Author: RR

Endocrine Therapy Omission in ER-Low Early Stage Breast Cancer Linked to Worse Survival Outcomes

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 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Background
Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. Adjuvant Endocrine Therapy (ET) is a cornerstone in managing Estrogen Receptor (ER)–positive early-stage breast cancer, contributing significantly to reduced recurrence and improved Overall Survival (OS). However, its role in patients with ER-low disease, defined as tumors with 1%-10% ER positivity by ImmunoHistoChemistry (IHC), remains unclear and controversial.

Study Objective
The present study was conducted to determine the association between ET omission and OS in high-risk, ER-low early-stage breast cancer patients who received chemotherapy, leveraging Real-World Data from the National Cancer Database (NCDB).

Methods
A retrospective cohort analysis was conducted using the 2021 NCDB Participant User File, focusing on female patients diagnosed with Stage I–III ER-positive breast cancer between 2018 and 2020. ER-low status was defined as 1%-10% ER expression per ASCO/CAP guidelines. Progesterone Receptor (PR)–positive disease was defined as 1% or more receptor expression. This study included patients who received neoadjuvant or adjuvant chemotherapy, reflecting a high-risk population with aggressive tumor features. The study excluded male patients, Stage IV disease, noninvasive cancers, and cases with incomplete treatment or outcome data. The final cohort comprised 7,018 ER-low patients who received chemotherapy.

Key Findings

  • Endocrine Therapy (ET) Usage Patterns:
    Among patients with ER-low breast cancer receiving chemotherapy, 42% did not initiate ET within 12 months post-surgery. ET omission was more prevalent in tumors that were:

    • Progesterone Receptor (PR)–negative
    • HER2–negative
    • High grade (2 or 3)
    • High proliferative index (Ki67 ≥20%)
    • Treated with NeoAdjuvant Chemotherapy (NAC)
  • Survival Impact:
    Over a median follow-up of 3 years, 586 deaths occurred. ET omission was associated with significantly poorer OS:

    • Overall HR: 1.23 (95% CI, 1.04–1.46; P =0.02)
    • ER 1%-5% subgroup: HR 1.15 (95% CI, 0.91–1.45; P =0.24)
    • ER 6%-10% subgroup: HR 1.42 (95% CI, 1.00–2.02; P =0.048)
  • Effect in Residual Disease (RD) After NAC:
    • For patients with RD, ET omission led to worse OS (HR, 1.26; 95% CI, 1.00–1.57; P =0.046)
    • No OS difference was observed in patients who achieved pathologic Complete Response (pCR) (HR, 1.06; P =0.84)
  • 3-Year OS Estimates:
    • With ET: 92.3% (95% CI, 91.3–93.3%)
    • Without ET: 89.1% (95% CI, 87.8–90.5%)

Clinical Implications
These findings suggest that omission of ET in ER-low breast cancer is associated with an increased risk of mortality, particularly in patients with:

  • Residual disease after neoadjuvant chemotherapy
  • Tumors with higher ER expression (6%-10%)

This supports the clinical value of ET even in ER-low disease subsets, which have historically been managed more like Triple-Negative Breast Cancer (TNBC) due to their aggressive features and ambiguous endocrine responsiveness.

Guideline and Research Context
The 2010 ASCO/CAP guidelines established 1% or more ER positivity as the threshold for ET eligibility. Yet, international variation remains. Swedish guidelines, for instance, never adopted the lower threshold, and recent European discourse suggests reverting to 10% or more. Compounding the uncertainty, clinical trials often exclude ER-low tumors or treat them as TNBC. Retrospective studies from Sweden and China have shown mixed results regarding ET’s benefit in ER-low disease, further emphasizing the need for prospective data.

Discussion
Despite the relatively small proportion of ER-low tumors (3% of ER-positive breast cancer), the findings could impact the care of tens of thousands of patients globally. The biologic heterogeneity of ER-low tumors, often resembling basal-like subtypes, complicates treatment decisions. Still, evidence from this large cohort supports offering ET, particularly in patients with residual disease post-neoadjuvant chemotherapy, or tumors on the higher end of the ER-low spectrum. Additionally, the data align with emerging strategies to escalate therapy in ER-low BC, including use of CDK4/6 inhibitors (e.g., Abemaciclib, Ribociclib), which have demonstrated benefit even in this subgroup.

Limitations

  • Lack of data on ET adherence, recurrence, or cause of death
  • Short follow-up (3 years)
  • Potential confounding due to observational design
  • Lack of molecular characterization to distinguish responders

Nevertheless, sensitivity analyses confirmed the robustness of findings.

Conclusion
Omission of endocrine therapy in ER-low, early-stage breast cancer, especially following chemotherapy, is linked to inferior Overall Survival. The strongest signal of benefit is in patients with residual disease post- neoadjuvant chemotherapy and those with ER expression closer to 10%. Until randomized trials clarify endocrine sensitivity in this population, clinicians should counsel patients on the potential survival benefit of ET, even in cases with limited ER expression.

Key Takeaway for Oncologists:
In the absence of prospective trial data, Real-World Evidence supports continued use of endocrine therapy in patients with ER-low early-stage breast cancer, particularly those with residual disease after neoadjuvant chemotherapy or higher ER expression within the 1%-10% range.

Endocrine Therapy Omission in Estrogen Receptor–Low (1%-10%) Early-Stage Breast Cancer. Choong GM, Hoskin TL, Boughey JC, et al. J Clin Oncol 2025;43:1875-1885.

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

RR

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Real-World Tolerability of Capecitabine and Oxaliplatin (CAPOX) in Localized Colorectal Cancer: Insights from a Single-Institution Analysis

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 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Among patients with Stage II-III CRC, 20-40% will develop metastatic disease.

Approximately 80% of patients present with localized disease, offering an opportunity for curative-intent therapy through surgical resection followed by adjuvant or neoadjuvant treatment approaches. The current standard of care for localized colon cancer involves surgery followed by risk-adapted adjuvant chemotherapy, while patients with localized rectal cancer may receive neoadjuvant chemoradiotherapy or chemotherapy before surgical resection. In select cases, a nonoperative “watch-and-wait” strategy is pursued to preserve organ function following a complete clinical response to neoadjuvant therapy.

Among available chemotherapy regimens, Capecitabine plus Oxaliplatin (CAPOX) has become a mainstay for patients with localized CRC in both adjuvant and neoadjuvant settings.

