Category: Meeting Updates

Late Breaking Abstract – ASCO GI: 2026. Identifying a Less Neurotoxic First-Line Backbone in Metastatic Esophagogastric Cancer: Insights from the LyRiCX Trial

RR

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.

Background

First-line systemic therapy for metastatic or unresectable esophagogastric adenocarcinoma has traditionally relied on platinum-based chemotherapy, most commonly Oxaliplatin-containing regimens combined with fluoropyrimidines. While these regimens have demonstrated meaningful activity, cumulative peripheral neuropathy remains a significant treatment-limiting toxicity. Oxaliplatin-induced neurotoxicity can adversely affect patient quality of life and frequently restricts the duration of therapy or the ability to deliver subsequent lines of treatment.

With the integration of immune checkpoint inhibitors such as Nivolumab into the first-line management of selected patients with advanced gastroesophageal cancers, the choice of chemotherapy backbone has become increasingly relevant. Selecting regimens that maintain antitumor efficacy while minimizing long-term toxicity is particularly important, in a treatment landscape where patients may receive multiple sequential therapies.

The Phase II LyRiCX trial was designed to address this challenge by comparing three first-line chemotherapy backbones in patients with HER2-negative metastatic or unresectable esophagogastric adenocarcinoma, with a focus on balancing efficacy and neurotoxicity.

Study Design and Patient Population

LyRiCX was a multicenter, open-label, randomized Phase II study conducted across medical centers in the Netherlands. Adults with previously untreated, pathologically confirmed HER2-negative metastatic or unresectable esophagogastric adenocarcinoma, with no pre-existing neuropathy more than Grade 1, were eligible for enrollment.

Participants were randomized to one of three chemotherapy regimens:

  • F-Nal-Iri: Nanoliposomal Irinotecan 70 mg/m2, Leucovorin 400 mg/m2, and Fluorouracil 2400 mg/m2 every 2 weeks
  • CapCar: Capecitabine 1000 mg/m2 plus Carboplatin AUC5 every 3 weeks
  • CapOx: Capecitabine 1000 mg/m2 plus Oxaliplatin 130 mg/m2 every 3 weeks

Before the regulatory approval of Nivolumab (OPDIVO®) in this setting (through August 2022), patients were randomized in a 2:2:1 ratio to F-Nal-Iri, CapCar, or CapOx. After immunotherapy became available, treatment allocation incorporated PD-L1 status as measured by the Combined Positive Score (CPS):

  • CPS <5 or contraindication to Nivolumab: randomized to chemotherapy alone (F-Nal-Iri, CapCar, or CapOx; 2:2:1).
  • CPS ≥5: randomized to CapCar or CapOx combined with Nivolumab (2:1).

The trial employed a predefined “pick-the-winner” strategy to determine the most favorable regimen. The co–Primary endpoints were:

  • Incidence of Grade 2–4 neurotoxicity
  • Progression-Free Survival (PFS)

Between September 2019 and January 2025, 320 patients were enrolled. The median age was 65 years and 81% of participants were male. Treatment distribution included:

  • F-Nal-Iri: 83 patients
  • CapCar: 157 patients (including 74 receiving Nivolumab)
  • CapOx: 80 patients (including 36 receiving Nivolumab)

The median PFS follow-up was 24.1 months.

Neurotoxicity Outcomes

The most striking finding from LyRiCX was the dramatic difference in neurotoxicity rates across treatment arms.

Grade 2–4 neurotoxicity occurred in:

  • 0% of patients receiving F-Nal-Iri
  • 2.5% of patients receiving CapCar ± Nivolumab
  • 46.3% of patients receiving CapOx ± Nivolumab

Statistical analysis showed no significant difference in neurotoxicity between CapCar and F-Nal-Iri. In contrast, neurotoxicity was significantly higher with CapOx compared with both alternative regimens (P<0.001 for both comparisons).

These findings highlight the substantial neurologic toxicity burden associated with oxaliplatin-based therapy in this patient population.

Efficacy Results

Despite marked differences in neurotoxicity, efficacy outcomes were broadly comparable across treatment arms.

