Category: Hem/Onc Updates

Durvalumab + FLOT Establishes New Benchmark in Curative-Intent Therapy for Gastric and GEJ Cancers

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SUMMARY: The American Cancer Society estimates that in the US about 30,300 new gastric cancer cases will be diagnosed in 2025 and about 10,780 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 gastric cancer. Additionally, one of the strongest risk factors for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Despite the intent of cure in resectable gastric and GastroEsophageal Junction (GEJ) cancers, long-term survival remains suboptimal, with fewer than half of patients alive at five years. Current perioperative chemotherapy strategies, such as the FLOT regimen (5-FU, Leucovorin, Oxaliplatin, and Docetaxel), are widely accepted as the standard of care, particularly in Western countries. However, recurrence remains a frequent challenge, underscoring the need for enhanced systemic control.

The global, randomized, double-blind Phase 3 MATTERHORN trial evaluated whether adding the immune checkpoint inhibitor Durvalumab to FLOT could improve clinical outcomes in patients with resectable, locally advanced gastric or GEJ adenocarcinoma. This approach leverages prior success of immunotherapy in metastatic settings, where checkpoint inhibitors are already approved in combination with chemotherapy, but expands the strategy into the curative-intent, perioperative context.

Durvalumab (IMFINZI®) is a human immunoglobulin G1 monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics, and unleashes the T cells.

Trial Design and Treatment Protocol
In this study, a total of 948 treatment-naïve patients with Stage II to IVa resectable gastric or GEJ adenocarcinoma were randomized 1:1 to receive either Durvalumab plus FLOT (N=474) or placebo plus FLOT (N=474).  Treatment consisted of Durvalumab 1500 mg or Placebo every 4 weeks (Q4W) on Day 1 + FLOT (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel) on Days 1 and 15 for 4 cycles (2 cycles each neoadjuvant/adjuvant), followed by Durvalumab 1500 mg or Placebo on Day 1 Q4W for 10 cycles. Participants were enrolled across Asia, Europe, North America, and South America, reflecting the global burden of disease. Key stratification factors included geographic region (Asia vs non-Asia), nodal status, and PD-L1 expression. The median age was approximately 62 years, and around 70% of patients had gastric tumors, with the remainder involving the GEJ. Most patients (70%) had node-positive disease at baseline. Treatment groups were well balanced. Treatment was administered perioperatively, consisting of two neoadjuvant and two adjuvant cycles. Durvalumab or placebo was continued post-chemotherapy as monotherapy for 10 additional cycles. The Primary endpoint was Event-Free Survival (EFS), with Secondary endpoints including Overall Survival (OS), pathologic Complete Response (pCR), and Safety.

Efficacy Findings
At a median follow-up of 31.5 months, the addition of Durvalumab to FLOT significantly improved EFS compared to placebo. The median EFS had not yet been reached in the Durvalumab arm, whereas it was 32.8 months in the placebo group (Hazard Ratio [HR] 0.71; 95% CI, 0.58–0.86; P<0.001), translating to a roughly 30% reduction in the risk of progression, recurrence, or death. Importantly, Durvalumab did not delay surgery or adjuvant therapy initiation. Notably, 24-month EFS rates were higher with Durvalumab (67.4%) compared to placebo (58.5%), indicating a durable benefit. Subgroup analyses consistently favored the Durvalumab combination across clinical and demographic variables, including PD-L1 expression status, nodal involvement, and geographic region, although some subgroups lacked sufficient power for statistical significance.

An early OS analysis, though not yet mature, suggested a favorable trend for the Durvalumab arm (HR 0.78; 95% CI, 0.62–0.97), with median OS not reached in that group compared to 47.2 months in the placebo group.

In addition to EFS, the Durvalumab-containing regimen improved pathologic Complete Response rates as well as Major Pathological Response, suggesting more effective eradication of micrometastatic disease with immunotherapy-enhanced perioperative treatment.

The final Overall Survival results from the MATTERHORN trial were presented at the ESMO Congress 2025. In this definitive analysis, perioperative Durvalumab added to FLOT chemotherapy delivered a statistically significant and clinically meaningful survival advantage over placebo plus FLOT (HR=0.78; 95% CI, 0.63–0.96; P=0.021). Notably, the OS benefit was observed across PD-L1 expression levels, with comparable hazard ratios in both the TAP <1% and TAP ≥1% subgroups, suggesting that the activity of Durvalumab in the perioperative setting is not restricted to PD-L1–positive disease.