Rationale for CAPOX Use

Capecitabine (XELODA®), an oral fluoropyrimidine prodrug, is metabolized to 5-Fluorouracil (5-FU) in the liver and tumor tissue. Oxaliplatin, a platinum analog, induces cytotoxicity through DNA crosslinking, leading to apoptosis. The combination of these agents results in synergistic antitumor activity and has demonstrated robust efficacy in CRC.

The pivotal International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration established that 3 months of CAPOX provides similar efficacy to 6 months of Oxaliplatin-based therapy in the low-risk subgroup of patients, while significantly reducing cumulative neurotoxicity, treatment burden, and cost. These findings drove widespread adoption of CAPOX as the preferred regimen for adjuvant treatment of localized CRC. Furthermore, studies such as RAPIDO and OPRA have supported CAPOX use in the neoadjuvant management of rectal cancer.

Despite this, real-world tolerability data from U.S. patients remain limited, and prior evidence suggests that Capecitabine-based regimens may be less well tolerated in American populations, particularly among women. These gaps highlight the need to better understand how CAPOX performs in U.S. clinical practice.

Study Objective

This retrospective, single-institution analysis sought to evaluate the real-world tolerability of CAPOX in patients with localized CRC treated with curative intent, either in the adjuvant or neoadjuvant setting.

Methods

  • Design and Setting:
    Retrospective cohort study including patients treated across 17 academic and community oncology clinics within a single cancer care network.
  • Eligibility Criteria:
    Adults (≥18 years) with Stage II or III colon or rectal cancer who initiated CAPOX between June 1, 2017, and June 1, 2023, and received at least one treatment cycle.
  • Endpoints:
    • Primary endpoint: Completion of all intended CAPOX cycles (as determined by treating clinicians, regardless of dose modification).
    • Secondary endpoints: Incidence of grade ≥3 adverse events, hospitalizations related to treatment toxicity, and dose reductions.
  • Data Collection:
    Patient demographics, tumor characteristics, treatment details, and toxicity data were extracted from electronic medical records and pharmacy databases. Creatinine clearance was calculated via the Cockcroft-Gault formula to guide capecitabine dose adjustments.

Patient Population

A total of 153 patients were included (median age: 61 years).

  • Sex: 51% male, 49% female
  • Race: 81% White, 15.7% Black
  • Tumor site: 63% colon, 37% rectal
  • Stage: 21.6% Stage II, 78.4% Stage III
  • ECOG performance status: 0 (42.5%), 1 (50%)
  • Renal function: Majority with creatinine clearance ≥50 mL/min; 3.9% had CrCl 30–50 mL/min and received upfront dose adjustment.

Key Findings

  • Treatment Completion:
    • Only 44.4% (95% CI, 36–52) completed all intended CAPOX cycles.
    • Completion was lower among female patients (34.6%) compared with the overall cohort.
    • Completion rates varied by treatment duration:
      • 4 cycles: 55% (95% CI, 43–66)
      • 6 cycles: 41% (95% CI, 23–59)
      • 8 cycles: 33% (95% CI, 20–45)
  • Dose Modifications:
    • 24% received upfront dose adjustments for renal function or performance status.
    • Average starting doses of both agents were comparable between patients who completed versus discontinued treatment.
  • Toxicity:
    • Grade ≥3 adverse events: 30.7% (95% CI, 23–38)
    • Hospitalizations due to toxicity: 17.6% (95% CI, 11–23)
    • Premature discontinuation: 21.5% stopped Oxaliplatin early; 40.5% discontinued both agents.
    • Regimen modification: 6.5% switched to FOLFOX or 5-FU/Leucovorin; 27% continued single-agent Capecitabine.
  • Predictors of Completion:
    Multivariable analysis identified race, sex, and intended cycle number as independent predictors of treatment completion.

Interpretation and Context

The completion rate in this real-world study (44%) was markedly lower than the ~85% and 64% completion rates observed in the 3- and 6-month CAPOX arms, respectively, of the IDEA trial. Differences in patient selection, clinical setting, and regional tolerability may explain this discrepancy.

Notably, female sex was associated with lower tolerability, echoing prior reports that women experience greater Fluoropyrimidine-related toxicity. This may relate to lower lean body mass relative to body surface area, resulting in higher effective drug exposure, as well as potential differences in drug metabolism, hormonal influence, and cultural reporting patterns.

Racial differences were also observed, with White patients demonstrating poorer tolerability compared with Black patients, findings that contrast with some previous single-center U.S. studies and warrant further exploration.

Interestingly, age ≥70 years and ECOG performance status ≥1 were not significantly associated with early discontinuation, although the small number of elderly patients limits conclusions.

Clinical Relevance

These findings underscore that toxicity remains a major barrier to completing CAPOX therapy in U.S. clinical practice. Given the importance of treatment dose intensity for cure, optimizing patient selection and providing proactive supportive care are crucial to maximizing therapeutic benefit.

The data also call for reconsideration of CAPOX versus FOLFOX selection in certain patient subsets. While CAPOX offers the convenience of oral administration and shorter duration, FOLFOX may be more tolerable in select populations, particularly women or patients at risk for Capecitabine toxicity.

Limitations

This study was retrospective and single-institution in nature, with potential for incomplete data capture and limited generalizability. Lack of DPYD genotype testing prevented assessment of pharmacogenetic contributions to toxicity. Despite these limitations, inclusion of both academic and community centers enhances the representativeness of findings.

Conclusion

In this large, real-world analysis, fewer than half of patients with localized CRC receiving CAPOX completed their intended cycles, primarily due to treatment-related toxicity. Female sex, White race, and longer planned therapy duration were associated with lower completion rates. These data highlight the need for personalized treatment strategies, vigilant toxicity monitoring, and robust supportive measures to ensure optimal delivery of curative-intent chemotherapy.

As CAPOX continues to anchor adjuvant and neoadjuvant treatment protocols for CRC, understanding its real-world tolerability will remain essential for aligning evidence-based guidelines with practical patient care realities in oncology practice.

Real-World Tolerability of Capecitabine and Oxaliplatin in Patients in the United States With Localized Colorectal Cancer Undergoing Curative-Intent Treatment. Mears V, Naleid N, Pawar O, et al. JCO Oncol Pract 2025;21:1355-1363

FDA Approves BLENREP® Combination for Relapsed or Refractory Multiple Myeloma

RR

SUMMARY: The FDA on October 23, 2025, approved Belantamab mafodotin-blmf (BLENREP®), a B-Cell Maturation Antigen (BCMA)-directed antibody and microtubule inhibitor conjugate, with Bortezomib and Dexamethasone for adults with Relapsed or Refractory Multiple Myeloma (RRMM) who have received at least two prior lines of therapy, including a Proteasome Inhibitor and an immunomodulatory agent.

