Category: Hem/Onc Updates

Late Breaking Abstract – 2026 ASCO GI Symposium: Redefining First-Line Therapy in HER2-Positive Gastroesophageal Adenocarcinoma with Zanidatamab-Based Combinations

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SUMMARY: The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer will be diagnosed in 2026 and about 10,740 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.

Persistent Unmet Need in HER2-Positive Disease

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 20% of patients with GastroEsophageal Adenocarcinoma (GEA), encompassing gastric, gastroesophageal junction, and esophageal adenocarcinomas, harbor HER2-positive tumors. Despite the incorporation of HER2-directed therapy into first-line management more than a decade ago, long-term outcomes remain suboptimal. With Trastuzumab (HERCEPTIN®) plus chemotherapy, median Progression-Free Survival (PFS) has historically hovered around 10 months, and median Overall Survival (OS) around 20 months.

More recently, the addition of immune checkpoint inhibition has modestly improved outcomes in selected patients. Based on KEYNOTE-811, Pembrolizumab (KEYTRUDA®) plus Trastuzumab and chemotherapy is now standard for PD-L1–positive tumors. However, early relapse, often within the first year, remains common, underscoring the need for more effective HER2-targeted strategies.

Zanidatamab: A Next-Generation HER2-Targeted Approach

Preclinical and clinical data suggest greater antibody saturation on HER2-expressing tumor cells than with Trastuzumab or Pertuzumab (PERJETA®).

Zanidatamab (ZIIHERA®) is a novel, humanized IgG1 bispecific monoclonal antibody designed to bind two non-overlapping extracellular domains of HER2 (ECD2 and ECD4). This biparatopic binding leads to enhanced HER2 receptor clustering, internalization, and downregulation, resulting in more complete inhibition of HER2 signaling compared with single-epitope antibodies. Beyond direct signal blockade, Zanidatamab’s unique binding geometry promotes robust immune-mediated antitumor activity, including Complement-Dependent Cytotoxicity (CDC), Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP).

Zanidatamab’s clinical momentum was reinforced by its FDA accelerated approval in November 2024 for previously treated, unresectable or metastatic HER2-positive biliary tract cancer, highlighting the platform’s broader relevance across HER2-driven gastrointestinal malignancies.

Rationale for Combining HER2 Blockade and Immunotherapy

The HERIZON-GEA-01 trial also explored synergy between dual HER2 targeting and immune checkpoint inhibition. Tislelizumab (TEVIMBRA®), a humanized IgG4 anti-PD-1 monoclonal antibody, is engineered to minimize Fc-gamma receptor binding on macrophages, potentially reducing antibody-dependent clearance of activated T cells. Tislelizumab received FDA approval in March 2024 for previously treated metastatic esophageal Squamous Cell Carcinoma, supporting its activity in upper gastrointestinal cancers.

HERIZON-GEA-01: Trial Design and Patient Population

HERIZON-GEA-01 (NCT05152147) is a global, open-label, Phase III study evaluating Zanidatamab-based regimens versus standard Trastuzumab plus chemotherapy in the first-line setting for HER2-positive metastatic GEA (GastroEsophageal Adenocarcinoma).

A total of 914 patients with unresectable, locally advanced, recurrent, or metastatic disease were enrolled between December 2021 and February 2025. More than two-thirds had gastric primaries. Patients had received no prior systemic therapy, HER2-targeted therapy, or immunotherapy in this setting.

Participants were randomized 1:1:1 to:

  • Arm A: Trastuzumab plus chemotherapy
  • Arm B: Zanidatamab plus chemotherapy
  • Arm C: Zanidatamab plus Tislelizumab plus chemotherapy

CAPOX was the chemotherapy backbone in approximately 90% of patients. Zanidatamab-based regimens in Arm B and Arm C were compared with standard Trastuzumab plus chemotherapy in Arm A. The dual Primary endpoints were PFS by Blinded Independent Review and OS.

Efficacy Results: Clinically Meaningful and Practice-Changing

At the interim analysis (data cutoff October 2025; median follow-up 26 months), there was a clear and consistent improvement in Progression-Free Survival with Zanidatamab-based therapy compared with Trastuzumab plus chemotherapy. Median PFS reached 12.4 months with Zanidatamab plus chemotherapy and 12.4 months with Zanidatamab plus Tislelizumab and chemotherapy, compared with 8.1–8.2 months in the Trastuzumab control arm. These gains translated into a 35–37% reduction in the risk of disease progression or death, with Hazard Ratios of 0.65 for Zanidatamab plus chemotherapy and 0.63 for the triplet regimen (both P <0.0001). Importantly, the separation of the PFS curves was maintained over time, highlighting the durability of benefit. The 1-year PFS was 38.0% with Zanidatamab plus chemotherapy and 43.9% with the triplet, versus 20.9% and 38.2% respectively with Trastuzumab-based therapy. The 2-year PFS was 31.5% and 20.9%, respectively, compared with 15.6% in the Trastuzumab group. These findings mark the first time a majority of patients receiving first-line HER2-targeted therapy remain progression-free at one year, a notable advance in a disease historically characterized by early relapse.

Median OS improved from 19.2 months with Trastuzumab plus chemotherapy to 24.4 months with Zanidatamab plus chemotherapy and 26.4 months with Zanidatamab plus Tislelizumab and chemotherapy. The addition of Tislelizumab yielded a statistically significant 28% reduction in the risk of death (HR 0.72; P =0.0043). While OS data for Zanidatamab plus chemotherapy alone were not yet statistically significant at this interim analysis (HR 0.80; P =0.0564), the observed survival extension of more than five months suggests meaningful clinical activity, with further analyses planned as follow-up matures. The 2-year OS was 50.3% with Zanidatamab plus chemotherapy and 54.3% with the triplet, versus 42.2% and 43.8% respectively with Trastuzumab-based therapy. The 30-month OS was 38.8% and 43.8%, respectively, compared with 30.0% in the Trastuzumab group.

Notably, the triplet regimen is the first HER2-directed first-line strategy to achieve median Overall Survival exceeding two years in a randomized phase III trial. Further, the benefits in both PFS and OS were consistent across key subgroups, including geographic region and PD-L1 status, an especially notable finding given that checkpoint inhibitor benefit has traditionally been restricted to PD-L1–positive tumors.

Depth and Durability of Response

Zanidatamab-based regimens also produced deeper and more durable responses. Confirmed Objective Response Rates approached 70% in both Zanidatamab arms, with Complete Response rates nearing 20% when Tislelizumab was added. Median duration of response was particularly striking, exceeding 20 months with the triplet regimen and substantially longer than the 8-month duration observed with Trastuzumab plus chemotherapy.

Safety and Tolerability

The safety profiles of Zanidatamab and Tislelizumab were consistent with their known toxicities. Grade ≥3 treatment-related adverse events occurred in approximately 59% of patients receiving Zanidatamab plus chemotherapy and 72% with the addition of Tislelizumab, compared with 60% in the Trastuzumab arm.

Diarrhea was the most common toxicity across all arms, typically occurring early and resolving within several weeks. Rates of HER2-targeted therapy discontinuation due to adverse events were higher with Zanidatamab-based regimens but remained manageable, with no new safety signals identified.

