Category: Hem/Onc Updates

FDA Approves LIFYORLI® with nab-Paclitaxel for Platinum-Resistant Ovarian Cancer

RR

SUMMARY: The FDA on March 25, 2026, approved Relacorilant (LIFYORLI®), a glucocorticoid receptor antagonist, in combination with nab-Paclitaxel for the treatment of adults with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic treatment regimens, at least one of which included Bevacizumab.

It is estimated that in the United States, approximately 21,010 women will be diagnosed with ovarian cancer in 2026 and 12,450 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women. It accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival rate of about 20-30%.

Background: Persistent Unmet Need in PROC

Platinum-Resistant Ovarian Cancer (PROC) remains one of the most challenging clinical scenarios in gynecologic oncology, with historically poor outcomes and a median Overall Survival ranging from approximately 10 to 17 months in clinical trials. Therapeutic options have been limited and largely consist of single-agent chemotherapy, with or without Bevacizumab, as well as select biomarker-driven therapies such as Mirvetuximab soravtansine (ELAHERE®) for Folate Receptor α (FRα)-positive disease and Trastuzumab Deruxtecan ENHERTU®) for HER2-positive tumors. However, these targeted approaches apply only to a subset of patients, underscoring the need for broadly applicable strategies.

A Novel Therapeutic Approach: Targeting the Glucocorticoid Receptor

Relacorilant introduces a first-in-class mechanism in ovarian cancer as a Selective Glucocorticoid Receptor Antagonist (SGRA). Cortisol signaling through the glucocorticoid receptor promotes tumor survival by upregulating anti-apoptotic pathways, thereby contributing to chemotherapy resistance. By selectively inhibiting this pathway, Relacorilant enhances tumor sensitivity to cytotoxic agents. Importantly, the glucocorticoid receptor is expressed in more than 95% of epithelial ovarian cancers, distinguishing this approach from biomarker-restricted therapies and enabling a potential “all-comers” strategy.

ROSELLA Trial Design

The Phase 3 ROSELLA trial was a global, randomized, open-label study evaluating Relacorilant in combination with nab-Paclitaxel versus nab-Paclitaxel alone in patients with Platinum-Resistant Ovarian Cancer (PROC).

  • Study Population: 381 patients with 1-3 prior lines of therapy; all previously treated with Bevacizumab
  • Intervention: Relacorilant 150 mg orally,  day before, day of, and day after nab-Paclitaxel plus nab-Paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of each 28-day cycle (N=188)
  • Comparator: Nab-paclitaxel monotherapy 100 mg/m2 IV on the aforementioned schedule (N=193)
  • Primary Endpoints: Progression-free survival (PFS) by blinded independent central review and overall survival (OS)
  • Follow-up: Median of 24.8 months

Baseline characteristics were well balanced, with a heavily pretreated population, 61% had prior PARP inhibitor exposure and 44% had received three prior lines of therapy.

Efficacy: Dual Primary Endpoints Achieved

ROSELLA met both Primary endpoints, demonstrating clinically meaningful improvements in survival outcomes:

Overall Survival

  • Median OS: 16.0 vs 11.9 months
  • Hazard ratio (HR): 0.65 (35% reduction in risk of death)
  • 18-month OS: 46% vs 27%
  • Statistical significance: P=0.0004

Progression-Free Survival

  • Median PFS: 6.5 vs 5.5 months
  • HR: 0.70
  • Statistical significance: P≈0.008

The survival benefit was consistent across all prespecified subgroups, including patients with poor prognostic features. Notably, second PFS was also improved, suggesting that the benefit of Relacorilant extends beyond first progression.

Safety and Tolerability

The addition of Relacorilant did not introduce new safety signals and was generally well tolerated. The adverse event profile was consistent with known toxicities of nab-Paclitaxel. Common adverse events were neutropenia, anemia, fatigue, and nausea. Overall, the regimen demonstrated a favorable risk–benefit profile.