Context and Rationale

Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2025 remains an incurable disease.

Patients with newly diagnosed multiple myeloma often receive triplet and quadruplet regimens that incorporate Proteasome Inhibitors, immunomodulators, and anti-CD38 antibodies as first line therapy, as these regimens are associated with prolonged Progression Free Survival (PFS) and Overall Survival (OS). However, most patients relapse and frontline use of Lenalidomide therapy has increased the number of patients with Lenalidomide-refractory disease at the time of the first relapse. New novel combinations are needed for patients who have relapsed or refractory myeloma, after disease progression during frontline therapy.

B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and multiple myeloma. B-Cell Maturation Antigen is therefore an established target in myeloma.

Belantamab Mafodotin: A Multimodal Antibody-Drug Conjugate

Belantamab mafodotin is a BCMA-targeting antibody-drug conjugate comprising a humanised B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. Auristatin F induces cytotoxicity, Antibody-Dependent Cellular Cytotoxicity and phagocytosis, and induction of immunogenic cell death. Early-phase data demonstrated sustained, deep responses in heavily pretreated populations, suggesting potential benefit when used earlier in the disease course in combination with established backbones.

Study Design: DREAMM-7

The Phase III DREAMM-7 trial (DRiving Excellence in Approaches to Multiple Myeloma) was an open-label, multicenter, randomized study comparing Belantamab mafodotin plus Bortezomib and Dexamethasone (BVd) versus Daratumumab plus Bortezomib and Dexamethasone (DVd) in patients with RRMM who had received at least one prior line of therapy. A total of 494 patients were randomized 1:1 to BVd (N=243) or DVd (N=251). Baseline characteristics were well balanced between arms: approximately half of participants (51%) had received one prior line of therapy, 52% had prior Lenalidomide exposure, 34% were Lenalidomide-refractory, and 28% harbored high-risk cytogenetic abnormalities. The Primary endpoint was PFS as assessed by an Independent Review Committee. Key Secondary endpoints included OS, Duration of Response (DOR), Minimal Residual Disease (MRD) negativity by Next-Generation Sequencing, Overall Response Rate (ORR), and safety.

Primary Analysis: Robust Progression-Free Survival Benefit

At a median follow-up of 28.2 months, the trial met its Primary endpoint. The median PFS was 36.6 months (95% CI, 28.4–not reached) in the BVd arm versus 13.4 months (95% CI, 11.1–17.5) in the DVd arm, corresponding to a 59% reduction in risk of progression or death (HR=0.41; 95% CI, 0.31–0.53; P<0.00001).

BVd achieved higher rates of Complete Response or better with MRD negativity (25% vs 10%) and a more favorable DOR distribution (P<0.001). Median DOR was 35.6 months with BVd compared to 17.8 months with DVd. Treatment benefits with BVd were preserved even after subsequent therapy (PFS2 HR= 0.56; 95% CI, 0.41–0.76). Although median OS was not reached at this time point, a strong trend favored BVd (HR=0.57; 95% CI, 0.40–0.80).

Second Interim Analysis: Statistically Significant OS Advantage

At the second interim analysis, conducted at a median follow-up of 39.4 months, BVd demonstrated a 42% reduction in the risk of death versus DVd (HR=0.58; 95% CI, 0.43–0.79; P=0.00023). Median OS was not reached in either arm, but projected estimates were striking, 84 months for BVd compared with 51 months for DVd. The 3-year OS rate was 74% with BVd versus 60% with DVd, with survival separation evident as early as 4 months and sustained over time.

Subgroup Analysis and FDA Approval

In the subset of patients who had received two or more prior lines of therapy (the population used for regulatory evaluation, N=108 in the BVd and N=109 in the DVd groups), BVd maintained substantial efficacy. Median PFS was 31.3 months (95% CI, 23.5–NR) compared with 10.4 months (95% CI, 7.0–13.4) with DVd (HR, 0.31; 95% CI, 0.21–0.47). Median OS was not reached with BVd and 35.7 months with DVd (HR, 0.49; 95% CI, 0.32–0.76), representing a 51% reduction in risk of death.

Depth of Response and MRD Negativity

The BVd regimen achieved statistically significant improvements in MRD negativity, with rates more than 2.5 times higher than those observed with DVd (P<0.00001). Superior depth and durability of response were reflected in all major efficacy endpoints, including DOR and PFS2, underscoring the potential for more sustained disease control with the Belantamab-containing triplet.

Safety Profile and Ocular Events

Adverse events were consistent with prior experience for the individual agents. Grade ≥3 thrombocytopenia occurred in 56% of patients receiving BVd versus 35% with DVd; grade ≥3 anemia and neutropenia were comparable between groups. Ocular events, a known risk associated with Belantamab mafodotin, were manageable with dose modifications and rarely led to discontinuation. Only 10% of patients in the BVd arm discontinued therapy due to ocular toxicity.

Clinical Implications

The DREAMM-7 results represent the first head-to-head Phase III evidence of a statistically significant OS advantage for a BCMA-targeting therapy in RRMM compared with a Daratumumab-based regimen. The combination of Belantamab mafodotin with Bortezomib and Dexamethasone delivered a tripling of median PFS, a clinically meaningful OS benefit, and deeper MRD-negative responses, establishing a compelling new benchmark for patients experiencing their first relapse or later. These data reinforcing the OS benefit and may solidify BVd as a new standard of care for relapsed or refractory multiple myeloma.

Belantamab Mafodotin, Bortezomib, and Dexamethasone Vs Daratumumab, Bortezomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Overall Survival Analysis and Updated Efficacy Outcomes of the Phase 3 Dreamm-7 Trial. Hungria V, Robak P, Hus M, et al. Blood (2024) 144 (Supplement 1): 772. https://doi.org/10.1182/blood-2024-200336

Extended-Duration Low-Intensity Apixaban Reduces Recurrent VTE Risk in Patients with Provoked Events and Enduring Risk Factors: Results From the HI-PRO Trial

RR

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke.