Durvalumab also enhanced pathological response metrics. Patients treated with Durvalumab achieved substantially higher nodal negativity rates (ypN0, 58.2% vs 44.8%), indicating deeper locoregional tumor clearance and supporting the biologic premise that checkpoint inhibition can potentiate chemotherapy-mediated cytoreduction. Improvements in Event-Free Survival were consistent across the spectrum of pathological response categories including partial, major, and complete responders, highlighting that meaningful clinical benefit extends beyond patients achieving ypCR.

Safety and Tolerability
The addition of Durvalumab did not compromise surgical outcomes or delay the initiation of adjuvant therapy. The incidence of grade 3/4 adverse events was similar between arms (72% with Durvalumab vs 71% with placebo), as were rates of serious adverse events (48% vs 44%) and treatment-related deaths (5% vs 4%). These findings reinforce the safety of incorporating immunotherapy into the perioperative setting without increasing toxicity burden or interfering with multimodal management.

Biomarker Insights and Future Directions
Approximately 90% of patients were PD-L1–positive in both groups, and 5% had MicroSatellite Instability–High (MSI-H) tumors (lower than the rates of 7% to 9% commonly seen). Although these biomarker-defined subpopulations are known to respond favorably to immunotherapy, their relatively small representation in the study suggests the observed benefits were driven by broader immunomodulatory effects rather than biomarker enrichment alone.

The optimal duration of adjuvant Durvalumab remains an open question. In MATTERHORN, Durvalumab was continued for 10 cycles post-chemotherapy, but further investigation may determine whether shorter courses or biomarker-guided de-escalation could yield similar benefits while minimizing toxicity and cost.

Clinical Implications

The MATTERHORN findings reinforce that integrating Durvalumab into the perioperative FLOT regimen confers durable improvements in both Overall and Event-Free Survival for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. Importantly, the magnitude of benefit remained stable across key clinical and biological subgroups, including PD-L1 status and nodal involvement, underscoring the robustness and generalizability of the treatment effect.

Combined with the earlier JCO publication detailing significant gains in Event-Free Survival, these results strengthen the rationale for incorporating immunotherapy into curative-intent treatment pathways for early-stage upper gastrointestinal cancers. Durvalumab + FLOT is poised to emerge as a new global standard of care, reflecting the broader paradigm shift toward perioperative immune-checkpoint blockade in resectable solid tumors.

Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: A randomised, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma. Tabernero J, Al-Batran, Wainberg ZA, et al. LBA81- Presented at ESMO Congress 2025, Berlin.

FDA Approves KOMZIFTI® for Relapsed or Refractory Acute Myeloid Leukemia with a NPM1 mutation

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SUMMARY: The FDA on November 13, 2025, approved Ziftomenib (KOMZIFTI&reg;), a menin inhibitor, for adults with relapsed or refractory Acute Myeloid Leukemia (AML) with a susceptible Nucleophosmin 1 (NPM1) mutation who have no satisfactory alternative treatment options.

The American Cancer Society estimates that in 2025, 22,010 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,090 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. With the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

NPM1 mutations present in up to 30% of newly diagnosed adult AML define a unique disease subset recognized by both the WHO and the International Consensus Classification. Although NPM1-mutated AML often responds well to initial intensive therapy, outcomes deteriorate sharply after relapse or refractory disease. Patients in this setting frequently face limited therapeutic options and dismal response rates with conventional salvage strategies.

Mounting evidence shows that NPM1-mutated and KMT2A-rearranged (KMT2A-r) leukemias rely on an aberrant transcriptional program maintained through the interaction between menin and KMT2A. This dependency includes pathologic overexpression of HOX and MEIS1, which reinforce leukemic self-renewal and block differentiation. Inhibiting the menin–KMT2A complex has therefore emerged as a compelling therapeutic strategy capable of reversing leukemic transcriptional programs.