Clinical Context and Positioning

The results of ROSELLA are particularly notable in the context of prior studies in PROC. For example:

  • The addition of Bevacizumab in earlier trials improved PFS but not Overall Survival
  • Immune checkpoint inhibitors have shown limited benefit in unselected PROC populations, with modest gains in select biomarker-defined subsets
  • Biomarker-driven therapies such as FRα- and HER2-targeted agents remain restricted to smaller patient populations

In contrast, Relacorilant offers a biomarker-independent approach, with broad applicability and a demonstrated survival advantage. Furthermore, all patients in ROSELLA had prior Bevacizumab exposure, reflecting contemporary treatment patterns and enhancing the real-world relevance of the findings.

Mechanistic and Translational Insights

Exploratory analyses from earlier-phase studies suggest that the benefit of Relacorilant is independent of the level of glucocorticoid receptor expression, supporting its use without biomarker selection. Ongoing and future studies will further refine understanding of predictive biomarkers, including receptor expression, cortisol dynamics, and pathway activation signatures.

Limitations

Key limitations of the ROSELLA trial include:

  • Open-label design (mitigated by objective endpoints and blinded PFS assessment)
  • Limited data in patients with more than three prior lines of therapy
  • Underrepresentation of certain racial and ethnic groups
  • Limited conclusions for rare histologic subtypes

Despite these considerations, the robustness of the dataset, including mature OS data and balanced post-progression therapies, supports the validity of the findings.

Clinical Implications

ROSELLA represents a meaningful advance in the management of Platinum-Resistant Ovarian Cancer (PROC). The combination of Relacorilant and nab-Paclitaxel is the first regimen in this setting to demonstrate a significant improvement in both Progression-Free and Overall Survival compared with a weekly taxane backbone.

With a 35% reduction in mortality risk and a median Overall Survival gain exceeding 4 months, this regimen has the potential to redefine the treatment paradigm for PROC, particularly given its applicability without the need for biomarker testing.

Key Takeaways

  • Relacorilant introduces a novel mechanism targeting glucocorticoid receptor–mediated chemotherapy resistance
  • ROSELLA demonstrated significant improvements in both OS and PFS
  • Benefit was consistent across subgroups, including heavily pretreated patients
  • The regimen is well tolerated with no new safety concerns
  • Represents a potential new standard of care in Platinum-Resistant Ovarian Cancer without biomarker restriction

Overall survival with relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): a phase 3 randomised controlled trial. Lorusso D, Gladieff L, O’Malley D et al. The Lancet 2026; DOI: 10.1016/S0140-6736(26)00462-9

Teclistamab Plus Daratumumab Sets a New Standard of Care in Early Relapsed or Refractory Myeloma

RR

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,000 new cases will be diagnosed in 2026, and 10,850 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.

Relapsed or Refractory Multiple Myeloma (RRMM) remains a complex clinical challenge, even as therapeutic options continue to expand. Progressive immune dysfunction, cumulative treatment toxicity, and repeated relapses often limit the durability of benefit with conventional salvage regimens. Moreover, the increasingly effective frontline landscape has raised the bar for second- and later-line therapy, leaving fewer highly active, well-tolerated options for patients early in relapse.

BCMA-directed therapies have transformed expectations in advanced disease, particularly with CAR-T cell approaches demonstrating deep responses and prolonged disease control. However, manufacturing timelines, resource intensity, and patient fitness requirements limit universal access. Consequently, there is a critical need for off-the-shelf, immunotherapy-based regimens that deliver CAR-T–like efficacy with broader applicability.

Teclistamab (TECVAYLI®), a bispecific T-cell engaging antibody targeting CD3 on T cells and BCMA on myeloma cells, has previously shown meaningful and durable responses in heavily pretreated RRMM. Daratumumab (DARZALEX®), an anti-CD38 monoclonal antibody, remains a foundational therapy across all disease stages, offering both direct antimyeloma activity and immune modulation. Preclinical and clinical observations suggest that Daratumumab-mediated depletion of immunosuppressive cellular subsets enhances T-cell fitness, providing a strong biological rationale for combination with BCMA-directed bispecific antibodies.