Clinically, VTE is classified as provoked, occurring after transient risk factors such as surgery, trauma, or immobility, or unprovoked, when no clear trigger is identified. Standard management involves 3 months of anticoagulation for provoked events and extended therapy for unprovoked events because of their higher recurrence risk (6–10% per year after discontinuation). However, many patients present with provoked VTE in the context of enduring risk factors such as obesity, chronic inflammatory disease, atherosclerotic cardiovascular disease or chronic pulmonary conditions, factors that may sustain a prothrombotic milieu even after the transient trigger has resolved. Current guidelines offer limited direction for this increasingly common patient subset.

Study Rationale and Design

The Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients with Provoked Venous Thromboembolism (HI-PRO) trial sought to clarify whether continued low-intensity anticoagulation could safely reduce recurrence risk in such patients. This single-center, double-blind, randomized study enrolled 600 adults who had completed at least 3 months of standard anticoagulation for a provoked VTE and who also had at least one enduring risk factor for recurrence. Participants were randomized 1:1 to receive Apixaban (ELIQUIS®) 2.5 mg twice daily or placebo for 12 months.

Enduring risk factors included obesity (BMI ≥30), chronic lung disease, autoimmune or inflammatory disorders, and atherosclerotic cardiovascular disease (limited to ≤35% of patients per arm to control for aspirin use). Eligible VTE events included deep vein thrombosis, pulmonary embolism (including isolated subsegmental PE), or both.

The Primary efficacy endpoint was symptomatic recurrent VTE by day 365. The Primary safety endpoint was major bleeding per International Society on Thrombosis and Haemostasis (ISTH) criteria.

Results

The study population had a mean age of 59.5 years, 57% were women, and 19% were non-White.

By 12 months, symptomatic recurrent VTE occurred in 1.3% of patients receiving Apixaban versus 10.0% of those receiving placebo (Hazard Ratio [HR] 0.13; 95% CI, 0.04–0.36; P<0.001), representing an 87% relative risk reduction. The composite cardiovascular outcome, including cardiovascular death, nonfatal myocardial infarction, stroke, or limb ischemic events, was infrequent and comparable between groups (0.7% vs. 1.0%).

Major bleeding was rare, occurring in one patient (0.3%) in the apixaban group and none in the placebo group. Clinically relevant nonmajor bleeding occurred more often with Apixaban (4.8% vs. 1.7%; HR 2.68; 95% CI, 0.96–7.43; P=0.06), with vaginal, hematuric, and rectal bleeding being the most common types. Nonfatal adverse events were balanced between arms.

Medication adherence was high throughout the study, and no deaths were attributed to bleeding or cardiovascular causes.

Interpretation

Extended-duration, low-intensity Apixaban provided robust protection against recurrent VTE in patients with provoked events and ongoing risk factors, an underrepresented and clinically relevant population. The recurrence rate in the placebo group (10% at 1 year) underscores that the conventional dichotomy of provoked versus unprovoked VTE may oversimplify recurrence risk. Patients with enduring prothrombotic conditions appear to have recurrence risks comparable to those with unprovoked events.

The low incidence of major bleeding supports the safety of this approach, though the modest increase in nonmajor bleeding emphasizes the need for individualized risk–benefit assessment, especially in those also receiving antiplatelet therapy.

Clinical Implications

The HI-PRO findings challenge the traditional framework that limits extended anticoagulation to unprovoked VTE and cancer-associated thrombosis. Instead, they highlight that patients with provoked VTE but persistent risk factors, such as chronic inflammatory states, cardiometabolic disease, or obesity, may benefit from continued low-intensity anticoagulation beyond the initial 3-month course.

Incorporating enduring risk factors into recurrence-risk models and treatment algorithms could help refine long-term management. Emerging approaches such as VTE-PREDICT scoring, polygenic risk assessment, and AI-driven modeling may further individualize these decisions.

Takeaway

Among patients with provoked VTE and ongoing risk factors, 12 months of low-dose Apixaban therapy significantly reduced recurrent VTE with a favorable safety profile. The HI-PRO trial supports a more nuanced, risk-adapted approach to secondary prevention, where the duration and intensity of anticoagulation are guided not solely by the event’s provoked or unprovoked status, but by the persistence of underlying prothrombotic conditions.

Apixaban for Extended Treatment of Provoked Venous Thromboembolism. Piazza G, Bikdeli B, Pandey AK, et al. for the HI-PRO Trial Investigators. N Engl J Med 2025;393:1166-1176.

FDA Approves TAR-200 Monotherapy: A Novel Bladder-Sparing Strategy in BCG-Unresponsive High-Risk NMIBC

RR

SUMMARY: The FDA on September 9, 2025, approved Gemcitabine intravesical system (INLEXZO®) for adults with Bacillus Calmette-Guérin (BCG)-unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma in Situ (CIS), with or without papillary tumors. Gemcitabine intravesical system is co-packaged with a urinary catheter and stylet, used for insertion through the urinary catheter into the bladder.

Background

According to the American Cancer Society, it is estimated that 84,870 new cases of bladder cancer will be diagnosed in 2025 and 17,420 will die of the disease. Bladder cancer is the fourth most common cancer in men but is less common in women and the average age at the time of diagnosis is 73 years. With regards to racial predisposition, Caucasians are more likely to be diagnosed with bladder cancer than African Americans or Hispanic Americans.

Approximately 50% of all bladder cancers are non-invasive or in situ cancers. The current standard intervention for superficial bladder cancers-Non-Muscle Invasive Bladder Cancer (NMIBC) involves removing the bladder tumor and intravesical treatment with Bacillus Calmette-Guérin (BCG) immunotherapy, for patients with high-risk Non-Muscle Invasive Bladder Cancer, including those with Carcinoma in Situ, High Grade T1, or large-volume or recurrent Ta tumors, to reduce the risk of recurrence. Although 80% of patients have an initial complete response to BCG, more than half of patients have recurrence and progression within the first year, and develop resistance to BCG.

FDA-approved therapies for BCG-unresponsive carcinoma in situ (CIS) include systemic Pembrolizumab (KEYTRUDA®), intravesical Nadofaragene firadenovec (ADSTILADRIN®), and intravesical Nogapendekin alfa inbakicept (ANKTIVA®) plus BCG. However, these options are constrained by modest Complete Response (CR) rates, limited response durability, immune-related toxicities, procedural burden from repeated catheterizations, and the need for concurrent BCG in some regimens. Moreover, there are no approved therapies specifically indicated for BCG-unresponsive high-risk papillary disease–only NMIBC, highlighting an urgent unmet need for effective, durable, and tolerable bladder-sparing alternatives.