Clinical Implications and Future Directions

HERIZON-GEA-01 represents a landmark study in HER2-positive gastroesophageal adenocarcinoma. It is the first phase III trial to demonstrate superiority of a novel HER2-targeted agent over Trastuzumab in the first-line metastatic setting, and the first to achieve median PFS beyond one year and median OS beyond two years in this population.

While cross-trial comparisons should be interpreted cautiously, outcomes with Zanidatamab plus Tislelizumab and chemotherapy compare favorably with historical results from KEYNOTE-811. The observation of benefit irrespective of PD-L1 status further broadens the potential impact of this strategy.

As longer follow-up matures and guideline bodies evaluate these data, Zanidatamab, particularly in combination with immunotherapy appears poised to redefine the standard of care for HER2-positive metastatic gastroesophageal adenocarcinoma, offering patients a meaningful extension of disease control and survival.

Zanidatamab + chemotherapy ± tislelizumab for first-line HER2-positive locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma: Primary analysis from HERIZON-GEA-01. Elimova E, Rha SY, Shitara K, et al. 2026 ASCO Gastrointestinal Cancers Symposium. Abstract LBA285. Presented January 8, 2026.

Reconsidering Menopausal Hormone Therapy in BRCA1/2 Carriers: Emerging Evidence Challenges Longstanding Concerns

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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 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

The tumor suppressor genes such as BRCA1 and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation, and the deleterious effects of the mutations are seen even when a second copy of the gene in an individual is normal. Women with germline BRCA1 or BRCA2 mutations face markedly elevated lifetime risks of breast cancer, estimated at up to 70%. More than half of these cancers occur before the age of 50, underscoring the importance of informed counseling regarding risk-modifying exposures. 

For much of the latter half of the 20th century, Hormone Replacement Therapy (HRT) was widely prescribed to alleviate menopausal symptoms and protect against long-term complications such as osteoporosis. This practice shifted dramatically in 2002, when the Women’s Health Initiative reported increased risks of cardiovascular events and breast cancer associated with hormone therapy in older, postmenopausal women. In the aftermath, both patients and clinicians largely retreated from Menopausal Hormone Therapy (MHT), and its use declined sharply.

While those findings reshaped care in the general population, their applicability to women with hereditary cancer predisposition, particularly carriers of pathogenic BRCA1 or BRCA2 variants, has remained uncertain. These women face markedly elevated risks of ovarian and fallopian tube cancers and are therefore advised to undergo risk-reducing bilateral salpingo-oophorectomy at relatively young ages. The procedure is effective for cancer prevention but induces abrupt surgical menopause, often decades earlier than natural menopause, with well-documented short- and long-term consequences including vasomotor symptoms, sexual dysfunction, bone loss, and adverse cardiovascular and cognitive effects.

Menopausal Hormone Therapy (MHT) is the most effective intervention for mitigating these outcomes of early menopause. However, concerns that hormone exposure could further increase breast cancer risk in BRCA carriers have led to substantial hesitation, misinformation, and, in many cases, prolonged untreated symptoms. Researchers have emphasized, recommending premenopausal oophorectomy without offering a safe strategy to manage its consequences creates an untenable clinical dilemma.

Study Design: Emulating a Trial in a High-Risk Population

To address this evidence gap, investigators conducted the largest prospective matched analysis to date examining MHT use and breast cancer risk in BRCA1 and BRCA2 carriers. Using data from a longitudinal cohort, the study sought to emulate a randomized clinical trial by carefully matching women who initiated MHT after menopause, predominantly surgical menopause, to those who did not.

Eligible participants had no prior cancer history, no bilateral mastectomy, and had entered menopause. A total of 676 matched pairs were created, matched one-to-one by gene mutation (BRCA1 or BRCA2), year of birth, and age at menopause. Participants ranged in age from 22 to 76 years, with a mean age of 43.8 years. MHT formulations initiated after menopause included estrogen-only therapy, combined estrogen–progestogen therapy, progestogen alone, tibolone, and conjugated equine estrogen plus bazedoxifene. Cox proportional hazards models were used to estimate breast cancer risk.

Results: No Signal of Increased Breast Cancer Risk

After a mean follow-up of 5.6 years from the date of first MHT use, breast cancer incidence was significantly lower among women who used MHT compared with their matched, unexposed counterparts. Incident breast cancer occurred in 12.9% of MHT users versus 18.9% of non-users (P = 0.002).

Notably, estrogen-only therapy was associated with a substantial reduction in breast cancer risk, corresponding to a 63% relative decrease compared with non-users. In contrast, no increased or decreased risk was observed with combined estrogen–progestogen therapy, progestogen monotherapy, or tibolone. Among the 43 women who received conjugated equine estrogen plus bazedoxifene, no breast cancer diagnoses were reported during follow-up, an exploratory finding that warrants further investigation. Importantly, risk estimates were consistent across BRCA1 and BRCA2 carriers, underscoring the relevance of these findings across mutation subtypes.

Clinical Implications

These data provide critical reassurance for clinicians managing young women with hereditary breast and ovarian cancer syndromes. In contrast to earlier studies conducted in the general population, MHT use in BRCA1/2 carriers was not associated with an increased risk of breast cancer, regardless of formulation. Estrogen-only regimens, in particular, appeared protective, although causality cannot be inferred.

While limitations include a relatively modest follow-up duration and small numbers in certain subgroups, this prospective analysis offers the strongest evidence to date supporting the safety of MHT in this high-risk population. The findings reinforce the need for individualized, evidence-based counseling that balances cancer risk reduction with quality-of-life preservation.

Moving Forward

As MHT formulations continue to evolve, ongoing research will be essential to refine risk stratification and optimize menopause management strategies in BRCA mutation carriers. For now, these results support a personalized approach to MHT use in women experiencing surgical or natural menopause after risk-reducing oophorectomy, provided there are no contraindications. For many patients, informed use of MHT may offer not only symptom relief, but also a path toward improved long-term health and wellbeing without compromising breast cancer risk.

GS3-01. Menopausal Hormone Therapy and the Risk of Breast Cancer in Women with a Pathogenic Variant in BRCA1 or BRCA2. Kotsopoulos J, Seca M, Jacek G, et al. Presented at the 2025 San Antonio Breast Cancer Symposium (SABCS; Abstract GS3-01). 

Exploring GLP-1 Receptor Agonists as a Novel Adjunct in Sickle Cell Disease

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SUMMARY: Sickle Cell Disease (SCD) or Sickle Cell anemia is an Autosomal Recessive disorder caused by mutations in the hemoglobin beta-globin gene, and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the US is approximately 40-60 years.

HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (Vaso-Occlusive Crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 Thalassemia (double heterozygote for HbS and b-0 Thalassemia) is clinically indistinguishable from HbSS disease. Management of Sickle Cell Disease includes pain control, transfusion support and Hydroxyurea. None of the presently available therapies addresses the underlying cause of this disease nor do they fully ameliorate disease manifestations. Allogeneic bone marrow transplantation can cure this genetic disorder, but less than 20% of eligible patients have a related HLA-matched donor. There is therefore a great unmet need to find new therapies for Sickle Cell Disease.

