-dose (N=900) Apixaban group. The baseline characteristics of the patients in this trial were similar to those in observational studies and randomized trials. The median age of the patients was 69 years, and 43% were men. Among patients with active cancer, the most frequent sites of the primary cancer were the breast (22.7%), colon or rectum (15.2%), gynecologic system (12.1%), and lung (11.3%). The Primary efficacy outcome was centrally adjudicated fatal or nonfatal recurrent VTE over the 12-month follow-up period and key Secondary outcome was clinically relevant bleeding, which was defined as a composite of adjudicated major or clinically relevant nonmajor bleeding during the 12-month follow-up period.

The results were compelling: the reduced-dose regimen demonstrated noninferiority to the full dose in preventing VTE recurrence. Specifically, recurrent events occurred in 2.1% of patients in the reduced-dose group compared to 2.8% in the full-dose group (adjusted subhazard ratio=0.76; P=0.001 for noninferiority). More importantly, the incidence of clinically relevant bleeding – a composite measure that included both major and non-major events with real-world impact – was significantly lower in the reduced-dose group (12.1% vs. 15.6%; adjusted subhazard ratio=0.75; P=0.03). The incidence of death was similar in the two groups (19.6% in the full-dose group and 17.7% in the reduced-dose group), and most deaths were related to cancer.

Notably, the study defined clinically relevant bleeding more broadly than previous trials—capturing both major and non-major events that impact patient well-being and quality of life. This approach reflects the reality that even so-called “minor” bleeds can significantly affect daily functioning and emotional health, particularly in patients with incurable malignancies.

In conclusion, reduced-dose Apixaban offers a clinically effective and safer alternative for extended anticoagulation in patients with active cancer, successfully preventing recurrent venous thromboembolism while minimizing bleeding risks. With cancer patients living longer due to advances in immunotherapy and targeted treatments, clinicians are increasingly tasked with navigating long-term thrombosis prevention strategies. The API-CAT trial helps address a key evidence gap and marks a significant advancement in the long-term management of cancer-associated thrombosis and reinforces the importance of personalized care in oncology.

Cancer-Associated Venous Thromboembolism- Beyond 6 Months. Mahe I, Carrier M, Mayeur D, et al. for the API-CAT Investigators. N Engl J Med 2025;392:1439-1440

Exploring the emerging HER2-Low and HER2-Ultralow subtypes in breast cancer therapy advancements

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Written by: Denise Yardley, MD
Sponsored by: Daiichi-Sankyo

The landscape of breast cancer treatment is advancing with innovative discoveries challenging the traditional HER2 classification. The identification of HER2-low and HER2-ultralow subtypes offers a more nuanced understanding of tumor biology, paving the way for personalized therapies that promise better outcomes for a wider range of patients. This fresh perspective reshapes clinical practice, indicating a new era in the fight against breast cancer where precision medicine leads the charge.

Breast cancer remains an extremely heterogeneous disease, with a number of subtypes characterized by distinct molecular and clinical features. One key classifying marker is the human epidermal growth factor receptor 2 (HER2). The expression of HER2 or lack thereof traditionally serves to categorize tumors as either HER2 positive or HER2 negative, based on the detected level of HER2 protein expression. The emergence of new antibody conjugate drugs challenged the reliance of conventional HER2 targeted therapies on 3+ HER2 expression by immunohistochemistry (IHC) or gene amplification, thereby establishing HER2 low as a novel breast cancer entity that stands to benefit from HER2 targeted therapies. As a result of DESTINY-Breast 04 in 2022, ASCO CAP guidelines for HER2 testing, affirming the importance of accurately identifying with HER2 low to ensure optimal patient selection for HER2 targeted therapies, were revised in 2023 to include advancements in diagnostic techniques that have led to the identification of two additional subtypes: HER2-low and HER2-ultralow breast cancer. Identifying these novel HER2 subtypes have significant implications for treatment and prognosis.

The identification of the HER2 prototype oncogene served as a ripe therapeutic target in breast cancer as well as other cancers. The focus of these therapeutic interventions were on the small 15-20% group of tumors demonstrating HER2 protein overexpression as a function of HER2 gene amplification. The development and subsequent efficacy of the targeted monoclonal anti-HER2 antibody trastuzumab led to its approval for metastatic breast cancer in 1998 followed by the approval of pertuzumab in 2012. Trastuzumab worked by binding the HER2 protein receptor, inhibiting HER2 homodimerization thus preventing HER2-mediated signalling while pertuzumab inhibited HER2 heterodimerization with HER3, a related growth factor receptor. However, a low or moderate expression of the HER2 target without gene amplification failed to benefit from conventional anti-HER2 agents (NSABP B-47).