The MajesTEC-3 trial was designed to test whether combining Teclistamab with Daratumumab could improve outcomes compared with established Daratumumab-based regimens in patients with earlier-line RRMM.

Study Design and Patient Population

MajesTEC-3 (NCT05083169) is an ongoing, randomized, open-label, Phase 3 trial conducted across 150 centers in 20 countries. Eligible patients had relapsed or refractory multiple myeloma after one to three prior lines of therapy, including prior exposure to both an immunomodulatory agent and a proteasome inhibitor. Patients with prior BCMA-directed therapy or anti-CD38–refractory disease were excluded.

A total of 587 patients were randomized 1:1 to receive either:

  • Teclistamab plus subcutaneous Daratumumab, or
  • Investigator’s choice of standard Daratumumab-based therapy, consisting of Daratumumab and Dexamethasone combined with either Pomalidomide (DPd) or Bortezomib (DVd).

Randomization was stratified by choice of control regimen, International Staging System stage, prior exposure to anti-CD38 antibodies, and number of prior treatment lines. The median patient age was approximately 64–65 years, with a median of two prior lines of therapy. Importantly, more than one-third of enrolled patients had high-risk cytogenetic features, reflecting a clinically relevant population.

Treatment Administration: A Patient-Centered, Steroid-Sparing Approach

Patients in the investigational arm received subcutaneous Teclistamab using a step-up dosing strategy, followed by a progressively extended dosing interval, transitioning to monthly administration from cycle 7 onward. Daratumumab was administered subcutaneously according to its approved schedule.

Notably, the regimen became steroid-free after cycle 1, an important quality-of-life consideration for patients requiring long-term therapy. Infection prophylaxis, immunoglobulin supplementation, and monitoring of IgG levels were mandated, with protocol amendments reinforcing best practices for infection prevention during BCMA-directed therapy. The Primary end point was Progression-Free Survival (PFS), as assessed by an Independent Review Committee.

Primary Endpoint: Striking Improvement in Progression-Free Survival

At a median follow-up of 34.5 months, Teclistamab plus Daratumumab demonstrated a highly significant and clinically transformative improvement in PFS compared with DPd or DVd.

  • The estimated 36-month PFS rate was 83.4% with Teclistamab–Daratumumab versus 29.7% with standard Daratumumab-based therapy.
  • This translated into an 83% reduction in the risk of disease progression or death (HR 0.17; 95% CI, 0.12–0.23; P<0.001).
  • The prespecified boundary for superiority was crossed at the first interim analysis.

Importantly, the PFS advantage was consistent across all prespecified and clinically relevant subgroups, including patients with high-risk cytogenetics and those treated in earlier versus later relapse.

Depth and Durability of Response

Beyond delaying progression, Teclistamab–Daratumumab induced exceptionally deep and durable responses:

  • Complete Response or better was achieved in 81.8% of patients receiving the combination, compared with 32.1% in the control arm.
  • Overall Response Rates were also higher (89.0% vs. 75.3%).
  • Rates of Minimal Residual Disease negativity at a sensitivity of 10⁻⁵ were more than threefold higher with Teclistamab–Daratumumab (58.4% vs. 17.1%).

Responses occurred rapidly, with a median time to first response of just over one month, and deepened over time. At three years, nearly 90% of responders in the investigational arm remained in response, suggesting the emergence of a plateau in disease control.

Overall Survival and Symptom Outcomes

Although follow-up for overall survival continues, early analyses favored Teclistamab–Daratumumab, with a high proportion of patients remaining alive beyond two years. Improvements were also observed in time to worsening of myeloma-related symptoms, underscoring the regimen’s clinical and patient-reported benefit.

Safety and Tolerability: Manageable With Established Protocols

The safety profile of Teclistamab–Daratumumab was consistent with the known risks of BCMA-directed bispecific antibodies and Daratumumab. Serious adverse events occurred more frequently in the investigational arm, driven primarily by cytopenias and infections.