Background: Inflammation and Vasculopathy at the Core of SCD

Sickle cell disease (SCD) is defined by chronic hemolysis, recurrent vaso-occlusion, and a persistent thrombo-inflammatory state. These processes drive episodic pain crises, progressive end-organ damage, cardiopulmonary complications, and premature mortality. Despite advances in disease-directed therapies, vascular dysfunction, oxidative stress, and systemic inflammation remain central, and incompletely addressed features of SCD pathophysiology.

Glucagon-Like Peptide-1 receptor agonists (GLP-1a), widely used in metabolic disease, have demonstrated pleiotropic effects beyond glycemic control. Preclinical and translational studies suggest GLP-1a exert anti-inflammatory, endothelial-protective, and antithrombotic effects through modulation of NF-κB, ERK/AMPK, and JAK/STAT signaling pathways, suppression of oxidative stress, macrophage polarization, and reduced platelet aggregation. Importantly, GLP-1 receptor activation in monocytes, macrophages, and neutrophils has been shown to attenuate NF-κB signaling and limit NLRP3 inflammasome priming, mechanisms highly relevant to SCD biology. Given these overlapping pathways of vascular injury and inflammation in SCD, investigators hypothesized that GLP-1a therapy could favorably modify the vascular and inflammatory milieu in SCD.

Study Design: Real-World Evidence from a Global Cohort

To explore this hypothesis, researchers conducted a retrospective, Propensity Score–Matched cohort study using the TriNetX Analytics Network, a global research platform aggregating de-identified data from more than 275 million patients worldwide.

The analysis identified over 238,000 individuals treated for SCD between 2005 and 2022, including 5,638 patients exposed to GLP-1a therapy. After 1:1 Propensity Score Matching, accounting for demographics, SCD-directed therapies, comorbidities, laboratory values (including HbA1c), and cardiovascular medications, 4,807 matched pairs were included in the final analysis.

The cohorts were well balanced, with a mean age in the early 50s, 73% female representation, and similar racial distribution. Comorbidities such as hypertension, diabetes, and overweight/obesity were comparable between groups. Mean follow-up was 3 years, and the average duration of GLP-1a exposure among users was approximately 136 days.

Primary outcomes included all-cause mortality, sickle cell crisis, ischemic stroke or Transient Ischemic Attack (TIA), and Venous ThromboEmbolism (VTE). Secondary outcomes encompassed health care utilization and major organ complications, including hospitalization, ICU admission, Acute kidney injury (AKI), thrombocytopenia, Heart Failure (HF), Pulmonary Fibrosis (PF), Pulmonary Hypertension (PH), and Myocardial Infarction (MI).

Results: Consistent Risk Reduction Across Clinical Endpoints

GLP-1a use was associated with significant reductions across all primary outcomes. Most notably, patients receiving GLP-1a experienced a markedly lower risk of all-cause mortality compared with non-users (2.5% vs. 7.0%; OR 0.33; 95% CI, 0.27–0.41). Rates of sickle cell crisis were also reduced (3.5% vs. 4.3%), as were ischemic stroke/TIA and VTE events.

Beyond these Primary endpoints, GLP-1a therapy was linked to broad reductions in secondary outcomes and health care utilization. Patients receiving GLP-1a demonstrated lower rates of hospitalization and ICU admission, along with significantly reduced risks of AKI, thrombocytopenia, HF, PH, PF, and MI. Collectively, these findings suggest potential benefits spanning hematologic, cardiovascular, renal, and pulmonary domains.

Clinical Interpretation: A Potential Disease-Modifying Signal

While causality cannot be established due to the retrospective, observational design, the consistency and magnitude of benefit across multiple clinically meaningful outcomes are notable. Investigators acknowledged limitations inherent to Real-World Data, including reliance on ICD coding and limited clinical granularity, which precluded detailed phenotyping or assessment of disease severity and treatment sequencing.

Importantly, concerns surrounding GLP-1a–associated dehydration and its theoretical potential to exacerbate sickling were not reflected in increased crisis rates; in fact, sickle cell crises were less frequent among GLP-1a users. The observed reductions in cardiopulmonary complications may reflect downstream benefits of attenuated inflammation, reduced vaso-occlusion, and improved endothelial function.

Implications and Future Directions

These findings provide compelling, hypothesis-generating evidence that GLP-1 receptor agonists may confer disease-modifying benefits in SCD when used as an adjunct to existing therapies. Beyond individual patient outcomes, reductions in hospitalization and ICU utilization suggest a meaningful impact on overall health care burden.

Prospective, randomized clinical trials will be essential to confirm these observations, clarify optimal patient selection, and define safety considerations specific to the SCD population. If validated, GLP-1a therapy could represent a novel strategy targeting the inflammatory and vasculopathic underpinnings of sickle cell disease.

Key Takeaways

  • GLP-1 receptor agonist use was associated with significantly lower all-cause mortality in patients with SCD.
  • Reduced risks of sickle cell crisis, ischemic stroke/TIA, and Venous Thromboembolism were observed.
  • GLP-1a therapy was linked to fewer hospitalizations, ICU admissions, and cardiopulmonary complications.
  • Findings support prospective trials to evaluate GLP-1a as a potential disease-modifying adjunct in SCD management.

Targeting inflammation in sickle cell disease: Association of GLP-1 agonist use with improved survival and reduced sickle cell crisis and cardiopulmonary complications. Cheema AY, Munir M, Mandala A, et al. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2025; Orlando. Abstract 2970.

FDA Approves First Line ENHERTU® plus PERJETA® for HER2-Positive Metastatic Breast Cancer

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SUMMARY: The FDA on December 15, 2025, approved ENHERTU® in combination with Pertuzumab for the first-line treatment of adults with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer as determined by an FDA-approved test.

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 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer. Tolaney SM, Jiang Z, Zhang Q, et al. for the DESTINY-Breast09 Trial Investigators. N Engl J Med. DOI: 10.1056/NEJMoa2508668

Real-World Outcomes with CD20×CD3 Bispecific Antibodies in Relapsed/Refractory Large B-Cell Lymphoma: Insights from the Multicenter REALBiTE Consortium

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SUMMARY: The American Cancer Society estimates that in 2026, about 79,320 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,970 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States and more than 25,000 cases of DLBCL are diagnosed each year in the United States, accounting for more than 25 percent of all lymphoma cases. The incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population.

Background
DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless of molecular subtype, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL. Approximately 30-40% of patients experience disease progression or relapse during the first 2 years and attempts to improve on R-CHOP regimen have not been successful.

Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL), including Diffuse Large B-Cell Lymphoma (DLBCL), remains a challenging disease state with historically poor outcomes after multiple lines of therapy. CD20×CD3 Bispecific Antibodies (BsAbs), including Epcoritamab (EPKINLY®) and Glofitamab (COLUMVI®), represent a major therapeutic advance by redirecting endogenous T cells to malignant B cells through off-the-shelf immune engagement. Pivotal trials demonstrated encouraging response rates, leading to regulatory approvals in the United States. However, clinical trials often enroll selected patients with favorable performance status and limited comorbidity, underscoring the need for robust Real-World Evidence (RWE) to better understand effectiveness, durability, and outcomes in routine practice.

Study Design and Patient Population
The REALBiTE Consortium conducted a large multicenter retrospective analysis across 21 U.S. academic centers, evaluating patients with R/R DLBCL treated with commercially available Epcoritamab or Glofitamab between January 2023 and October 2024, with updated follow-up through May 2025.