Extensive pathology training efforts and quality assurance programs followed to reliably achieve high concordance for identifying and characterizing tumors denoted as HER2+ with the intent of identifying tumors most likely to benefit from classical HER2 targeted agents. The HER2 testing algorithm resulted in a binary categorization of tumors that were either HER2 negative or HER2 positive, on the basis on an IHC score of 3+ or IHC 2+ with in situ hybridization (ISH) positive. HER2 negative was a catchall that included tumors that were completely devoid of the HER2 protein (IHC 0) as well as those that had low to moderate expression labelled as IHC 1+ and IHC 2+ but ISH negative. This distinction however was not clinically meaningful, and the two groups were combined and were not eligible for HER2 therapies. It was not at all clear if there was a distinct tumor biology associated with lower level HER2 expression. The monoclonal anti-HER2 antibodies were ineffective in HER2 low tumors because their activity relies mainly on the blockade of aberrant HER2 signaling via dimerization inhibition, HER2 internalization, and/or antibody dependent cellular cytotoxicity (ADCC). Since these therapies bind the extracellular domain of the HER2 receptor, effective efficacy hinged on HER2 receptor overexpression which facilitates ADCC.

Despite the impact of the success of these agents in improving outcomes in HER2+ overexpressing tumors, a subgroup of patients failed to respond or experience disease recurrence, creating a robust pathway for the development of more effective and well tolerated second line therapies. Antibody drug conjugates (ADC), already a mainstay in hematologic malignancies, functioned as tumoral antibody specific antibodies connected via a linker to a potent cytotoxic payload. Trastuzumab emtansine (T-DM1) soon emerged, incorporating the antitumor properties of trastuzumab joined via a noncleavable linker with the cytotoxic activity of the microtubule inhibitory agent DM1. Use of this ADC allowed for targeted receptor binding and transport of cytotoxic chemotherapy, specifically into cancer cells, with subsequent disruption of the intracellular signaling pathways. The results of the EMILIA trial moved trastuzumab emtansine as a new standard in the second line setting of HER2+ MBC, following the demonstration of improved PFS and OS coupled with a more favorable toxicity profile than lapatinib and capecitabine.

Given these advances, refractoriness in classical HER2+ breast cancers developed to trastuzumab emtansine fostering the development of the third generation ADC trastuzumab deruxtecan, with a monoclonal anti-HER2 antibody linked to a topoisomerase payload through a tetrapeptide cleavable linker. This ADC had a higher drug to antibody ratio of 8 and was effective in trastuzumab emtansine insensitive HER2+ breast tumors. A series of trials referred to as DESTINY trials, evaluated this third generation ADC with DESTINY Breast 01, 02, and 03 in HER2+ breast cancer while DESTINY Breast 04 and 06 looked at HER2 low breast cancer, embracing the 80% of breast cancers assessed as HER2 negative and historically not candidates for anti-HER2 therapy. The DAISY trial was deigned to evaluate trastuzumab deruxtecan according to HER2 expression levels showing the greatest response in the HER2 overexpressing tumors defined by IHC 3+ or ISH positive followed by cohort 2 consisting of HER2 low tumors defined as IHC2+/ISH negative or HER2 nonexpressing tumors or IHC 0. This suggested that very low levels of HER2 expression could allow for receptor binding of trastuzumab deruxtecan and furthermore, that the definition of HER2 low needed to be expanded to include HER2 ultralow, cases that show faintly perceptible HER2 staining that is greater than 0% and < 10% (currently considered IHC 0). What emerged was that HER2 expression is now increasingly perceived as a continuum that defies the former classical dichotomous distinction of HER2 positive and HER2 negative cancers that traditionally guided treatment decision making. While monoclonal antibodies were ineffective in HER2 low tumors because their activity relies mainly on binding of the extracellular domain of the HER2 receptor and is more effective if the receptor is overexpressed facilitating ADCC. This is in stark contrast to the ADC trastuzumab deruxtecan, which can overcome some of these monoclonal antibody limitations by also being able to release a cytotoxic payload that can be internalized by surrounding cells that do not express HER2 (bystander effect). With the introduction of the third generation ADC therapies in what was previously collectively classified as HER2 negative tumors, a paradigm shift in the treatment of tumors without conventionally defined HER2 overexpression or HER2 gene amplification has occurred.

The identification of HER2-low and HER2-ultralow breast cancer represents a significant advancement in the field of breast cancer research and treatment. HER2 IHC scoring, nomenclature, testing modalities and current treatment protocols are evolving and the reproducibility of pathologists truly being able to separate IHC HER2 0 and HER2 1+ persists. Alternative assays and/or testing modalities to better discriminate low levels of HER2 protein expression may lead to future algorithms but at present, ongoing research and clinical trials are essential to further understand the biological behavior and clinical significance of HER2-low and HER2-ultralow breast cancer. As an example, the majority of HER2-low and HER2-ultralow breast cancers are hormone receptor-positive (HR+) which has important implications for treatment with the combinations of hormone therapy with HER2-targeted therapy and the potential to further improve outcomes for patients with HR+/HER2-low and HR+/HER2-ultralow breast cancer. Of overriding importance, is the need for additional studies to also evaluate the long-term outcomes of patients with these HER2 subtypes and to identify additional HER2-targeted therapies that may be effective. The DESTINY Breast 04 and 06 trials highlight the need for refining the diagnostic techniques, and to develop standardized testing protocols, to ensure accurate classification of HER2 status. By embracing personalized treatment approaches, clinicians can improve outcomes for patients with HER2-low and HER2-ultralow breast cancer and provide more effective and targeted care. The traditional dichotomy of HER2 status has now been supplanted by the expanding spectrum of HER2 positivity in breast cancer. Comprehensive characterization of the evolving spectrum of HER2 tumors, to further define their clinical and molecular features, is of paramount importance.