Median Progression-Free Survival was:

  • 4.5 months with F-Nal-Iri
  • 5.7 months with CapCar ± Nivolumab
  • 5.9 months with CapOx ± Nivolumab

Among patients who did not receive immunotherapy, statistical analyses showed no significant differences in PFS between:

  • F-Nal-Iri and CapCar
  • F-Nal-Iri and CapOx

Similarly, comparisons between CapCar ± Nivolumab and CapOx ± Nivolumab did not demonstrate a statistically significant difference in PFS.

Taken together, these data indicate that non-Oxaliplatin regimens reduce neurotoxicity without significantly compromising disease control

Safety and Adverse Events

Overall safety profiles were generally comparable across treatment groups, and no unexpected safety signals were identified. Grade 3–4 adverse events occurred at similar frequencies among the regimens, with the notable exception of neurotoxicity. Anemia was observed across all treatment arms and appeared somewhat more frequently in the CapCar-based group, although this difference did not translate into a clear safety disadvantage.

Importantly, neurotoxicity remained the dominant differentiating toxicity, occurring at markedly higher rates in the CapOx arm relative to the other regimens.

Clinical Implications

The LyRiCX study provides important insight into the optimization of chemotherapy backbones for metastatic esophagogastric adenocarcinoma. While Oxaliplatin-containing regimens remain widely used, the substantial risk of cumulative neuropathy may have significant downstream consequences for quality of life and treatment sequencing.

Both CapCar and F-Nal-Iri demonstrated dramatically lower rates of clinically significant neurotoxicity while maintaining similar Progression-Free Survival compared with CapOx. Among the evaluated regimens, CapCar emerged as the most practical and favorable option, offering several advantages:

  • Minimal risk of treatment-limiting neuropathy
  • Comparable efficacy outcomes
  • No requirement for central venous access
  • Use of widely available off-patent agents, supporting cost efficiency

As treatment strategies continue to evolve with the integration of immunotherapy and additional targeted therapies, selecting chemotherapy backbones that preserve patient function and enable subsequent treatment options will remain a critical component of clinical decision-making.

Key Takeaway for Oncology Practice:

The LyRiCX trial suggests that Capecitabine plus Carboplatin may represent a highly favorable first-line chemotherapy backbone for HER2-negative metastatic or unresectable esophagogastric adenocarcinoma, providing comparable disease control to Oxaliplatin-based therapy while substantially reducing the risk of neurotoxicity.

Liposomal irinotecan, carboplatin or oxaliplatin (LyRICX) with or without nivolumab in the first-line treatment of metastatic or irresectable esophagogastric adenocarcinoma: A randomized phase 2 study. Kamp D, van Velzen M, Kessels R, et al. J Clin Oncol 44, LBA287(2026): DOI: 10.1200/JCO.2026.44.2_suppl.LBA287 

Late Breaking Abstract – 2026 ASCO GU Symposium: Advancing Adjuvant Therapy in Clear Cell Renal Cell Carcinoma

RR

SUMMARY: The American Cancer Society estimates that 80,450 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2026 and about 15,160 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.

Adjuvant immunotherapy has become an important component of treatment for patients with clear cell Renal Cell Carcinoma (ccRCC) who are at elevated risk for recurrence following nephrectomy. The role of adjuvant immune checkpoint blockade was established by the Phase 3 KEYNOTE-564 study, which demonstrated that adjuvant Pembrolizumab (KEYTRUDA®) significantly improves outcomes in this patient population.

Updated results from KEYNOTE-564 with a median follow-up of approximately 57 months confirmed a statistically significant Overall Survival (OS) benefit with adjuvant Pembrolizumab compared with placebo. Median OS was not reached in either group, but treatment with Pembrolizumab reduced the risk of death by 38% (HR 0.62; P=0.0024). At 48 months, the estimated OS rate was 91.2% among patients treated with Pembrolizumab versus 86.0% for those receiving placebo. The survival advantage was consistent across clinically relevant subgroups, including patients with M0 disease, those with M1 disease rendered no evidence of disease (M1 NED), and across PD-L1 expression levels and sarcomatoid histology status.