Across multiple analyses, more than 300 patients were evaluated, reflecting a heavily pretreated, high-risk population:

  • Over half were primary refractory to frontline therapy
  • A substantial proportion had double-hit or triple-hit lymphoma
  • Approximately 60% had prior CAR T-cell therapy, many of whom were CAR T-refractory
  • Nearly 70% would have been ineligible for registrational trials due to comorbidities, disease burden, or performance status

This cohort therefore represents a realistic cross-section of patients encountered in contemporary lymphoma practice.

Efficacy Outcomes in the Real World
Despite high-risk features, Overall Response Rates (ORR) with BsAbs in routine practice were comparable to pivotal clinical trials:

  • ORR approximately 51–54%
  • Complete Response (CR) rates ranging from 23–33%

However, response durability was limited:

  • Median Progression-Free Survival (PFS): ~2.5–2.6 months
  • Median Overall Survival (OS): ~7.7–7.8 months
  • Six-month PFS and OS rates were approximately 36% and 60%, respectively

These findings highlight a key real-world gap: while BsAbs induce meaningful initial responses, early disease progression remains common, particularly in biologically aggressive disease.

Predictors of Progression and Resistance
Several baseline clinical and biologic factors were associated with inferior outcomes:

  • Double-hit or triple-hit lymphoma
  • High International Prognostic Index (IPI)
  • Poor performance status (ECOG ≥2)
  • Primary refractory disease
  • Refractoriness to the line of therapy immediately preceding BsAbs

Importantly, loss or absence of CD20 expression emerged as a critical resistance mechanism. Among patients with paired biopsies, nearly 90% lost CD20 expression following BsAb therapy, with rapid progression thereafter. Additionally, undetectable CD20 by immunohistochemistry prior to BsAb initiation was strongly associated with inferior PFS and OS, underscoring the clinical relevance of confirming target antigen expression before treatment.

Safety and Causes of Mortality
Progressive lymphoma was the leading cause of death, accounting for more than 80% of fatalities, followed by infections. Treatment-related deaths due to Cytokine Release Syndrome (CRS) or Immune effector Cell–Associated Neurotoxicity Syndrome (ICANS) were infrequent, reinforcing the manageable safety profile of BsAbs in experienced centers. Notably, infection-related mortality occurred early and late, highlighting the need for vigilance with immune suppression and supportive care.

Outcomes After Progression on Bispecific Antibodies
Disease progression following BsAb therapy was often rapid, with a median time to progression of approximately 1.5 months. Nearly half of progressing patients received no further anti-lymphoma therapy, reflecting clinical decline and limited salvage options.

Among patients who did receive subsequent treatment:

  • Chemoimmunotherapy was most commonly used but achieved modest responses (~30%)
  • Loncastuximab tesirine showed limited activity
  • CAR T-cell therapy, when feasible, demonstrated the most favorable outcomes, with ORRs around 50% and high CR rates
  • Allogeneic hematopoietic cell transplantation, used as consolidation in selected responders, resulted in encouraging short-term disease control, with many patients remaining progression-free at follow-up

Nevertheless, overall post-BsAb survival remained poor, with median OS after salvage therapy of less than 4 months.

Clinical Implications
These Real-World Data confirm that Epcoritamab and Glofitamab are active therapies in heavily pretreated R/R LBCL, even among patients excluded from clinical trials. However, the short duration of benefit in most patients emphasizes the aggressive biology of this population and the urgent need for improved sequencing strategies.

Key clinical takeaways include:

  • Assessment of CD20 expression prior to BsAb initiation is critical
  • Early identification of patients unlikely to benefit may help guide alternative strategies
  • Clinical trial enrollment, novel combinations, or consolidation approaches (CAR T or allogeneic transplant) should be strongly considered for eligible responders
  • Durable remissions, while uncommon, do occur, suggesting that a subset of patients can derive long-term benefit with appropriate selection

Conclusion
The REALBiTE Consortium provides the most comprehensive real-world assessment to date of CD20×CD3 bispecific antibodies in R/R LBCL. While Response Rates mirror those seen in pivotal trials, real-world PFS and OS are shorter, reflecting broader patient inclusion and aggressive disease biology. These findings reinforce the transformative potential of BsAbs while highlighting the need for better predictive biomarkers, rational combinations, and optimized sequencing to improve long-term outcomes for this challenging patient population.

Outcomes following disease progression after epcoritamab or glofitamab in the real-world outcomes of bispecific T-cell engagers (REALBiTE) multi-center, retrospective cohort study. Brooks T, Mian A, Nedved A, et al. Blood. 2025;146(suppl 1):402. doi:10.1182/blood-2025-402

Routine Preoperative Breast MRI for Early-Stage Cancers May Not Be Beneficial: Outcome Data from Alliance A011104

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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 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

The Evolving Role of Breast MRI in Clinical Practice

Breast Magnetic Resonance Imaging (MRI) has become an important adjunct to mammography and ultrasound across a range of clinical scenarios. Its high sensitivity makes it particularly valuable in complex cases where conventional imaging may be limited, such as dense breast tissue or multifocal disease. As utilization has expanded, a critical question has emerged: does the additional disease detected by breast MRI translate into improved oncologic outcomes?

Established Clinical Indications for Breast MRI

Breast MRI is most clearly supported in selected high-risk and diagnostic settings, where its superior sensitivity can meaningfully inform care.

High-Risk Screening
MRI is recommended for patients with a substantially elevated lifetime risk of breast cancer, including those with:

  • Pathogenic BRCA1/2 variants or first-degree relatives of known carriers
  • Hereditary cancer syndromes such as Li-Fraumeni or Cowden syndrome
  • Prior therapeutic chest irradiation between ages 10 and 30
  • A calculated lifetime breast cancer risk of ≥20–25% using validated risk models

Evaluation of Known Breast Cancer (Staging and Extent)
In patients with newly diagnosed breast cancer, MRI may help define disease burden when conventional imaging is insufficient:

  • Detection of multifocal or multicentric disease, including contralateral breast involvement
  • Improved visualization in dense breast tissue
  • Enhanced detection of invasive lobular carcinoma, which can be underestimated on mammography
  • Identification of occult primary tumors in patients presenting with axillary adenopathy
  • Assessment of posterior lesions and potential chest wall involvement

Diagnostic Evaluation of Symptoms or Indeterminate Findings
MRI is also used selectively to clarify challenging diagnostic scenarios, including:

  • Pathologic nipple discharge or suspected Paget disease
  • Indeterminate mammographic or ultrasound findings that cannot be confidently biopsied
  • Evaluation of breast implant integrity
  • Unexplained new nipple inversion

Treatment Monitoring and Post-Treatment Assessment
In the therapeutic setting, breast MRI may assist with:

  • Monitoring response to neoadjuvant chemotherapy
  • Evaluating residual disease after breast-conserving surgery
  • Distinguishing post-treatment changes from locoregional recurrence

While these indications are well accepted, the impact of breast MRI on long-term outcomes in newly diagnosed breast cancer has remained uncertain.

Does Preoperative Breast MRI Improve Outcomes? Insights from Alliance A011104

Trial Rationale and Design

Despite widespread adoption of preoperative breast MRI for local staging and surgical planning, robust evidence demonstrating improved oncologic outcomes has been limited. The Alliance A011104 phase III trial was designed to directly address whether identifying mammographically occult disease with MRI, and modifying surgery accordingly, reduces local-regional recurrence.