Ziftomenib, a potent and selective oral menin inhibitor, disrupts this interaction and restores myeloid differentiation in preclinical models. The registrational Phase II portion of the KOMET-001 study provides the most definitive evidence to date of its clinical potential in relapsed/refractory NPM1-mutated AML, and was used for the primary efficacy analysis and formed the basis for the FDA approval.

Mechanistic Rationale for Menin Inhibition

Menin serves as a scaffold protein essential for recruitment of the KMT2A/MLL methyltransferase complex to chromatin. This interaction drives leukemogenic transcriptional circuits in both KMT2A-r and NPM1-mutated AML, promoting expression of HOXA9, MEIS1, PBX3, and downstream effectors such as FLT3 and BCL2.

Key mechanistic insights include:

  • Menin–KMT2A blockade releases mutant NPM1 from chromatin, reducing HOX/MEIS1 signaling and triggering differentiation.
  • Ziftomenib promotes terminal maturation of AML blasts, rather than direct cytotoxicity, consistent with its differentiation-based mechanism.
  • NPM1 cytoplasmic mislocalization, a hallmark of the mutation, creates vulnerabilities that can be exploited through menin inhibition and related targeted approaches.

This biology underpins the therapeutic activity observed in KOMET-001 and supports the broader pursuit of menin inhibition across multiple AML subtypes.

KOMET-001 Trial Overview

KOMET-001 is a global, multicenter Phase I/II study evaluating single-agent Ziftomenib in adults with relapsed/refractory NPM1-mutated or KMT2A-rearranged AML. The Phase II portion which serves as the registrational dataset, focused on patients with relapsed/refractory NPM1-mutated disease treated at the recommended monotherapy dose of Ziftomenib 600 mg once daily.

Among the 92 patients with relapsed/refractory NPM1-mutated AML included in Phase II:

  • Median age: 69 years (range 33–84); 64% were ≥65 years
  • Median prior therapies: 2 lines (range 1–7)
  • Prior venetoclax exposure: 59%
  • Prior allogeneic transplantation: 24%
  • Common co-mutations: FLT3 (56%), IDH1/2 (33%)
  • ECOG 0–1: 83%

Efficacy was established based on the rate of Complete Remission (CR) plus CR with partial hematological recovery (CRh), the duration of CR plus CRh, and the rate of conversion from transfusion dependence to transfusion independence. The median follow-up was 4.2 months.

This heavily pretreated population reflects real-world patients with few remaining therapeutic options and particularly poor expected outcomes.

Efficacy Findings

Ziftomenib met its Primary endpoint with a CR/CRh rate of 22% (95% CI 14–32; P=0.0058), exceeding the historical 12% benchmark for this setting.

Key efficacy results:

  • CR/CRh rate: 22% (14% CR; 8% CRh)
  • Composite CR rate: 26%
  • Overall Response Rate (ORR): 33%
  • Median time to first response: 1.9 months
  • Median duration of response: 4.6 months
  • MRD negativity: 61% of evaluable CR/CRh responders
  • Median Overall Survival (OS): 6.6 months
  • Median OS among responders: 18.4 months

Two responders were successfully bridged to allogeneic stem cell transplantation and resumed Ziftomenib maintenance afterwards.

Efficacy was maintained across clinically relevant subgroups:

  • Age <65 vs ≥65: 21% vs 22% CR/CRh
  • Prior venetoclax exposure: 22% CR/CRh
  • Prior HSCT: 23% CR/CRh
  • FLT3 co-mutations: 13% (ITD), 33% (TKD)
  • IDH1/2 co-mutations: 50% and 31%, respectively

The activity in Venetoclax-exposed patients is particularly noteworthy given real-world salvage CR rates as low as 4% in this population.

Transfusion Independence

  • RBC independence conversion: 23%
  • Platelet independence conversion: 15%
  • Overall transfusion independence conversion: 20%

These improvements reflect meaningful clinical benefit and enhanced quality of life.