Building upon these findings, investigators have explored whether combining immunotherapy with other targeted agents could further reduce recurrence risk. The Phase 3 LITESPARK-022 trial evaluated the addition of the Hypoxia-Inducible Factor-2α inhibitor Belzutifan (WELIREG®) to adjuvant Pembrolizumab in patients with high-risk ccRCC following surgery.

Study Design

LITESPARK-022 is a randomized, double-blind, placebo-controlled Phase 3 trial that enrolled 1,841 patients with ccRCC at increased risk of recurrence after nephrectomy.

Eligible patients included those with:

  • Intermediate-to-high risk M0 disease
    • pT2 tumors with grade 4 or sarcomatoid features, N0
    • pT3 tumors of any grade, N0
  • High-risk M0 disease
    • pT4 tumors of any grade, N0
    • Any pT stage with nodal involvement (N+)
  • M1 NED disease
    • Patients with metastatic disease who had undergone surgery and achieved no radiographic evidence of disease

Participants were randomized in a 1:1 ratio to receive either Pembrolizumab plus Belzutifan (N=921), Pembrolizumab plus placebo (N=920). Treatment consisted of Pembrolizumab 400 mg IV every 6 weeks for 9 cycles (approximately 1 year) and Belzutifan 120 mg orally once daily or placebo. Randomization was stratified according to risk category and tumor grade. The Primary endpoint was Disease-free survival (DFS) assessed by investigators and Secondary endpoints included Overall Survival (OS), Safety and tolerability.

Results discussed here represent the first interim analysis, conducted after a median follow-up duration was 28.4 months. Treatment completion rates were similar between groups (about 70%)

Efficacy Outcomes

The addition of Belzutifan to Pembrolizumab resulted in a statistically significant improvement in Disease-Free Survival, compared to Pembrolizumab plus placebo, meeting the Primary endpoint of the study (HR=0.72; 95% CI: 0.59–0.87; P=0.0003. This corresponds to a 28% reduction in the risk of recurrence or death with the combination regimen. The Median DFS had not yet been reached in either arm at the time of analysis. The estimated 24-month DFS rates were 80.7% in the Pembrolizumab plus Belzutifan group and 73.7% in the Pembrolizumab plus placebo group.

This represents the first Phase 3 adjuvant RCC trial demonstrating superiority of a combination therapy over active immunotherapy alone.

Overall Survival

Overall survival results remain immature. At the time of the interim analysis, only 29% of the events required for the final OS analysis had occurred, preventing definitive conclusions regarding survival benefit.

Safety Profile

As expected with the addition of Belzutifan, the combination regimen was associated with higher rates of treatment-related toxicity. Grade ≥3 Adverse Events for Pembrolizumab plus Belzutifan combination was 52.1% versus 30.2% for the Pembrolizumab plus placebo group. The most frequently reported grade ≥3 events included Anemia (12.1% vs 0.4%), Elevated ALT (6.4% vs 2.0%) and Hypoxia (4.6% vs 0%). Despite increased toxicity, grade 5 adverse events were rare and similar between arms, and no new safety signals were identified.

Clinical Implications

The findings from LITESPARK-022 suggest that combining Belzutifan with Pembrolizumab may further improve outcomes for patients with high-risk ccRCC following nephrectomy. However, the improved DFS must be balanced against the increased toxicity profile. Experts emphasize that careful patient selection will be essential if this regimen is adopted in clinical practice. Patients with baseline pulmonary or cardiovascular comorbidities, who may be more vulnerable to Belzutifan-associated hypoxia or anemia, may require additional consideration.

Furthermore, longer follow-up will be necessary to determine whether overall survival benefit emerges, as well as the impact on quality of life, and long-term safety of the combination regimen

Key Takeaways for Clinical Practice

  • Adjuvant Pembrolizumab remains a standard of care for patients with ccRCC at increased risk of recurrence following nephrectomy.
  • The LITESPARK-022 trial demonstrated a significant improvement in DFS when Belzutifan was added to Pembrolizumab.
  • The combination reduced the risk of recurrence or death by 28% compared with Pembrolizumab alone.
  • Toxicity was higher, particularly with respect to anemia and hypoxia, but was generally manageable with dose modification and supportive care.
  • Ongoing follow-up will determine whether Overall Survival and Patient-Reported Outcomes support broader adoption of this strategy.

