Author: RR

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

RR

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

RR

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

RR

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

RR

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

RR

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.