This randomized study enrolled 319 patients with newly diagnosed clinical Stage I–II breast cancer who were eligible for breast-conserving surgery and had biologically aggressive disease, including Triple-Negative breast cancer or Hormone Receptor-negative/HER2-positive tumors. Patients with germline BRCA mutations, bilateral disease, or prior breast cancer were excluded. Participants were randomly assigned to undergo preoperative breast MRI within 30 days of diagnostic mammography or to proceed without MRI.

Patient Characteristics and Treatment

The median age at enrollment was approximately 59 years, with most patients presenting with small, node-negative tumors. Systemic therapy was commonly employed, with 85% of patients receiving chemotherapy and a subset treated in the neoadjuvant setting. Importantly, presurgical ultrasound, while not mandated, was widely utilized across institutions, reflecting contemporary practice.

Key Findings: No Improvement in Local-Regional Control

With a median follow-up exceeding five years, the trial demonstrated no significant difference in local-regional outcomes between the MRI and no-MRI arms.

  • Rates of breast-conserving surgery were high and comparable between groups
  • The majority of patients underwent sentinel lymph node biopsy alone
  • Pathologic Complete Response rates among patients receiving neoadjuvant chemotherapy did not differ significantly between arms
  • Adjuvant radiation use was similar in both groups

Among patients evaluable for the Primary endpoint, 5-year local-regional control exceeded 90% in both arms, with no statistically meaningful difference observed. Distant Recurrence-Free Survival and Overall Survival were also excellent and equivalent regardless of MRI use.

Exploratory subgroup analyses failed to identify any patient population that derived a local control benefit from preoperative MRI.

Interpreting the Results: Why Was No Benefit Observed?

Several explanations may account for the lack of observed advantage with preoperative breast MRI. First, contemporary multimodality therapy, including effective systemic treatment and radiation, may adequately control small foci of disease detected only by MRI, reducing the necessity for surgical excision. Second, advances in mammographic technology and the routine incorporation of ultrasound may have narrowed the incremental value of MRI for local staging compared with earlier eras.

Ongoing analyses from the trial are exploring whether MRI influences other surgical outcomes, such as margin status and reoperation rates.

Clinical Implications and Take-Home Message

In patients with early-stage Triple-Negative or HER2-positive breast cancer treated with modern multimodality therapy, local-regional recurrence rates are low. Results from Alliance A011104 indicate that routine use of preoperative breast MRI for local staging and surgical planning does not improve local-regional control in this setting.

These findings support a more selective, indication-driven approach to breast MRI, reserving its use for high-risk screening, specific diagnostic dilemmas, and carefully chosen staging scenarios, rather than routine deployment in all newly diagnosed patients.

As imaging technologies and systemic therapies continue to evolve, ongoing evaluation of how best to integrate advanced imaging into patient-centered, value-based care remains essential.

Effect of Preoperative Breast MRI Staging on Local Regional Recurrence (LRR) in Early Stage Breast cancer: Alliance A011104/ACRIN 6694. Bedrosian I, Ballman K, McCall LM, et al. Presented at the 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract GS2-07.

JAYPIRCA® versus IMBRUVICA® in Treatment Naïve CLL/SLL: Insights from the Phase III BRUIN CLL-314 Trial

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SUMMARY: The American Cancer Society estimates that for 2026, about 22,760 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4350 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Progress and Persistent Gaps with Covalent BTK Inhibitors

The advent of covalent Bruton Tyrosine Kinase inhibitors (cBTKi), Ibrutinib (IMBRUVICA®), Acalabrutinib (CALQUENCE®), and Zanubrutinib (BRUKINSA®), has fundamentally altered the treatment paradigm for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). These agents have demonstrated robust activity across both treatment-naïve (TN) and relapsed/refractory (R/R) settings, establishing BTK inhibition as a cornerstone of therapy.

Despite these advances, cBTKi share inherent pharmacologic and clinical limitations. Short half-lives, variable oral bioavailability, and off-target kinase inhibition can lead to incomplete target suppression, cumulative toxicity, treatment interruptions, and ultimately compromised long-term efficacy. While second-generation agents such as Acalabrutinib and Zanubrutinib were developed to improve selectivity and tolerability, their benefits over Ibrutinib have been demonstrated primarily in the R/R setting, and direct comparisons in the treatment-naïve population have been lacking.

Rationale for Noncovalent BTK Inhibition

Pirtobrutinib (JAYPIRCA®) represents a mechanistically distinct approach to BTK inhibition. As a highly selective, noncovalent BTK inhibitor (ncBTKi), it binds independently of the C481 residue, enabling sustained target inhibition even in the presence of common resistance mutations. Its low nanomolar potency and pharmacokinetic profile allow for continuous BTK suppression throughout the dosing interval, raising the possibility of enhanced efficacy with improved tolerability relative to cBTKi.

BRUIN CLL-314: Trial Design and Objectives

BRUIN CLL-314 (LOXO-BTK-20030) is a global, randomized, open-label Phase III study and, to date, the first trial to directly compare a noncovalent BTK inhibitor with a covalent BTK inhibitor in CLL/SLL. The study enrolled 662 BTKi-naïve patients across 23 countries, including both treatment-naïve patients and those with R/R disease.

Participants were randomized 1:1 to receive Pirtobrutinib (200 mg once daily) or Ibrutinib (420 mg once daily), administered continuously until disease progression or unacceptable toxicity. Stratification factors included del(17p) status and number of prior lines of therapy. The Primary endpoint was Independent Review Committee (IRC)–assessed Overall Response Rate (ORR) in the Intention-to-Treat (ITT) population and in patients with R/R disease. Progression-Free Survival (PFS) was a key Secondary endpoint.

Patient Population

Baseline characteristics were well balanced between treatment arms. The median age was 67 years, approximately two-thirds of patients were male, and over half were enrolled from Europe. High-risk molecular features, including del(17p), unmutated IGHV, and complex karyotype, were evenly distributed. Among patients with R/R disease, the median number of prior therapies was one.

Efficacy Outcomes: ORR and Early PFS Signals

The study met its primary objective, demonstrating statistically significant noninferiority of Pirtobrutinib compared with Ibrutinib for IRC-assessed ORR.

  • Intent to Treat population: ORR was 87.0% with Pirtobrutinib versus 78.5% with Ibrutinib
  • Treatment-Naïve patients: ORR was 92.9% versus 85.8%, respectively
  • Relapsed/Refractory patients: ORR was 84.0% versus 74.8%, respectively

Notably, response rates consistently favored Pirtobrutinib across clinically relevant high-risk subgroups, including patients with del(17p), unmutated IGHV, and complex karyotype.

While PFS data remain immature, early descriptive analyses revealed a favorable trend for Pirtobrutinib. Investigator-assessed PFS suggested a reduction in the risk of progression or death across the ITT, Relapsed/Refractory, and treatment-naïve populations, with the most pronounced benefit observed in treatment-naïve patients, the subgroup with the longest follow-up to date.