  • Cytokine Release Syndrome was common but predominantly low grade and largely confined to the step-up dosing period.
  • Importantly, the incidence of CRS was lower than that reported with Teclistamab monotherapy, supporting a favorable interaction between the two agents.
  • Fatal adverse events were infrequent and decreased following protocol-reinforced infection-prevention strategies.

The trial highlights the critical importance of early immunoglobulin replacement, antimicrobial prophylaxis, and vigilant monitoring, now well established in guidelines for patients receiving BCMA-targeted therapies.

Context Within the Evolving Treatment Landscape

The magnitude of benefit observed with Teclistamab–Daratumumab is particularly notable given the strong performance of the control arm, which exceeded historical expectations from prior DPd and DVd studies. Even in this context, the combination delivered superior depth, durability, and consistency of response. As CAR-T therapies move earlier in the disease course, off-the-shelf immunotherapies such as Teclistamab–Daratumumab offer a complementary strategy, one that combines accessibility, scalability, and sustained disease control. Monthly dosing after the initial treatment phase further supports feasibility in community oncology settings.

Clinical Implications

The MajesTEC-3 trial establishes Teclistamab plus Daratumumab as a highly effective immunotherapy-based option for patients with early relapsed multiple myeloma, delivering unprecedented Progression-Free Survival and deep molecular responses without the logistical barriers of cellular therapy. With appropriate supportive care and infection-prevention strategies, this regimen may meaningfully reset expectations for long-term disease control in a population historically characterized by inevitable relapse.

Conclusion

In patients with multiple myeloma who had received one to three prior lines of therapy, Teclistamab combined with Daratumumab significantly outperformed established Daratumumab-based regimens, offering durable disease control, deep responses, and a manageable safety profile. These findings position Teclistamab–Daratumumab as a potential new standard in earlier-line Relapsed or Refractory Multiple Myeloma, and signal continued progress toward prolonged survival in this traditionally incurable disease.

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma. Costa LJ,  Bahlis NJ, Perrot A, et al. for the MajesTEC-3 Trial Investigators. N Engl J Med 2026;394:739-752.

Adjuvant Immunotherapy Improves Outcomes in Stage III dMMR Colon Cancer: Results from the ATOMIC Trial

RR

SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 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. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of CRC in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of CRC cases diagnosed in people under age 50.

It is estimated that 25% of patients diagnosed with Stage III disease have positive regional lymph nodes. These patients often receive 6 months of fluoropyrimidine-based adjuvant chemotherapy. The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Approximately 10% to 15% of nonmetastatic CRCs exhibit deficient mismatch repair (dMMR), accounting for an estimated 330,000 cases annually worldwide. Majority of dMMR tumors are sporadic, although some are associated with germline variants in genes that cause Hereditary Nonpolyposis Colon Cancer (HNPCC) or Lynch syndrome. These dMMR tumors are often seen in women, more likely to arise in the right side of the colon, and tend to grow large before they metastasize. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. These tumors respond poorly to Fluoropyrimidine-based chemotherapy alone, especially in the adjuvant setting. While immune checkpoint inhibitors are approved for dMMR colorectal cancer in the metastatic setting, their benefit in earlier stages, particularly post-resection, had not been previously established in a prospective trial.

Atezolizumab (TECENTRIQ®) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors expressed on activated T cells. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells.

The Phase 3 ATOMIC trial (NCT02912559), sponsored by the National Cancer Institute and conducted across multiple centers including NCTN sites and the German AIO group investigated whether the addition of Atezolizumab, a PD-L1 checkpoint inhibitor, to standard adjuvant chemotherapy could improve Disease-Free Survival (DFS) in patients with resected Stage III dMMR colon adenocarcinoma.