Safety and Tolerability

Ziftomenib demonstrated a favorable safety profile with low rates of treatment-related discontinuation (3%). Most adverse events were consistent with underlying AML or expected from differentiation-based therapies. Common Grade ≥3 TEAEs included febrile neutropenia (26%), anemia (20%) and thrombocytopenia (20%). Differentiation Syndrome occurred in 25% (15% grade 3; none grade 4–5) managed effectively using protocol-defined measures including cytoreduction and steroid prophylaxis, reinforcing the necessity of early recognition and continued therapy through differentiation-associated changes. Overall, ziftomenib showed no clear intrinsic myelosuppression, minimal cardiac toxicity, and a manageable safety profile appropriate for a predominantly older patient population.

Clinical Implications

The KOMET-001 data establish Ziftomenib as a meaningful therapeutic advance for patients with relapsed/refractory NPM1-mutated AML, an area historically characterized by low response rates and short survival. The durability of responses, high rate of MRD clearance, and consistent efficacy across age groups, co-mutational backgrounds, and prior therapies position Ziftomenib as a valuable monotherapy option and a potential bridge to curative transplantation. These results also strengthen the biological rationale for integrating menin inhibitors earlier in the treatment course. Ongoing frontline trials including the global Phase III KOMET-017 study will clarify the role of Ziftomenib-based combinations in newly diagnosed fit and unfit patients with NPM1-mutated or KMT2A-rearranged AML.

Conclusion

Ziftomenib, a first-in-class oral menin inhibitor, demonstrated clinically meaningful activity and durable responses in heavily pretreated relapsed/refractory NPM1-mutated AML, meeting its registrational Phase II endpoint. With a manageable safety profile including low myelosuppression, minimal QTc effects, and predictable differentiation syndrome, Ziftomenib represents an important new targeted therapy for a genetically defined AML subset.

The KOMET-001 results mark a significant step forward in addressing an area of profound unmet need, and they lay the foundation for expanding menin inhibition into earlier lines of therapy with the goal of transforming long-term outcomes for patients with NPM1-mutated AML.

Ziftomenib in Relapsed or Refractory NPM1-Mutated AML. Wang ES, Montesinos P, Foran J, et al. J Clin Oncol. 2025;43:3381-3390

Updated ASCO–ASTRO–SSO Guideline Clarifies Indications and Best Practices for Postmastectomy Radiation Therapy in Breast Cancer

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

Background

Postmastectomy radiation therapy (PMRT) remains a cornerstone of curative-intent treatment for many patients with invasive breast cancer, significantly reducing the risk of locoregional recurrence (LRR) and improving Disease-Specific Survival. However, with evolving systemic therapies, less extensive axillary surgery, and modern radiation techniques, the benefit of PMRT now varies widely across patient subgroups. Recognizing the need to update clinical decision-making in this context, the American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and Society of Surgical Oncology (SSO) have released a comprehensive new guideline to replace the 2016 version.

The new recommendations jointly published in Journal of Clinical Oncology, Practical Radiation Oncology, and Annals of Surgical Oncology provide refined guidance on when and how PMRT should be applied in both upfront surgical and post-neoadjuvant settings.

Development and Scope

A multidisciplinary task force representing Radiation, Medical, and Surgical Oncology collaborated with experts from the European Society for Radiotherapy and Oncology. The group conducted a systematic review of evidence published between 2005 and 2024 and used structured consensus methods to determine recommendation strength and evidence quality.
The guideline addresses four primary clinical domains:

  1. Indications for PMRT after upfront mastectomy.
  2. Indications for PMRT following Neoadjuvant Systemic Therapy (NAST).
  3. Appropriate treatment volumes and dose-fractionation schedules.
  4. Optimal delivery techniques and normal tissue sparing strategies.

The recommendations are intended for adult patients with breast cancer undergoing mastectomy and are directed toward Radiation, Surgical, and Medical Oncologists, as well as other oncology professionals involved in multidisciplinary breast cancer management.