Safety and Tolerability

Pirtobrutinib demonstrated a favorable safety profile compared with Ibrutinib. Rates of cardiac adverse events, including atrial fibrillation/flutter and hypertension, were lower with Pirtobrutinib, consistent with its higher selectivity for BTK and reduced off-target kinase inhibition.

Patient-reported outcomes further supported improved tolerability, with lower rates of symptomatic adverse events such as myalgia, bruising, headache, diarrhea, and cough. These findings are particularly relevant in CLL/SLL, where long-term therapy places a premium on safety, adherence, and quality of life.

Clinical Implications and Sequencing Considerations

The results of BRUIN CLL-314 carry important implications for clinical practice. Historically, noncovalent BTK inhibitors were positioned primarily as salvage therapy following cBTKi resistance. These data challenge that paradigm by demonstrating robust activity, favorable tolerability, and early PFS benefit for Pirtobrutinib in BTKi-naïve patients, including those treated in the frontline setting.

The pronounced benefit observed in treatment-naïve patients is especially noteworthy, as this represents the first randomized Phase III evidence directly comparing BTK inhibitors head to head in this population. For patients requiring long-term continuous therapy, improved tolerability may translate into prolonged disease control and better overall outcomes.

Sequencing remains an evolving consideration. Venetoclax-based fixed-duration regimens continue to provide an effective option following BTK inhibition, and prior studies suggest preserved activity of Venetoclax after Pirtobrutinib. For older patients or those anticipated to require limited lines of therapy, initial treatment choice may reasonably prioritize safety, convenience, and durability of response.

Study Limitations

Key limitations include the open-label design and relatively short follow-up for PFS. However, the use of a blinded IRC for response assessment and minimal imbalance in early treatment discontinuation mitigate concerns regarding bias. Ongoing follow-up and prespecified analyses will further clarify the long-term impact of Pirtobrutinib on disease control and survival outcomes.

Conclusion

BRUIN CLL-314 establishes Pirtobrutinib as a compelling next-generation BTK inhibitor, demonstrating noninferior, and numerically superior response rates compared with Ibrutinib, alongside early signals of improved Progression-Free Survival and a more favorable safety profile. These findings support the potential role of Pirtobrutinib not only after cBTKi failure but also in earlier lines of therapy, including the frontline setting, where durable efficacy and tolerability are paramount.

Pirtobrutinib Versus Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Woyach JA, Qiu L, Grosicki S, et al. J Clin Oncol. DOI: 10.1200/JCO-25-02477

Adjuvant Giredestrant Reduces Recurrence Risk in ER-Positive/HER2-Negative Early Breast Cancer: Results From the Phase III lidERA Trial

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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 321,910 new cases of female breast cancer were diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

Background: Addressing Residual Risk in ER-Positive Early Breast Cancer

Estrogen Receptor-positive (ER-positive) breast cancer represents approximately 70% of all breast cancer diagnoses. Despite the widespread use of adjuvant endocrine therapy as standard of care for patients with ER-positive, HER2-negative early breast cancer, long-term outcomes remain suboptimal. Up to one-third of patients experience disease recurrence during or after completion of adjuvant endocrine treatment, underscoring a persistent unmet need for more effective and better-tolerated therapeutic options that can improve adherence and long-term disease control.

Giredestrant: A Next-Generation Oral SERD

Giredestrant is an investigational, oral, next-generation Selective Estrogen Receptor antagonist and Degrader (SERD). It is designed to completely block estrogen receptor signaling by preventing estrogen binding and inducing receptor degradation. Preclinical and early clinical studies have demonstrated that Giredestrant is more potent than earlier-generation SERDs and exhibits superior antiproliferative activity compared with Aromatase Inhibitors, including Anastrozole, in the neoadjuvant setting. These attributes provided the rationale for evaluating Giredestrant in the adjuvant treatment of ER-positive/HER2-negative early breast cancer.

The lidERA Trial: Study Design and Patient Population

The global, randomized, open-label Phase III lidERA BC trial (NCT04961996) evaluated the efficacy and safety of adjuvant Giredestrant compared with standard-of-care endocrine therapy in patients with medium or high-risk Stage I–III ER-positive, HER2-negative early breast cancer.

A total of 4,170 patients were randomized 1:1 to receive either Giredestrant 30 mg orally once daily or physician’s choice of standard endocrine monotherapy (Tamoxifen or an Aromatase Inhibitor). Premenopausal and perimenopausal women, as well as men, received concurrent LHRH agonist therapy. Treatment was administered for up to five years or until disease recurrence or unacceptable toxicity. At baseline, the median age was 54 years, with nearly 60% of patients postmenopausal. Disease stage distribution included 13% Stage I, 47% Stage II, and 40% Stage III disease. Median follow-up at the prespecified interim analysis was 32.3 months. The Primary endpoint was invasive Disease-Free Survival (iDFS), excluding second primary non–breast cancers. Key Secondary endpoints included Overall Survival (OS), iDFS including second primary malignancies, Distant Recurrence-Free Interval (DRFI), Disease-Free Survival, and Safety.

Efficacy Results: Clinically Meaningful Improvement in iDFS

At the prespecified interim analysis, adjuvant Giredestrant demonstrated a statistically significant and clinically meaningful improvement in invasive DFS compared with standard-of-care endocrine therapy. Treatment with Giredestrant reduced the risk of invasive disease recurrence or death by 30% (Hazard Ratio [HR] 0.70; 95% CI, 0.57–0.87; P=0.0014).

Three-year iDFS rates were 92.4% in the Giredestrant arm versus 89.6% in the standard endocrine therapy arm. Importantly, the iDFS benefit was consistent across all clinically relevant subgroups, including disease stage, menopausal status, geographic region, and prior chemotherapy exposure. Giredestrant also significantly improved Distant Recurrence-Free Interval, with a 31% reduction in the risk of distant relapse (HR=0.69; 95% CI, 0.54–0.89), reinforcing its potential to prevent metastatic progression.

Overall Survival data were immature at the time of analysis. However, a favorable trend was observed in the Giredestrant arm (HR 0.79), with continued follow-up planned for subsequent analyses.

Safety and Tolerability

Giredestrant was generally well tolerated, with a safety profile consistent with previously reported data. The most common adverse events included arthralgia, hot flushes, and headache, occurring at similar rates in both treatment arms. Grade 3–4 adverse events were infrequent and comparable between groups. Notably, treatment discontinuations due to adverse events were lower with Giredestrant than with standard endocrine therapy (5.3% vs 8.2%), suggesting favorable tolerability that may translate into improved long-term adherence in the adjuvant setting.

Clinical Implications

The lidERA trial represents the first Phase III study to demonstrate a significant benefit with an oral SERD in early breast cancer. By delivering superior invasive Disease-Free Survival, reducing distant recurrence risk, and maintaining a manageable safety profile, Giredestrant addresses key limitations of current adjuvant endocrine strategies.

Given the high prevalence of ER-positive breast cancer and the substantial proportion of patients who relapse despite standard therapy, these findings position Giredestrant as a compelling candidate for a new standard of care in appropriately selected patients with HR-positive/HER2-negative early breast cancer.

 Conclusion

Results from the Phase III lidERA trial establish adjuvant Giredestrant as a highly promising next-generation endocrine therapy for ER-positive, HER2-negative early breast cancer. The observed improvements in invasive Disease-Free Survival and distant Recurrence-Free Interval, combined with favorable tolerability and a trend toward improved Overall Survival, support Giredestrant’s potential to meaningfully improve long-term outcomes for a broad patient population.

Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: Results from the global Phase III lidERA Breast Cancer trial. Bardia A, Schmid P, Martín M, et al. Presented at the 2025 San Antonio Breast Cancer Symposium (SABCS) (Abstract GS1-10)

Fixed-Duration vs Continuous Targeted Therapy in Frontline CLL: Insights from the Phase III CLL17 Trial

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SUMMARY: The American Cancer Society estimates that for 2026, about 22,760 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4350 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Evolving Treatment Paradigms in CLL            

The therapeutic landscape of CLL has undergone a profound transformation over the past decade, moving away from chemoimmunotherapy toward mechanism-based targeted agents. Brutons Tyrosine Kinase (BTK) inhibitors and the BCL2 inhibitor Venetoclax have become foundational therapies, delivering durable disease control across biologic risk groups. Historically, BTK inhibitors were administered continuously until progression or intolerance, whereas Venetoclax-based combinations introduced the possibility of time-limited treatment.

The rationale for fixed-duration therapy stems from the observation that rational combinations can induce deeper remissions, including undetectable Minimal Residual Disease (MRD), potentially allowing for treatment-free intervals and reduced cumulative toxicity. While Venetoclax–Rituximab in relapsed disease and Venetoclax–Obinutuzumab in the frontline setting validated this concept, the relative efficacy of fixed-duration regimens compared with continuous BTK inhibition remained an unanswered question, until now.

Trial Design and Patient Population

CLL17 is an international, investigator-initiated, Phase III randomized trial designed to directly compare fixed-duration and continuous targeted treatment strategies, in previously untreated CLL patients. A total of 909 treatment-naïve patients were enrolled across 174 centers in 13 countries and randomly assigned in a 1:1:1 ratio to receive:

Fixed-duration Venetoclax plus Obinutuzumab (N=303)

Fixed-duration Venetoclax plus Ibrutinib (N=305)

Continuous Ibrutinib monotherapy (N=301)

Randomization was stratified by fitness status, IGHV mutation status, and the presence of del(17p) and/or TP53 mutation. The study population reflected real-world heterogeneity, with a median age of 66 years, 44% classified as unfit (based on CIRS scores greater than 6, a creatinine clearance of less than 70 ml per minute, or both), more than half harboring unmutated IGHV, 7.6% of the patients with del(17p) or TP53 mutation (or both), and nearly 20% exhibiting complex karyotypes. High- and very high-risk disease by the CLL International Prognostic Index was present in more than 60% of patients, underscoring the clinical relevance of the cohort. The Primary endpoint was investigator-assessed Progression-Free Survival (PFS), with the trial powered to test the noninferiority of each fixed-duration regimen versus continuous Ibrutinib. Key Secondary endpoints included Overall Survival (OS), MRD negativity, Response Rates, and Safety.

Efficacy Outcomes: Noninferiority Achieved

At a median follow-up of 34.2 months, in this prespecified interim analysis, both fixed-duration strategies met the prespecified criteria for noninferiority compared with continuous Ibrutinib. Three-year PFS rates were remarkably similar across treatment arms:

81.1% with Venetoclax–Obinutuzumab

79.4% with Venetoclax–Ibrutinib

81.0% with continuous Ibrutinib

Hazard ratios for progression or death favored neither continuous nor fixed-duration therapy, providing the first prospective evidence that time-limited targeted regimens can match the disease control achieved with indefinite BTK inhibition in the frontline setting.

Overall Survival at three years exceeded 90% in all groups, with no meaningful differences observed at this interim analysis. Longer follow-up will be required to determine whether survival curves diverge with time, particularly in biologically high-risk subgroups.

Depth of Remission and MRD Dynamics

Marked differences emerged in depth of response. Undetectable MRD in peripheral blood at the end of treatment was achieved in:

73.3% of patients treated with Venetoclax–Obinutuzumab

47.2% of those receiving Venetoclax–Ibrutinib

0% of patients on continuous Ibrutinib

These findings reinforce the well-established limitation of single-agent BTK inhibition in achieving deep molecular remissions and highlight a key advantage of Venetoclax-based combinations. While end-of-treatment MRD has been associated with long-term outcomes in fixed-duration regimens, its prognostic value relative to continuous BTK inhibition remains less clear. Ongoing longitudinal MRD assessments in CLL17 may help clarify whether differences in MRD depth ultimately translate into durable clinical benefit.

Safety and Tolerability Considerations

Adverse events were common across all treatment arms, reflecting the immunocompromised nature of the CLL population. Infections affected nearly 80% of patients overall, with serious and fatal infections occurring more frequently in the Venetoclax–Obinutuzumab arm. Importantly, trial enrollment coincided with the COVID-19 pandemic, and approximately 10% of patients experienced severe COVID-19–related infections.

Cytopenias, particularly neutropenia, were more frequent with combination regimens, especially Venetoclax–Obinutuzumab. However, these events were largely confined to the first year of therapy and resolved after treatment completion. In contrast, cardiac toxicities, including atrial fibrillation and hypertension, were more commonly associated with Ibrutinib-containing regimens, consistent with prior experience.

Tumor lysis syndrome was infrequent (<5%) across Venetoclax-containing arms, demonstrating that standard ramp-up strategies and debulking approaches effectively mitigate this risk, even in older and unfit patients.

Subgroup Insights and Clinical Implications

Fixed-duration therapy performed well across most biologic subgroups. Notably, patients with unmutated IGHV did not experience inferior outcomes with time-limited treatment compared with continuous Ibrutinib, supporting broader use of fixed-duration strategies. Patients with mutated IGHV achieved particularly favorable outcomes with Venetoclax–Obinutuzumab, consistent with the more indolent biology of this subgroup.

For patients with del(17p) or TP53 mutations, outcomes were encouraging with BTK inhibitor–containing regimens, although the small sample size and limited follow-up preclude definitive conclusions. Continuous therapy did not clearly outperform fixed-duration Venetoclax–Ibrutinib in this population, highlighting the need for ongoing observation and biomarker-driven analyses.

Positioning CLL17 in the Current Treatment Landscape

The results of CLL17 complement and extend findings from earlier studies such as CLL13, CLL14, CAPTIVATE, and GLOW, while providing the first direct, randomized comparison between fixed-duration and continuous targeted therapy. Importantly, the trial was conducted during the emergence of next-generation BTK inhibitors with improved cardiac safety profiles, suggesting that the central question addressed by CLL17, time-limited versus continuous therapy, will remain clinically relevant regardless of the specific BTK inhibitor chosen.

Conclusions

The first analysis of the Phase III CLL17 trial demonstrates that fixed-duration Venetoclax–Obinutuzumab and Venetoclax–Ibrutinib are noninferior to continuous Ibrutinib in previously untreated CLL, with comparable Progression-Free Survival and excellent Overall Survival. These findings provide high-level evidence supporting fixed-duration therapy as a viable frontline strategy for most patients, offering the advantages of treatment-free intervals and deep remissions without compromising efficacy. As follow-up matures, CLL17 will further inform patient selection, remission durability, and the long-term significance of MRD. For now, the trial marks a pivotal step toward more personalized, time-limited treatment strategies in CLL.

Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia. Al-Sawaf O, Stumpf J,  Zhang C, et al. for the CLL17 Trial Investigators. Published December 6, 2025. DOI: 10.1056/NEJMoa2515458.

Neoadjuvant Niraparib Plus Dostarlimab in BRCA or PALB2-Mutated Triple Negative Breast Cancer: Phase II TBCRC 056 Results

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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 were diagnosed in 2025, and about 42,170 women died of the disease, largely due to metastatic recurrence.

Rationale for a Chemotherapy-Free Neoadjuvant Strategy

Patients with germline BRCA1/2 or PALB2–mutated breast cancer represent a biologically distinct population with heightened sensitivity to PARP inhibition. Beyond synthetic lethality, accumulating preclinical evidence suggests that PARP inhibitors activate the cGAS/STING pathway, increasing intratumoral inflammation, recruiting CD8+ T cells, and potentially priming tumors for immune checkpoint blockade.

While prior studies have not demonstrated a clear benefit for combining PARP inhibitors with immunotherapy in the advanced TNBC (Triple-Negative Breast Cancer) setting, investigators hypothesized that the early-stage, neoadjuvant context, characterized by less immune exhaustion and lower tumor burden, might offer a more permissive environment for synergy.

Study Design and Patient Population

TBCRC 056 is a randomized, Phase II study evaluating the PARP inhibitor Niraparib (ZEJULA&reg;) in combination with the anti–PD-1 antibody Dostarlimab (JEMPERLI&reg;) as neoadjuvant therapy for patients with HER2-negative breast cancer harboring germline BRCA1/2 or PALB2 mutations. The trial includes cohorts for both triple-negative and Estrogen Receptor (ER) positive disease. The current analysis focuses on TNBC cohorts (Arms A and B). Participants with ER positive breast cancer will be placed directly into Arm C. There is no randomization for these participants.

Eligible patients were ≥18 years old with Stage I–III TNBC, primary tumors ≥1.0 cm, HER2-negative disease, and confirmed germline BRCA1/2 or PALB2 mutations. Patients were randomized to:

  • Arm A: Niraparib 200 mg orally once daily plus Dostarlimab 500 mg IV every 3 weeks for 18 weeks
  • Arm B: Niraparib monotherapy for 3 weeks followed by Niraparib plus Dostarlimab for 15 weeks

Tumor biopsies were obtained at baseline and week 3 to assess immune modulation. Surgery followed 18 weeks of therapy, with optional additional neoadjuvant treatment at investigator discretion if residual disease was detected.

RCB (Residual Cancer Burden in the breast tissue and axillary lymph nodes) Categories:

  • RCB 0:No invasive cancer cells found (pCR).
  • RCB I (Minimal):Very small amount of residual disease.
  • RCB II (Moderate):Moderate amount of residual disease.
  • RCB III (Extensive):Significant amount of residual disease.

Endpoints and Statistical Considerations

The Primary endpoints were:

  • Pathologic Complete Response (pCR; RCB-0) rate in Arms A and B combined
  • Change in stromal Tumor-Infiltrating Lymphocytes (sTILs) from baseline to week 3

The study was powered to detect a pCR rate of ≥50%, allowing rejection of a null hypothesis pCR rate <30%.

Baseline Characteristics

A total of 46 patients with TNBC were enrolled across Arms A and B. The median age was 39.3 years, reflecting the young demographic typical of germline BRCA-associated disease. Most patients were White (84.8%), with representation from Black, Asian, and Hispanic populations. Clinically, 37.0% had Stage I disease, 45.7% Stage II, and 17.4% Stage III. The majority had node-negative and high-grade (grade 3) tumors. BRCA1 mutations predominated (82.6%), with the remainder harboring BRCA2 mutations. No PALB2-mutated TNBC patients were enrolled in this cohort.

Efficacy Outcomes: pCR and Residual Disease

Neoadjuvant Niraparib plus Dostarlimab achieved a pCR rate of 50.0% (90% CI, 37.1%–62.9%) among evaluable patients, meeting and exceeding the study’s predefined efficacy threshold.

Notably:

  • pCR rates were identical in both treatment strategies, at 50% in Arm A (concurrent therapy) and Arm B (niraparib lead-in)
  • The combined RCB-0/I rate was 60.0%, suggesting meaningful tumor eradication or minimal residual disease in a majority of patients
  • Approximately 24% of patients crossed over to additional preoperative therapy, reflecting real-world decision-making when residual disease is identified

These findings support the robustness of the regimen regardless of initial PARP inhibitor lead-in.

Immune Modulation and Biomarker Insights

A key translational objective of TBCRC 056 was to characterize early immune changes within the tumor microenvironment.

Both treatment arms demonstrated statistically significant increases in sTILs from baseline to week 3:

  • Arm A: Mean sTILs increased from 16% to 27.4%
  • Arm B: Mean sTILs increased from 19.5% to 42.1%, suggesting a pronounced immune activation following PARP inhibitor exposure

Importantly, patients who achieved pCR had higher baseline sTIL levels than those who did not, underscoring the prognostic relevance of preexisting immune infiltration. Baseline sTILs were also associated with achieving RCB-0/I.

In contrast, baseline PD-L1 expression, estrogen receptor status (ER-0 vs ER-low), and short-term changes in sTILs were not independently associated with pCR, highlighting the complexity of immune–genomic interactions in BRCA-driven TNBC.

Safety and Tolerability

The safety profile of Niraparib plus Dostarlimab was consistent with known toxicities of PARP inhibition and immune checkpoint blockade.

  • Grade ≥2 treatment-related adverse events occurred in 82.6% of patients
  • Grade 3 events were reported in 26.1%, and grade 4 events were rare (2.2%)
  • The most common higher-grade toxicities included anemia, fatigue, hypertension, hypothyroidism, and neutropenia

Treatment discontinuation occurred in 13% of patients, with discontinuations split between Niraparib and Dostarlimab, suggesting manageable but clinically relevant toxicity in a neoadjuvant setting.

Key Takeaways for Oncology Practice

  • TBCRC 056 demonstrates that a chemotherapy-free neoadjuvant therapy with Niraparib combined with Dostarlimab achieved a 50% pathologic Complete Response (pCR) rate in patients with germline BRCA-mutated early-stage TNBC, exceeding the study’s predefined efficacy threshold.
  • pCR rates were identical whether Dostarlimab was administered concurrently with Niraparib or following a short PARP inhibitor lead-in, suggesting flexibility in treatment sequencing.
  • Treatment was associated with a significant increase in stromal Tumor-Infiltrating Lymphocytes (sTILs) within 3 weeks, supporting biologic synergy between PARP inhibition and PD-1 blockade in early-stage disease.
  • Higher baseline sTIL levels were associated with both pCR and minimal residual disease (RCB-0/I), whereas baseline PD-L1 expression and ER-low status were not predictive.
  • These findings support further investigation of biomarker-driven, non-chemotherapy neoadjuvant strategies in genetically defined TNBC populations.

TBCRC-056: A phase II study of neoadjuvant niraparib with dostarlimab for patients with BRCA- or PALB2-mutated breast cancer: results from the TNBC cohorts. Mayer EL, Graham N, Leon-Ferre RA, et al. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF5-02.