Study Design and Population
The trial enrolled 712 patients with surgically resected Stage III colon cancer confirmed to have dMMR. Eligibility included patients aged 12 years and older (one pediatric patient was enrolled). MMR status was initially determined locally by immunohistochemistry and subsequently confirmed centrally. Participants were randomized 1:1 to receive:

  • Control arm: mFOLFOX6 (5-Fluorouracil, Leucovorin, and Oxaliplatin) for 6 months (N=357)
  • Experimental arm: mFOLFOX6 plus Atezolizumab (840 mg IV every 2 weeks) for 6 months, followed by maintenance Atezolizumab monotherapy for an additional 6 months (N=355)

Median patient age was 64 yr. 55.1% were female, 84% of tumors were proximal, 46% were clinical low risk (T1-3N1) and 54% were high risk (T4 and/or N2). Stratification was based on nodal status (N1/N1c vs N2), tumor depth (T1-T3 vs T4), and tumor location (proximal vs distal colon). The Primary endpoint was Disease-Free Survival (DFS). Secondary endpoints included Overall Survival (OS) and Adverse Event (AE) profile.

Results and Efficacy
After a median follow-up of 40.9 months, the Primary endpoint of DFS was significantly improved in the Atezolizumab arm. The 3-year DFS was 86.3% in the combination arm vs 76.2% in the mFOLFOX6-only arm (Hazard Ratio (HR)=0.50; P<0.001, crossing the prespecified efficacy boundary. This represents a 50% relative reduction in the risk of recurrence or death with the addition of Atezolizumab. Importantly, the benefit was consistent across predefined subgroups, including patients over 70 years old and those with both low and high-risk disease (based on T and N-stage). Tumor location, patient sex, and race did not impact the observed treatment benefit.

Safety and Tolerability
Grade 3 or more treatment-related adverse events occurred in 84.1% of patients receiving Atezolizumab plus chemotherapy, compared to 71.9% in those receiving chemotherapy alone. Although the addition of Atezolizumab resulted in a modest increase in toxicity, the side effect profile was consistent with prior experience with checkpoint inhibitors and considered manageable.

Clinical Implications
The ATOMIC trial is the first large, prospective, randomized Phase 3 study to demonstrate a clear benefit from adding immunotherapy to adjuvant chemotherapy in Stage III dMMR colon cancer. As highlighted by the investigators, current adjuvant treatment recommendations for dMMR tumors have historically been extrapolated from studies in mismatch repair–proficient populations or based on retrospective analyses. The robust DFS improvement observed here provides definitive evidence supporting a new treatment paradigm for this molecularly defined subgroup.

There was no significant difference in Overall Survival noted at this first analysis at a median follow-up of 40.9 months, and longer follow-up is required for mature estimates. Future OS analyses may be complicated by the use of subsequent checkpoint inhibitors in patients who recur. The researchers emphasized the clinical relevance of these findings, noting their applicability to both sporadic dMMR cancers and Lynch syndrome associated tumors.

Future Directions
The ATOMIC trial sets a new benchmark for adjuvant therapy in dMMR colon cancer. However, important questions remain. Chief among them is the optimal duration of immunotherapy in this setting. Atezolizumab was administered for nearly a year, including maintenance. Ongoing research should clarify whether such prolonged treatment is necessary or if shorter regimens could maintain efficacy while reducing toxicity.

Moreover, while this study confirms benefit in the postoperative setting, parallel efforts are warranted to evaluate checkpoint inhibition in the neoadjuvant context. Encouraging responses such as those seen in small studies of neoadjuvant immunotherapy in dMMR rectal cancer highlight the need to explore earlier immunotherapeutic intervention in colon cancer as well.

Conclusion
The ATOMIC trial provides compelling evidence that incorporating Atezolizumab into adjuvant therapy improves Disease-free survival in patients with Stage III dMMR colon cancer, marking a major advancement in the management of this biologically distinct subset. Given these results, the combination of Atezolizumab and mFOLFOX6 should be considered the new standard of care in this setting. This trial also exemplifies the power of cooperative group studies in driving progress for biomarker-defined subsets within common malignancies.