Key Recommendations

  1. PMRT After Upfront Mastectomy
  • Node-positive disease: PMRT is strongly recommended for most patients with pathologically positive axillary lymph nodes to reduce recurrence and breast cancer–specific mortality.
  • pT4 tumors: Strong recommendation for PMRT regardless of nodal status.
  • pT3N0 tumors: PMRT is conditionally recommended; omission or volume reduction may be appropriate when clinicopathologic features are favorable.
  • pT1–2N0 tumors: PMRT is generally not recommended but may be considered in the presence of multiple high-risk factors (e.g., triple-negative biology, LVI, young age, high grade, or central/medial tumor location).
  • Positive margins: In patients with positive surgical margins but no other PMRT indication, treatment limited to the chest wall or reconstructed breast alone is conditionally advised.
  1. PMRT After Neoadjuvant Systemic Therapy
  • Locally advanced disease (cT4 or cN2–3): PMRT is strongly recommended irrespective of pathologic response.
  • Residual nodal disease (ypN+): Strong recommendation for PMRT to the chest wall and regional nodes.
  • Pathologic complete response (ypN0) after cT1–3N1 or cT3N0 disease: PMRT is conditionally recommended for patients with high-risk features (young age, lymphovascular invasion, high residual cancer in breast); omission may be appropriate for select patients with favorable features.
  • cT1–2N0 disease with ypN0 response: PMRT is generally not indicated unless multiple high-risk factors are present such as young age, lymphovascular invasion, and high residual cancer in breast.
  • Positive post-neoadjuvant margins: PMRT is strongly recommended.
  1. Treatment Volumes and Dose-Fractionation
  • Target volumes: Irradiation should encompass the ipsilateral chest wall or reconstructed breast and regional lymphatics (axillary, supraclavicular, and internal mammary nodes). For selected pT3N0 cases, chest wall treatment alone or reconstructed breast alone may be reasonable.
  • Internal mammary coverage: Should be individualized based on tumor location, nodal burden, and risk features.
  • Fractionation: Moderate hypofractionation is preferred for most patients, including those with reconstruction, while conventional fractionation remains acceptable in select circumstances.
  • Boost therapy: A boost to the chest wall or scar may be considered for patients with T4 disease or close/positive margins. A nodal boost is recommended when residual nodal disease is suspected and surgical clearance is incomplete.
  1. Recommended Techniques for PMRT Delivery
  • Planning and delivery: CT-based volumetric planning using 3-dimensional conformal radiation therapy (3D-CRT) is the standard approach.
  • Advanced modalities: Intensity-Modulated Radiation Therapy (IMRT) or Volumetric Modulated Arc Therapy (VMAT) is advised when 3D-CRT cannot meet dosimetric goals; daily image guidance is recommended.
  • Cardiopulmonary sparing: Deep inspiration breath hold (DIBH) should be used whenever it reduces dose exposure to the heart and lungs, supported by real-time monitoring and image verification.
  • Bolus use: Routine use of tissue-equivalent bolus is not recommended. However, bolus may be selectively applied in cases with skin involvement, positive superficial margins, dermal lymphatic invasion, or extensive lymphovascular invasion.

Implementation Considerations

The guideline emphasizes individualized, multidisciplinary decision-making that weighs recurrence risk against treatment-related toxicities.

  • For patients with limited nodal disease (e.g., T1–2N1), omission of PMRT may be reasonable if the expected absolute benefit is low.
  • Patient preferences and quality-of-life considerations should inform discussions, especially regarding reconstructive implications and late toxicity risks.
  • The recommendations endorse shared decision-making across disciplines, highlighting the importance of coordinated care between surgeons, radiation oncologists, and medical oncologists.

Clinical Perspective

The expert panel acknowledged that radiation therapy after mastectomy can meaningfully reduce recurrence and improve survival, but the benefit must be balanced with the individual’s disease profile and values. The update also acknowledges persistent evidence gaps, particularly regarding patients who achieve nodal pathologic complete response after neoadjuvant therapy, underscoring the need for ongoing prospective research.

Postmastectomy Radiation Therapy: An ASTRO-ASCO-SSO Clinical Practice Guideline. Jimenez RB, Abdou Y, Anderson P, et al. J Clin Oncol, 2025;43:3292-3311

Amivantamab–Lazertinib Combination Improves Overall Survival in EGFR-Mutated Advanced NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer. Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations, and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21.

Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib (TAGRISSO®) target the EGFR signaling cascade. However, patients eventually develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors. These patients are often treated with platinum-based chemotherapy as the next line of therapy, resulting in a median Progression Free Survival of about 5 months.