A Novel Intravesical Approach

TAR-200 is an innovative, miniature, pretzel-shaped intravesical drug delivery system engineered to provide continuous local release of Gemcitabine directly into the bladder. The passive, non-resorbable device is placed via catheter in a brief outpatient procedure, without anesthesia, and remains in situ for three weeks. During that time, it slowly releases 225 mg of Gemcitabine before being removed through cystoscopy. This sustained, controlled drug exposure overcomes the short dwell time limitations of conventional intravesical chemotherapy and may enhance local tumor control with reduced systemic exposure.

The SunRISe-1 Trial Design

SunRISe-1 (NCT04640623) is a global, Phase IIb, parallel-cohort study designed to evaluate TAR-200 monotherapy and TAR-200 plus Cetrelimab (an anti–PD-1 antibody) in patients with BCG-unresponsive high-risk NMIBC. Between March 2021 and April 2024, patients were enrolled at 142 sites across 14 countries.

Initially, three cohorts were planned:

  • Cohort 1: TAR-200 plus Cetrelimab
  • Cohort 2: TAR-200 monotherapy
  • Cohort 3: Cetrelimab monotherapy

Based on emerging safety and efficacy data, the protocol was amended in June 2023 to prioritize TAR-200 monotherapy for CIS populations and to expand enrollment in this arm. A fourth cohort was subsequently added to evaluate TAR-200 monotherapy in patients with high-risk papillary disease-only NMIBC, an area with no approved therapies.

Efficacy and Safety Outcomes

The FDA approval of TAR-200 (INLEXZO®) was supported by data from Cohort 2, which included 85 patients with BCG-unresponsive CIS with or without papillary tumors. Eligible patients had histologically confirmed high-grade disease following adequate BCG exposure and an ECOG performance status of 0–2. The median patient age was 71 years, 80% were male, and two-thirds presented with CIS alone. Patients received TAR-200 once every 3 weeks for 6 months, followed by maintenance dosing every 12 weeks through month 24. Tumor assessments were performed via cystoscopy and cytology every 12 weeks, with mandatory biopsies at weeks 24 and 48.

At the data cutoff (March 31, 2025), the overall CR rate was 82.4%, representing the highest single-agent response rate reported in this disease setting. The median Duration of Response (DOR) reached 25.8 months, with estimated 12-month CR and DOR rates of 57.4% and 65.7%, respectively. Median follow-up among responders was 9.2 months.

Treatment was well tolerated, with most adverse events localized and manageable. The most frequent treatment-related events (≥10%) were pollakiuria (35%), dysuria (29%), urinary urgency (15%), and urinary tract infection (15%), consistent with localized bladder irritation rather than systemic toxicity.

Clinical Implications

The results from SunRISe-1 mark a pivotal advance in the management of BCG-unresponsive NMIBC. TAR-200 monotherapy demonstrated durable, high-level intravesical activity without the need for re-induction or systemic immune checkpoint inhibition. Its favorable risk-benefit profile, coupled with the logistical simplicity of outpatient placement, positions TAR-200 as a transformative bladder-sparing therapy for patients ineligible or unwilling to undergo cystectomy.

Unlike conventional intravesical treatments requiring patients to retain fluid instillations for 1–2 hours before voiding, TAR-200 provides continuous, controlled Gemcitabine release over weeks, fundamentally shifting the procedural and pharmacologic paradigm of NMIBC care in the urology clinic.

Conclusion

SunRISe-1 establishes TAR-200 monotherapy (INLEXZO®) as the first intravesical drug-releasing system with proven efficacy and safety in localized bladder cancer. With an 82% CR rate and durable responses extending beyond two years, TAR-200 represents a significant step forward in meeting the long-standing need for effective, tolerable, and durable bladder-sparing therapy in patients with BCG-unresponsive high-risk NMIBC.

TAR-200 for Bacillus Calmette-Guérin–Unresponsive High-Risk Non–Muscle-Invasive Bladder Cancer: Results From the Phase IIb SunRISe-1 Study. Daneshmand S, Van der Heijden MS, Jacob JM, et al. Journal of Clinical Oncology. https://doi.org/10.1200/JCO-25-01651

Maintaining Physician Preference in CLL Care and Its Impact on Outcomes

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Written by: M. Yair Levy, MD
Sponsored by: BeOne Medicines

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease that has seen a remarkable treatment evolution over the past decade. Approximately one-third of CLL patients will not require treatment, with clinical observation remaining the standard for asymptomatic patients.1 For CLL patients requiring treatment, historical regimens have been limited to cytotoxic chemotherapy, administered alone or in combination with anti-CD20 immunotherapy.2 In 2016, two classes of targeted therapies entered the CLL marketplace. Most notably among these are inhibitors of the anti-apoptotic protein B-cell lymphoma 2 (Bcl2), and the B-cell proliferative regulator Bruton’s tyrosine kinase (BTK).2 Introduction of first-generation covalent BTK inhibitors (cBTKis) was followed by second-generation, as well as non-covalent BTKis.2 The rapid expansion of targeted therapies over the last decade has profoundly impacted the clinical management of CLL.

The multitude of therapeutic options in today’s CLL treatment landscape, which often includes several drugs in a single class, provides oncologists the unprecedented opportunity to weigh the entire clinical picture for each patient, and personalize their treatment strategy accordingly. Clinicians leverage decades of medical training to gauge pharmacokinetic and pharmacodynamic differences between therapies, weighing drug-specific efficacy, tolerability and safety for each patient. There is also concurrent influence from reputable medical bodies, such as NCCN guidelines and FDA approved treatments. Most importantly, every CLL patient and their disease are unique. It is imperative to protect physicians’ decision-making freedom to the degree that it permits individualized treatment approaches and the prescription of specific therapies, without undue external influence.

Step therapy is a growing utilization management strategy among health plan Pharmacy Benefit Managers (PBMs) that threatens physician autonomy. As its colloquial name “fail-first” implies, step therapy is a cost-saving approach that requires a patient to have tried, and failed, alternative drug(s), before the PBM will cover the originally prescribed drug.3 Step therapies transfer the onus of decision-making from the treating physician to a commercial entity, robbing the clinician of their ability to personalize care and maximize patient outcomes. This leads to worsening provider burnout, depersonalization, and exacerbates oncology physician shortages. Step therapies also place additional burden on clinical support staff and negatively impact CLL patient outcomes.