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.

ZYNLONTA® in Combination with Rituximab Shows Dramatic Activity in High Risk Follicular Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2025, about 80,350 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,390 individuals will die of this disease. Indolent Non-Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).

Follicular Lymphoma is the most indolent form and second most common form of all NHLs, and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas and the average age of diagnosis is 65 years. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival (OS) of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years, with prognosis worsening after each subsequent relapse. Despite advances in treatment for Follicular Lymphoma, there remains an unmet need for additional options that offer treatment-free intervals with durable, complete responses.

Loncastuximab tesirine (ZYNLONTA®) is an Antibody-Drug Conjugate (ADC) and consists of a humanized monoclonal antibody (anti-CD19) linked to a cytotoxic alkylating agent (pyrrolobenzodiazepine dimer, or PBD). Upon binding to CD19 on B-calls, Loncastuximab is internalized into the cells and PBD is released inside the cells, where it crosslinks DNA and induces tumor cell death. Loncastuximab is presently indicated for the treatment of adult patients with relapsed or refractory Large B-Cell Lymphoma after two or more lines of systemic therapy, including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. Preliminary data suggested promising activity of Loncastuximab in Follicular Lymphoma, with and synergistic activity between Rtuximab-induced cytotoxicity and Loncastuximab.

The researchers in this study evaluated Loncastuximab tesirine combined with Rituximab for second-line and later treatment of Follicular Lymphoma. This single institution, investigator-initiated, Phase 2 trial enrolled 39 patients with Grade 1-3A Relapsed/Refractory Follicular Lymphoma treated with one or more lines of therapy, who presented with progression of disease within 24 months (POD24). Treatment for the initial 21 weeks consisted of Rituximab 375 mg/m2 IV weekly for 4 weeks followed by 1 dose every 8 weeks for a total of 5 doses in combination with Loncastuximab 0.15 mg/kg IV every 3 weeks for 2 doses followed by 0.075 mg/kg IV every 3 weeks for a total of 7 doses. Premedication with Dexamethasone 4 mg twice daily for 3 days was required. Patients achieving Complete Response at Week 21 discontinued Loncastuximab and received two more doses of Rituximab every 8 weeks. Patients with a partial response at week 21 continued both agents for 18 more weeks. No prophylaxis was required per study protocol. The median age of patients was 68 years and majority of patients were men (54%) with advanced-stage (82%), high-disease burden by GELF criteria (92%), and/or POD24 after frontline immunochemotherapy (51%). The median FLIPI score was 3 with most patients assigned to the high-risk group (61.5%). Median lines of prior therapy were 1, and R-CHOP was the most common first-line therapy (56.5%), followed by Bendamustine with Rituximab (25.6%), single-agent Rituximab (15.3%), and Fludarabine, Mitoxantrone, and Dexamethasone (2.6%). The Primary endpoint was Complete Metabolic Response (CMR) rate at week 12, assessed by the Lugano 2014 classification, in patients who had received at least three doses of Loncastuximab. The safety analysis included all patients who received one or more doses of Loncastuximab.

At a median follow-up of 18.2 months, the Objective Response Rate (ORR) at week 12 was 97.1%, with a CMR rate of 68.6% and a Partial Metabolic Response (PMR) rate of 28.6%. The CMR rate improved to 80% at week 21. All patients who achieved a CMR maintained their response. Baseline bone marrow involvement resolved in all patients (N=10) at week 12 reassessment. The response rates were similar in patients with POD24 and those without, each of which made up roughly half the patients in the trial. At 18 months, the Progression Free Survival (PFS) rate was 90.1% and the Overall Survival (OS) rate was 93.3%, and the median PFS and OS was not reached. The main adverse events with this therapy were skin rash that worsened with sun exposure, and fluid retention, which could be treated with diuretics.

In conclusion, a combination of Loncastuximab with Rituximab demonstrated dramatic activity with robust Complete Metabolic Rate and promising survival benefit with manageable toxicities, in patients with high risk Relapsed or Refractory Follicular Lymphoma. The results of this study support this combination as a new treatment option for this patient group, and multicenter expansion cohort is ongoing. Because of the high Complete Response by week 12, the researchers recently reduced the treatment length from 10 to 6 months, with the hope that relatively short course of treatment combined with lower toxicity will allow patients to better tolerate and complete the therapy.

Loncastuximab tesirine with rituximab in patients with relapsed or refractory follicular lymphoma: a single-centre, single-arm, phase 2 trial. Alderuccio JP, Alencar AJ, Schatz JH, et al. The Lancet. 2025;12:E23-E34.