Amivantamab (RYBREVANT®) is a fully human bispecific antibody directed against EGFR and MET receptors. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab down regulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Amivantamab also engages effector cells such as Natural Killer cells, monocytes, and macrophages via its optimized Fc domain. Amivantamab demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, and in patients with MET exon 14 skip mutations, as well as patients with EGFR exon 20 insertion mutations, whose disease progressed on or after platinum-based chemotherapy.

Lazertinib (LAZCLUZE®) is a highly selective, third-generation TKI that penetrates the CNS, with demonstrated efficacy in activating EGFR mutations and acquired T790M “gatekeeper” point mutation. Combining Amivantamab with Lazertinib has been shown to provide a synergistic benefit by targeting the extracellular and catalytic EGFR domains. The combination of Amivantamab plus Lazertinib has shown clinically meaningful and durable antitumor activity in patients with previously untreated or Osimertinib-pretreated EGFR-mutated advanced NSCLC, with clinical activity against a broad spectrum of secondary EGFR and MET molecular alterations and even in tumors of patients without an identified resistance mechanism.

The MARIPOSA trial is an international, randomized Phase 3 study, conducted to assess the efficacy and safety of a combination of Amivantamab and Lazertinib as compared with Osimertinib alone, as first-line treatment in patients with EGFR-mutated advanced NSCLC. In this study, a third arm evaluated Lazertinib monotherapy, to dissect the individual contributions of each component in the combination. This study included 1074 patients (N=1074) with untreated EGFR-mutated advanced NSCLC who were randomly assigned in a 2:2:1 ratio to receive Amivantamab plus Lazertinib (N=429), Osimertinib monotherapy (N=429), or Lazertinib monotherapy (N=216). Amivantamab was administered weekly at a dose of 1050 mg IV (or 1400 mg IV in patients with a body weight of 80 kg or more) for the first 4 weeks (cycle 1), with the first infusion split over a period of 2 days (with 350 mg given on cycle 1, day 1, and the remainder given on cycle 1, day 2). Starting at cycle 2, the same Amivantamab dose was administered every 2 weeks. Osimertinib 80 mg and Lazertinib 240 mg were taken orally daily respectively. The median age was 63 years, majority of patients were Asian women or White and had never smoked. Approximately 60% had EGFR exon 19 deletions and 40% had exon 21 L858R mutations. Randomization was stratified according to EGFR mutation type (ex19del or L858R), Asian race (yes or no), and history of brain metastases (yes or no). Crossover was not included in this trial design. The Primary end point was Progression-Free Survival (PFS) in the Amivantamab plus Lazertinib group as compared with the Osimertinib group, as assessed by Blinded Independent Central Review. Secondary end points included Overall Survival (OS), Objective Response (defined as a Complete or Partial Response), Duration of Response, and Safety.

The authors previously reported that the median PFS (Primary endpoint), was significantly longer in the Amivantamab plus Lazertinib group at 23.7 months compared to 16.6 months in the Osimertinib group ((HR for progression or death = 0.70; P<0.001).

The researchers in this publication reported the results of the protocol-specified final Overall Survival analysis.

The combination of Amivantamab plus Lazertinib demonstrated a significant Overall Survival (OS) advantage over Osimertinib in patients with previously untreated, EGFR-mutated advanced NSCLC. After a median follow-up of 37.8 months, treatment with Amivantamab–Lazertinib reduced the risk of death by 25% compared with Osimertinib (HR=0.75; 95% CI, 0.61–0.92; P=0.005). Estimated 3-year OS rates were 60% with the combination versus 51% with Osimertinib, while 24-month OS was 75% and 70%, respectively. These findings were supported by multiple parametric modeling approaches, indicating a projected survival benefit exceeding one year.

A greater proportion of patients in the Amivantamab–Lazertinib arm remained on treatment at data cutoff (38% vs 28%). The combination also prolonged time to symptomatic progression, time to treatment discontinuation, and time to next therapy relative to Osimertinib. Notably, most patients in both groups who discontinued study therapy received subsequent anticancer treatment, primarily chemotherapy-based regimens.

The superior outcomes observed with Amivantamab–Lazertinib are thought to stem from its dual targeting of EGFR and MET pathways, enabling proactive suppression of key resistance mechanisms. This regimen was also associated with a lower frequency of complex acquired resistance (28% vs 43%) and potentially beneficial immune-mediated activity.