PBM-mandated BTKi coverage is a common scenario that exemplifies how step therapy negatively impacts CLL patient outcomes. In my clinical experience, PBMs have required frontline use of the first-generation BTKi ibrutinib. Ibrutinib is an efficacious drug that has revolutionized CLL treatment, but it is poorly tolerated, as compared with 2nd generation BTKis, which directly contributes to decreased treatment compliance and impacts patient outcomes. Ibrutinib also carries the risk of adverse cardiologic events, including atrial arrythmias, ventricular arrhythmias and sudden death.4 As a provider who has lost a patient due to this adverse event, it’s imperative that safety risks of specific drugs are weighed by an experienced clinician on a case-to-case basis. Furthermore, there is an urgent need for step therapy reform that considers clinical data in determining drug coverage. In the case of BTKi coverage, there is clinical evidence demonstrating a lower risk of adverse cardiologic events with use of second-generation BTKi agents.4 As cancer patient advocates, oncologists must continue to push back against step therapies that infringe on patient safety and well-being, and may adversely affect outcomes.

As oncology drugs continue to enter the ever-changing healthcare marketplace, it’s increasingly critical that physicians communicate the importance of preserving autonomy to PBMs and other decision-making parties. There is potential for other drug pricing provisions, such as those included in the 2022 Inflation Reduction Act (IRA),5 to impact CLL patient outcomes in a manner similar to that which is seen with PBM-mediated step therapy. Under the IRA, the government may select certain medications for which it will cap the cost of for Medicare recipients.5 While designed to reduce patient financial burden, provisions of the IRA, such as the ability to target costs of small molecules (like BTKis) years before other drug types, may have harmful effects on oncology treatment.5 This risks physicians being forced to utilize certain medications for which cost setting has been established, similar to step therapy, and has already been shown to disincentivize the development of small molecule drugs since the IRA was enacted.5 Given that CLL primarily affects elderly populations,2 drug pricing provisions affecting Medicare could impact CLL prescribing patterns, and there is precedent to surmise that commercial payers may adopt similar strategies of government-sponsored programs.

In diseases like CLL where therapeutic nuances matter, restricting access to preferred agents can have profound consequences. While the extra hours spent justifying what seems like every clinical decision, completing paperwork, appealing denials, and engaging in peer-to-peer calls may feel like “death by a thousand paper cuts”, oncologists have the responsibility as patient advocates to do no harm. We must continue to advocate for policies that prioritize patient outcomes over cost-driven algorithms, and ensure that clinical decision-making remains in the hands of those best equipped to make it: the treating physicians.

References:

  1. Shadman M. Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review. JAMA. 2023;329(11):918-932. doi:10.1001/jama.2023.1946.
  2. Sekeres S, Lamkin EN, Bravo E Jr, Cool A, Taylor J. Resistance Mutations in CLL: Genetic Mechanisms Shaping the Future of Targeted Therapy. Genes (Basel). 2025;16(9):1064. Published 2025 Sep 10. doi:10.3390/genes16091064.
  3. Royce TJ, Schenkel C, Kirkwood K, Levit L, Levit K, Kircher S. Impact of Pharmacy Benefit Managers on Oncology Practices and Patients. JCO Oncol Pract. 2020;16(5):276-284. doi:10.1200/JOP.19.00606.
  4. Moslehi JJ, Furman RR, Tam CS, et al. Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib. Blood Adv. 2024;8(10):2478-2490. doi:10.1182/bloodadvances.2023011641.
  5. The Inflation Reduction Act and Medicare Drug Price “Negotiation”. Pharmaceutical Research and Manufacturers of America (PhRMA) website. https://phrma.org/policy-issues/government-price-setting/inflation-reduction-act. Accessed October 1, 2025.

Polygenic Risk Scores Predict Future Breast Cancer Events After In Situ Disease

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Preinvasive breast lesions such as Ductal Carcinoma In Situ (DCIS) and Lobular Carcinoma In Situ (LCIS) are well recognized precursors to invasive disease, yet clinicians currently lack precise tools to predict which patients will ultimately progress. Identifying individuals at highest risk is essential for guiding management, balancing the benefits of early intervention against the harms of overtreatment.

Epidemiologic data suggest that approximately 20–40% of untreated DCIS lesions eventually evolve into invasive breast cancer, while women diagnosed with LCIS have a 7–12-fold higher risk of developing invasive malignancy in either breast over time. Both entities also confer elevated risk for contralateral breast cancer. In this context, genomic risk stratification offers an opportunity to personalize surveillance and preventive strategies.

Understanding PRS313

The 313-SNP breast cancer Polygenic Risk Score (PRS313) quantifies an individual’s inherited susceptibility to breast cancer by integrating the effects of 313 Single Nucleotide Polymorphisms (SNPs) known to influence disease risk. Each variant contributes modestly on its own, but together they generate a composite score that captures the polygenic architecture of breast cancer predisposition.

Using DNA derived from blood or saliva, PRS313 calculates a weighted sum of risk alleles to estimate lifetime breast cancer risk. This score can stratify women into distinct risk quartiles, offering refined insight beyond traditional factors such as family history, breast density, and age. Importantly, PRS313 has been validated in population studies as a predictor of primary breast cancer risk. Recent research now explores its ability to forecast subsequent disease after an initial diagnosis of in situ carcinoma.

Study Overview

Investigators from the ICICLE (Investigate the genetiCs of In situ Carcinoma of the ductaL subtypE) and GLACIER (Genetics of LobulAr Carcinoma In situ in EuRope) studies conducted a retrospective analysis to evaluate whether PRS313 could predict subsequent breast cancer events following DCIS or LCIS.

The study included 2,169 women with DCIS and 185 with LCIS, each followed for a median of 11 years. Cox regression models assessed associations between PRS313 and several outcomes: any subsequent in situ or invasive breast cancer (including distant metastasis), ipsilateral breast disease, invasive ipsilateral disease, and contralateral breast cancer. For DCIS, results were analyzed by PRS313 quartiles; for LCIS, risk was modeled as a continuous variable.

Key Findings

Analysis revealed a significant association between increasing PRS313 and contralateral breast cancer after DCIS (hazard ratio [HR], 1.30; 95% CI, 1.08–1.56). Women in the highest PRS313 quartile were roughly twice as likely to develop contralateral disease compared with those in the lowest quartile. However, PRS313 was not significantly associated with ipsilateral recurrence in DCIS.