Conclusion

The Phase 3 LITESPARK-022 trial represents an important step forward in the adjuvant treatment landscape for clear cell Renal Cell Carcinoma. By demonstrating a clinically meaningful improvement in Disease-Free Survival with the addition of Belzutifan to Pembrolizumab, the study introduces a promising new therapeutic approach for patients at high risk of recurrence after nephrectomy. Continued follow-up will clarify the long-term survival benefit and help define the role of this combination in routine clinical practice.

Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): The randomized phase 3 LITESPARK-022 study. Choueiri TK, Motzer RJ, Karam JA, et al. 2026 ASCO Genitourinary Cancers Symposium. J Clin Oncol 44, 2026 (suppl 7; abstr LBA418)

Expanding Targeted First-Line Options in BRAF V600E–Mutant Metastatic Colorectal Cancer: Insights From the BREAKWATER Trial

RR

SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 158,850 new cases of CRC will be diagnosed in the United States in 2026 and about 55,230 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

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

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

Encorafenib (BRAFTOVI®) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as Vemurafenib (ZELBORAF®) and Dabrafenib (TAFINLAR®), with a prolonged target dissociation half-life and higher potency.

Metastatic colorectal cancer (mCRC) harboring the BRAF V600E mutation represents a biologically aggressive subtype associated with poor prognosis, higher rate of peritoneal metastasis, and historically limited responsiveness to conventional chemotherapy. Approximately 8% to 12% of patients with mCRC carry this mutation, and outcomes with traditional first-line regimens have been suboptimal. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Historically, patients with these mutations experienced shorter survival when treated with chemotherapy with or without biologics such as Bevacizumab, compared to their BRAF wild-type counterparts. While the BEACON CRC trial established the Encorafenib plus Cetuximab (EC) doublet as standard in the previously treated setting, the optimal first-line strategy remained undefined.

The global Phase III BREAKWATER trial was designed to evaluate whether combining targeted agents with standard chemotherapy could improve outcomes for patients with previously untreated BRAF V600E–mutant mCRC. Earlier analyses from the study demonstrated that the combination of Encorafenib and Cetuximab with modified FOLFOX6 (mFOLFOX6) significantly improved Response Rates and Progression-Free Survival compared with chemotherapy with or without Bevacizumab. These findings ultimately led to accelerated FDA approval in December 2024 for the targeted triplet regimen in the first-line setting.

However, Oxaliplatin-based therapy is not suitable for all patients. Cumulative exposure to Oxaliplatin is frequently associated with peripheral neuropathy, prompting clinicians to consider Irinotecan-based regimens such as FOLFIRI as an alternative chemotherapy backbone in the first-line setting. It is estimated that 20% to 25% of patients with newly diagnosed BRAF V600E–mutant mCRC receive FOLFIRI as part of their initial treatment strategy. To address this clinical reality, investigators expanded the BREAKWATER trial to evaluate whether targeted therapy could also enhance outcomes when combined with Irinotecan-based chemotherapy.

Study Design and Patient Population

Cohort 3 of the BREAKWATER study specifically examined the combination of Encorafenib plus Cetuximab with FOLFIRI, compared with FOLFIRI with or without Bevacizumab, representing standard care in this setting. Eligible patients had previously untreated BRAF V600E–mutant mCRC, measurable disease according to RECIST 1.1 criteria, and an ECOG Performance Status of 0 or 1.

A total of 147 patients were randomized in a 1:1 ratio to receive either the targeted therapy combination plus FOLFIRI (N=73) or the control regimen (N=74). Baseline characteristics were balanced between treatment arms, with a median patient age of 62 years, 46% male, and 60% with ECOG performance status 0. The Primary endpoint was Objective Response Rate (ORR) as assessed by Blinded Independent Central Review, while Progression-Free Survival (PFS) served as the key Secondary endpoint. Additional endpoints included Overall Survival (OS), Duration of Response (DOR), Time To Response (TTR), and Safety.