Among participants with baseline brain metastases (approximately 40% in each group), intracranial outcomes favored Amivantamab–Lazertinib and were consistent with those from the MARIPOSA-2 trial, supporting its efficacy in CNS disease.

As expected, Grade ≥3 adverse events were more frequent with Amivantamab–Lazertinib (80% vs 52%), most commonly dermatologic reactions, venous thromboembolism, and infusion-related events. However, no new safety signals emerged. Emerging evidence from other studies, such as COCOON, suggests that prophylactic strategies (enhanced dermatologic care, anticoagulation, and optimized infusion protocols) can substantially reduce these toxicities. Furthermore, a newly approved subcutaneous formulation of Amivantamab markedly lowers infusion-related reactions (13% vs 66%) and reduces administration time from hours to minutes while maintaining efficacy.

Overall, the MARIPOSA trial establishes Amivantamab–Lazertinib as a superior first-line, chemotherapy-free option for patients with EGFR-mutated advanced NSCLC, offering meaningful improvements in both Progression-Free and Overall Survival compared with Osimertinib.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC. Yang JC, Lu S, Hayashi H, et al. for the MARIPOSA Investigators. N Engl J Med 2025;393:1681-1693.

 

Educational Message: Precision Medicine in mCRC: Navigating Complexity in the Era of Targeted Therapy

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Written by: David Cosgrove, MD
Sponsored by: Takeda

Treatment algorithms for patients with metastatic colorectal cancer (mCRC) have become increasingly complex in recent years, as new drug approvals have created additional therapeutic avenues for specific subsets of patients.1 Traditionally, mCRC patients who are fit enough for active therapy would undergo combination cytotoxic chemotherapy utilizing a fluoropyrimidine backbone, until disease progression or unacceptable toxicity. There were a limited number of effective agents available, and specific combinations were selected primarily based on patient comorbidity and toxicity risk, rather than on any tumor-specific factors. Predictably, within this model, response rates were modest and long-term outcomes remained grim.

Today, the majority of mCRC patients will still receive initial treatment with cytotoxic chemotherapy, but diagnostic testing is often incorporated to uncover actionable tumor-specific genomic and/or immune signatures, and these insights may be leveraged to guide the use of specific targeted therapies with improved patient outcomes.2,3,4 Information on tumor mismatch repair status (or microsatellite instability), specific mutations within KRAS/NRAS/BRAF, POLE/POLD-1, overexpression of HER2, and fusions within the NTRK gene all now contribute to treatment decisions at the time of diagnosis and at the time of disease progression where a treatment plan change is indicated. In addition to the recent approval of drugs to target these molecular signatures, an accompanying shift in drug formulation has impacted the mCRC treatment landscape.

Traditional mCRC anticancer agents were formulated for intravenous administration and delivered in an oncology office or hospital infusion suite. Dosing choices, supportive care medications, and treatment adjustments were typically decided by the treating oncologist, in conjunction with infusion nurses and the supporting clinical team; pharmacists played a role in dose confirmation, drug-drug interaction checks and admixture, but direct input beyond that was limited. Today, a majority of the new FDA-approved mCRC therapies are formulated for oral administration. Oral formulations free patients from being tethered to an infusion suite and alter the frequency and personnel involved in treatment touchpoints. The shift to oral formulations has expanded the role of pharmacy teams in patient education, dosing input, dispensing and toxicity assessment, while maintaining their role in drug safety.

Most oncology clinics have had to adapt their staffing and patient flow model to account for this new dynamic. Patient education is a key component to chemotherapy delivery – with traditional intravenous agents, infusion room nurses and oncology nurse educators typically took on this role, performing toxicity assessments and managing side effects chair-side. Traditionally, cytotoxic agents within the same drug class and mechanism of action often exhibited similar toxicity profiles, further simplifying toxicity risk assessments and corresponding patient education. With today’s newer, oral formulations, mechanisms of action and toxicity profiles are more varied – some retain cytotoxic effects, such as capecitabine or tipiracil/trifluridine, whereas others carry very specific toxicity profiles.