In contrast, among women with LCIS, higher PRS313 correlated strongly with ipsilateral breast cancer risk (HR, 2.16; 95% CI, 1.22–3.81). The association was even more pronounced among participants with a family history of breast cancer, where PRS313 increases translated to more than a threefold elevation in ipsilateral disease risk, rising to nearly fourfold when women who had undergone mastectomy or radiotherapy were excluded.

Lead investigator comments emphasized that while LCIS is often managed conservatively, these findings suggest that patients with a strong family history and high PRS313 may derive benefit from additional risk-reducing interventions, such as endocrine therapy or intensified surveillance.

Clinical Implications

This study provides compelling evidence that polygenic risk assessment can refine prognostication in women with in situ breast cancer, distinguishing those most likely to develop future disease. The results support integrating PRS313 into post-diagnosis risk discussions to help patients make informed decisions regarding surgery, chemoprevention, and long-term follow-up intensity.

“By combining genomic data with clinicopathologic features,” the authors noted, “clinicians can deliver more individualized care, moving beyond histologic appearance, to a truly personalized estimate of recurrence risk.”

Study Limitations

The researchers acknowledged several limitations. PRS313 was originally designed to predict invasive breast cancer risk rather than in situ disease specifically, and relevant genetic variants unique to DCIS or LCIS may remain undiscovered. Additionally, the relatively small LCIS cohort limited statistical power and generalizability across ancestries. Ongoing validation in larger and more diverse populations will be necessary before broad clinical implementation.

Conclusion

The ICICLE and GLACIER analyses underscore the potential of PRS313 as a predictive biomarker for future breast cancer events, particularly contralateral disease after DCIS and ipsilateral disease after LCIS. Incorporating polygenic risk profiling into the management of in situ breast lesions could help identify patients who warrant closer monitoring or preventive therapy, while sparing others from unnecessary intervention.

As genomic medicine advances, tools like PRS313 may become integral to personalized breast cancer prevention and survivorship care, aligning treatment intensity with each woman’s unique genetic risk landscape.

Breast Cancer Polygenic Risk Score Associated with Outcomes after In Situ Breast Disease. Timbres J, Kohut K, Mavaddat N, et al. Cancer Epidemiol Biomarkers Prev OF1–OF10. https://doi.org/10.1158/1055-9965.EPI-25-0529. Published: 01 October 2025.

 

FDA Approves LIBTAYO® for Adjuvant Treatment of Cutaneous Squamous Cell Carcinoma

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SUMMARY: The FDA on October 8, 2025 approved Cemiplimab-rwlc (LIBTAYO®) for the adjuvant treatment of adults with Cutaneous Squamous Cell Carcinoma (CSCC) at high risk of recurrence after surgery and radiation.

Cutaneous Squamous Cell Carcinoma (CSCC) is the second most common skin cancer worldwide, with an estimated 2.4 million new cases annually. While surgery with or without adjuvant radiotherapy achieves cure in the vast majority of patients, approximately 5% experience locoregional or distant recurrence. Patients with high-risk features, such as nodal involvement, perineural invasion, or locally recurrent disease, remain particularly vulnerable to relapse following definitive local therapy.

Previous efforts to improve outcomes through systemic adjuvant approaches have been largely unsuccessful. Notably, the POST/TROG 05.01 trial demonstrated no additional benefit of adjuvant Carboplatin-based chemoradiation over radiotherapy alone, underscoring the unmet need for effective systemic adjuvant strategies in this population.

Trial Design

The C-POST (NCT03969004) is an ongoing, international, randomized Phase 3 study evaluating whether adjuvant immunotherapy with Cemiplimab, a PD-1 inhibitor previously approved for advanced and metastatic CSCC, could reduce recurrence risk following surgery and postoperative radiotherapy in patients with high-risk disease. A total of 415 patients were randomized 1:1 to receive Cemiplimab-rwlc or placebo after completing adjuvant radiation therapy (within 2–10 weeks before randomization). Eligible patients had either nodal high-risk features (e.g., extracapsular extension or 3 or more positive nodes) or non-nodal features (e.g., T4 tumors with bone invasion, in-transit metastases, perineural invasion, or locally recurrent tumors with additional risk factors). Cemiplimab was administered intravenously at 350 mg IV every 3 weeks for 12 weeks, then 700 mg every 6 weeks for up to 36 additional weeks (total of 48 weeks or less). The Primary endpoint was Disease-Free Survival (DFS). Secondary endpoints included freedom from locoregional and distant recurrence, Overall Survival (OS), and safety.

Efficacy Results

After a median follow-up of 24 months, Cemiplimab demonstrated a substantial DFS benefit over placebo.

  • Events: 24 with Cemiplimab vs. 65 with placebo
  • Hazard Ratio for disease recurrence or death: 0.32 (95% CI, 0.20–0.51; P<0.001)
  • Estimated 24-month DFS: 87.1% (95% CI, 80.3–91.6) vs. 64.1% (95% CI, 55.9–71.1)

The Kaplan–Meier curves separated early and remained distinctly apart over time, indicating both a rapid and durable treatment benefit.

Patterns of Recurrence

Cemiplimab significantly reduced both locoregional and distant recurrences:

  • Freedom from locoregional recurrence at 24 months: 94.6% vs. 76.7% (HR=0.20; 95% CI, 0.09–0.40)
  • Freedom from distant recurrence at 24 months: 94.3% vs. 83.8% (HR=0.35; 95% CI, 0.17–0.72)

The benefit was observed consistently across prespecified subgroups, including those stratified by PD-L1 tumor expression (<1% or ≥1%).

Safety Profile

Adverse events (AEs) of grade ≥3 occurred in 23.9% of Cemiplimab-treated patients compared with 14.2% in the placebo group. Treatment discontinuation due to AEs occurred in 9.8% versus 1.5%, respectively. The overall safety profile was consistent with known Cemiplimab toxicities, and quality-of-life scores remained largely stable throughout treatment. One treatment-related death was reported.

At the time of analysis, Overall Survival (OS) data were immature, with 25 deaths reported (12 in the Cemiplimab group, 13 in placebo). The 2-year OS was 94.8% vs. 92.3% (HR, 0.86; 95% CI, 0.39–1.90). Subsequent analyses will clarify whether the DFS advantage translates into a survival benefit.