Significant Improvement in Objective Response Rate

At the time of the March 1, 2025 data cutoff, the combination of Encorafenib, Cetuximab, and FOLFIRI demonstrated a clinically meaningful and statistically significant improvement in confirmed Objective Response Rate compared with the control regimen.

The confirmed ORR reached 64.4% with the targeted therapy combination, compared with 39.2% in the control arm, corresponding to an odds ratio of 2.76 (P=0.0011). Responses included Complete Responses in 4.1% of patients receiving the targeted regimen versus 1.4% in the control group, while Partial Responses occurred in 60.3% and 37.8% of patients, respectively.

Importantly, the responses observed with the targeted regimen were rapid and durable. The median time to response was similar between groups, occurring at approximately 6.9 weeks with Encorafenib plus Cetuximab and FOLFIRI and 7.1 weeks with the control regimen. Although the median Duration of Response had not yet been reached in either group, a greater proportion of patients receiving the targeted combination experienced sustained responses lasting at least six months (57.4% vs 34.5%). Responses lasting 12 months or longer were observed only in the experimental arm.

Clinical benefit with the targeted regimen was consistent across prespecified patient subgroups, further supporting the robustness of the treatment effect.

Early Signals for Survival Benefit

While Overall Survival data remain immature, early findings suggest a potential survival advantage with the targeted regimen. At the time of analysis, 15.1% of patients in the Encorafenib–Cetuximab–FOLFIRI group had died, compared with 27.0% in the control arm, translating to a hazard ratio of 0.49. Longer follow-up will be required to confirm the durability of this emerging survival signal.

Treatment exposure also favored the experimental arm. Nearly 70% of patients receiving the targeted regimen remained on treatment, compared with approximately one-third of patients in the control group, with a median treatment duration of 9.9 months versus 7.4 months, respectively.

Manageable Safety Profile

The safety profile of the triplet regimen was consistent with the known effects of each agent, and the addition of Encorafenib and Cetuximab did not substantially compromise treatment tolerability. The most frequently reported adverse events with the combination regimen included nausea, diarrhea, and vomiting. Serious treatment-emergent adverse events occurred in 39.4% of patients in the experimental arm vs 36.8% in the control arm. Importantly, the incorporation of targeted therapy did not lead to a meaningful increase in chemotherapy discontinuation, with FOLFIRI discontinuation rates of 9.9% in the experimental arm versus 8.8% in the control group. Investigators also reported no new safety signals, reinforcing the feasibility of combining targeted therapy with an Irinotecan-based chemotherapy backbone.

Clinical Implications

The results from BREAKWATER Cohort 3, build on the earlier success of Encorafenib and Cetuximab combined with Oxaliplatin-based chemotherapy, and provide important new insights for clinical practice. For patients who may not be optimal candidates for Oxaliplatin due to concerns such as cumulative neurotoxicity, the Encorafenib–Cetuximab–FOLFIRI regimen represents a compelling alternative.

Taken together, the findings support the growing role of targeted therapy- based combinations in the first-line treatment of BRAF V600E–mutant mCRC, offering both improved response rates and the potential for durable disease control.

Looking Ahead

The BREAKWATER trial remains ongoing, and continued follow-up will clarify the long-term durability of responses and the ultimate impact on Overall Survival. Nonetheless, the current analysis highlights the expanding therapeutic landscape for patients with this challenging molecular subtype of colorectal cancer.

If confirmed with longer follow-up, the combination of Encorafenib, Cetuximab, and FOLFIRI may emerge as another frontline standard-of-care option, providing clinicians with greater flexibility to tailor treatment strategies based on patient characteristics and toxicity considerations.

BREAKWATER: Primary analysis of first-line encorafenib + cetuximab + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer. Kopetz S, Wasan HS, Yoshino T, et al: 2026 ASCO GI Cancers Symposium. J Clin Oncol 44, 2026 (suppl 2; abstr 13)

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

RR

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

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 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

RR

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.

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)