As patients may no longer receive treatment in an infusion suite, a significant portion of the responsibility for providing patient-level therapeutic education has been transferred to the pharmacist and pharmacy team. This educational role may be replicated through a series of subsequent treatments, as newer agents are typically delivered sequentially to these patients in later lines of therapy, depending on patient functional status, and suitability for ongoing treatment. Equally as important as pre-treatment education, on-therapy toxicity assessments and potential dose adjustments are now typically shared responsibilities between the treating physician and pharmacy team, and often incorporate patient reported outcomes (PROs) or electronic patient reported outcomes (ePROs)5, as the patient is taking these medications at home, and not under the direct supervision of an infusion nurse team as with the intravenous therapies.

Today’s mCRC treatment model requires close collaboration between the treating oncologist, who has typically developed a long-term therapeutic relationship with the patient and has knowledge of patient-specific factors that will influence treatment tolerance and potential side effects, and the pharmacy team. Lack of a robust communication system and/or improper delegation of tasks pose significant risks to the vulnerable mCRC patient population. To this end, many centers have developed Medically Integrated Pharmacies (MIP) for specialized oncology drugs, which provide direct oversight of quality and safety metrics, enhance adherence, reduce the risk of access delays and deliver appropriate patient-centered care. In our practice, we have seen countless examples of the MIP team lowering barriers to access, expediting delivery and intervening with dose adjustments or concomitant medication changes to ensure our mCRC patients glean as much benefit from their therapies as possible, while maintaining their desired quality of life in the face of a devastating illness.

As crucial as these aspects of care are for the treatment team, financial risk is a major concern for the mCRC patients themselves. Most of the newer therapies approved in the mCRC space in recent years are high-cost agents, and unlike intravenous agents, which were delivered in a medical facility and therefore covered under the medical benefit portion of a patient’s health insurance plan, oral formulation drugs fall under the pharmacy benefit. While we have seen fewer outright denials of coverage for clinically appropriate drugs, challenges remain such as prior authorization, onerous paperwork and especially patient co-payment requirements.

Unfortunately, a number of my patients have also faced barriers from their insurance-mandated, Limited Distribution Network (LDN), which incorporates an external Pharmacy Benefit Manager (PBM) and requires dispensing through a mail-order specialty pharmacy.6 The inability to communicate closely with LDNs and PBM-mandated third-party decision makers has proven challenging – without an on-site team to understand the specifics of a patient’s case, treating providers have limited ability to control dosing adjustments, maintain drug supply and limit care delays. Care delays pose very serious risks, especially in the later stages of mCRC during which dosing flexibility is critical and the majority of patients require dose holds or adjustments on a regular basis. While this issue remains to be solved, having an active MIP in a treatment center with dedicated staff to facilitate co-pay assistance and access to manufacturer- or foundation-level support has proven instrumental in many practices. This resource helps alleviate financial burden and ensures the patient is not forced to make therapy choices based on ability to pay when facing this illness.

In summary, therapeutic management of mCRC has become increasingly complex in recent years. The introduction of new therapeutic agents offers renewed hope for patients dealing with this devastating disease, while simultaneously requiring oncology practices to adjust treatment team infrastructure, and has shifted the onus of delivering patient education to the pharmacy team, who must work in close collaboration with the treating physician. Today’s shift to oral drug formulations introduces financial risks for patients, as at-home medications fall under a prescription drug benefit which may introduce additional barriers such as may PBM-mandated LDNs or specialty pharmacy requirements. The creation of MIPs has significantly enhanced provider communication, reduced barriers to access, expedited therapy delivery, and supported timely dose adjustments or medication changes to help mCRC patients gain the most benefit from treatment. MIPs have also been essential in building a broader administrative team focused on ensuring patients receive maximum benefit from breakthrough anticancer agents, while minimizing both physical and financial toxicity.

References:

  1. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
  2. Yaeger R, Weiss J, Pelster M, et al. Adagrasib with or without Cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med 2023;388:44-54
  3. Kopetz S, Yoshino T, Cutsem EV, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med 2025
  4. Overman MJ, Lonardi S, Wong K, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773-779
  5. Basch E, Deal A, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA 2017 July 11;318(2):197-198
  6. https://www.ncoda.org/oold/

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

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

Background
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

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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

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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&reg;), 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

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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

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

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.