Clinical Implications

The C-POST trial establishes adjuvant Cemiplimab as the first systemic therapy to significantly improve DFS in patients with high-risk CSCC following curative-intent surgery and radiotherapy. The 68% reduction in recurrence or death risk, coupled with a manageable safety profile, positions Cemiplimab as a potential new standard of care for this challenging population.

Notably, most recurrences occurred within the first year after local therapy, mirroring the known natural history of CSCC, and Cemiplimab’s early and sustained benefit suggests a durable immune-mediated effect.

While OS data are pending, these findings mark a major advance in the adjuvant management of high-risk CSCC. The results also stand in contrast to the KEYNOTE-630 trial of adjuvant Pembrolizumab, which was discontinued for futility, highlighting possible differences in trial design or patient selection.

Conclusion

Adjuvant therapy with Cemiplimab significantly prolongs Disease-Free Survival compared with placebo in patients with high-risk Cutaneous Squamous Cell Carcinoma after surgery and radiotherapy. The 24-month DFS benefit, 87% versus 64%, represents a meaningful reduction in recurrence risk and provides clinicians with the first evidence-based systemic option in this setting. Ongoing follow-up will determine the ultimate impact on Overall Survival.

Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma. Rischin D, Porceddu S, Day F, et al. for the C-POST Trial Investigators. N Engl J Med 2025;393:774-785

FDA Approves ZEPZELCA® Plus TECENTRIQ® for First-Line Maintenance in Extensive-Stage Small Cell Lung Cancer

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SUMMARY: The FDA on October 2, 2025, approved Lurbinectedin (ZEPZELCA®)  in combination with Atezolizumab (TECENTRIQ®) or Atezolizumab and hyaluronidase-tqjs (TECENTRIQ HYBREZA®), for the maintenance treatment of adult patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC) whose disease has not progressed after first-line induction therapy with Atezolizumab or Atezolizumab and hyaluronidase-tqjs, Carboplatin, and Etoposide.

The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 10-15% of all lung cancers diagnosed annually in the US. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis.

Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. While initial responses to chemotherapy are often dramatic, relapse occurs in most patients, and recurrent disease typically demonstrates resistance to previously effective regimens. Consequently, extending response durability through maintenance therapy remains a key therapeutic goal.

Lurbinectedin is a selective alkylating agent that binds to guanine residues within DNA, leading to inhibition of oncogenic transcription factors and impairment of DNA repair pathways. This disrupts the cell cycle and induces tumor cell death.
Atezolizumab is a monoclonal antibody targeting Programmed Death-Ligand 1 (PD-L1), blocking its interaction with PD-1 and B7.1 receptors. By inhibiting PD-L1–mediated immune evasion, Atezolizumab restores anti-tumor T-cell activity and enhances immune-mediated tumor elimination.

The IMforte Trial: Study Design

The IMforte Trial is a global, open-label, randomized Phase III study (NCT05091567) conducted to evaluate the efficacy and safety of Lurbinectedin plus Atezolizumab as first-line maintenance therapy for adults with Extensive-Stage SCLC (ES-SCLC). In this study, a total of 660 treatment-naïve patients received induction therapy with Atezolizumab, Carboplatin, and Etoposide for four 21-day cycles. Of these, 483 patients without disease progression were randomized 1:1 to receive either:

  • Lurbinectedin 3.2 mg/m² IV every 3 weeks with G-CSF prophylaxis plus Atezolizumab 1200 mg IV every 3 weeks, or
  • Atezolizumab alone 1200 mg IV every 3 weeks

Treatment was continued until disease progression, unacceptable toxicity, or withdrawal. Stratification factors included baseline liver metastases, ECOG performance status, LDH levels, and receipt of prophylactic cranial irradiation. The Primary endpoints were Independent Review Facility (IRF)–assessed Progression-Free Survival (PFS) and Overall Survival (OS) from the start of maintenance therapy.

Efficacy Outcomes

After a median follow-up of 15 months, the IMforte study achieved both of its Primary endpoints:

  • Median PFS: 5.4 months with Lurbinectedin plus Atezolizumab vs 2.1 months with Atezolizumab alone (HR=0.54; 95% CI: 0.43–0.67; P<0.0001)
  • Median OS: 13.2 months vs 10.6 months, respectively (HR=0.73; 95% CI: 0.57–0.95; P=0.0174)

These outcomes reflect a 46% reduction in the risk of disease progression or death and a 27% reduction in the risk of death with the combination regimen. Median maintenance treatment duration was 4.1 months for the combination arm and 2.1 months for the monotherapy arm.

Safety and Tolerability

The combination of Lurbinectedin and Atezolizumab demonstrated a manageable safety profile with no new safety signals.

  • Any-grade treatment-related adverse events (TRAEs):5% (combo) vs 40.0% (monotherapy)
  • Grade 3–4 TRAEs: 25.6% vs 5.8%
  • Grade 5 TRAEs: 0.8% vs 0.4%

The most common adverse reactions (≥30%) were lymphopenia, thrombocytopenia, anemia, leukopenia, neutropenia, nausea, and fatigue/asthenia. Discontinuations due to adverse events occurred in 6.2% and 3.3% of patients, respectively.

Clinical Interpretation

IMforte is the first global Phase III study to demonstrate significant improvement in both PFS and OS with a first-line maintenance approach in ES-SCLC. By integrating the DNA-damaging activity of Lurbinectedin with the immune reactivation potential of PD-L1 blockade, the combination offers a dual mechanism to counter both tumor proliferation and immune evasion. These results establish Lurbinectedin plus Atezolizumab as a new standard maintenance option for patients whose disease remains controlled after induction chemoimmunotherapy, an important milestone in a disease where long-term survival has historically been rare.

Key Takeaways for Oncology Practice

  • Unmet Need: SCLC remains an aggressive malignancy with limited long-term treatment options.
  • Clinical Significance: IMforte is the first Phase III trial to demonstrate both OS and PFS gains with a first-line maintenance regimen in ES-SCLC.
  • Mechanistic Synergy: Combines DNA-targeted cytotoxic activity (Lurbinectedin) with PD-L1 blockade (Atezolizumab) for enhanced and durable tumor control.
  • Practice Impact: Establishes Lurbinectedin plus Atezolizumab as an FDA-approved maintenance option for patients with ES-SCLC who respond to induction chemoimmunotherapy.
  • Safety: Manageable toxicity profile; regular hematologic and clinical monitoring recommended.

Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Paz-Ares L, Borghaei H, Liu SV, et al. The Lancet 2025;405:2129-2143.