Atezolizumab plus FOLFOX for Stage III Mismatch Repair–Deficient Colon Cancer. Sinicrope F, Ou F-S, Arnold D, et al. N Engl J Med 2026;394:1155-1166.

DESTINY-Breast05: A New Direction in Postneoadjuvant Care for High-Risk HER2-Positive Early Breast Cancer

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

Background: Escalation Strategies in Residual Disease

The management of HER2-positive early breast cancer has undergone a profound transformation over the past two decades, driven by the integration of HER2-directed therapies across disease stages. In patients with Stage II–III disease, neoadjuvant therapy has become the standard treatment approach, enabling early assessment of treatment response and guiding postoperative therapy. Despite high rates of pathologic Complete Response (pCR) with contemporary neoadjuvant regimens, a clinically significant subset of patients exhibits residual invasive disease at surgery, an established marker of elevated recurrence risk.

The paradigm of risk-adapted postneoadjuvant therapy was firmly established by the KATHERINE trial, in which Trastuzumab emtansine (T-DM1-KADCYLA&reg;) demonstrated a substantial improvement in Invasive Disease–Free Survival (IDFS) and Overall Survival (OS), compared with Trastuzumab alone. However, outcomes in higher-risk subgroups, particularly those with node-positive or extensive residual disease remain suboptimal, and CNS relapses continue to represent an unmet need.

Trastuzumab deruxtecan (T-DXd-ENHERTU&reg;), a next-generation HER2-directed antibody–drug conjugate, has consistently demonstrated superior efficacy over T-DM1 in the metastatic setting, including activity in CNS disease. These data provided a strong rationale to evaluate whether T-DXd could further improve outcomes in the curative-intent, postneoadjuvant setting.

Trial Design and Patient Population

DESTINY-Breast05 is a global, Phase III, open-label, randomized trial evaluating T-DXd versus T-DM1 in patients with HER2-positive early breast cancer and residual invasive disease following neoadjuvant therapy, enriched for high-risk features.

Eligible patients had:

  • Residual invasive disease in breast and/or axillary nodes
  • Either inoperable disease at presentation or node-positive disease after neoadjuvant therapy
  • Prior receipt of standard neoadjuvant systemic therapy, including taxane-based chemotherapy and HER2-targeted therapy

A total of 1635 patients were randomized 1:1 to:

  • T-DXd (5.4 mg/kg) every 3 weeks (N=818)
  • T-DM1 (3.6 mg/kg) every 3 weeks (N=817)
    for up to 14 cycles.

The Primary endpoint was invasive DFS, with key Secondary endpoints including DFS, distant recurrence, CNS outcomes, and Overall Survival (OS). Notably, this trial enrolled a higher-risk population than prior studies:

  • ~52% presented with inoperable disease at disease presentation
  • ~81% had node-positive disease after neoadjuvant therapy
  • ~79% received dual HER2 blockade preoperatively


Efficacy: A New Benchmark for Invasive Disease–Free Survival

At a median follow-up of approximately 30 months, T-DXd demonstrated a clinically and statistically significant improvement in outcomes compared with T-DM1:

    • IDFS events or death: 6.2% (T-DXd) vs. 12.5% (T-DM1); Hazard ratio (HR): 0.47 (P<0.001)
    • 3-year IDFS: 92.4% vs. 83.7%
    • 3-year DFS: 92.3% vs. 83.5% (HR: 0.47)

The benefit was consistent across prespecified subgroups, including hormone receptor–positive disease driven largely by a reduction in distant recurrences, the dominant mode of failure. Importantly, the distant recurrence: 5.1% vs. 9.9% and CNS recurrence was numerically lower with T-DXd (2.1% vs. 3.1%)

Although Overall Survival data remain immature, the magnitude of IDFS improvement strongly supports a meaningful long-term benefit.

Safety Profile: Balancing Efficacy with Toxicity

The safety profiles of both agents were consistent with prior experience, though distinct in nature. The common adverse events with T-DXd included nausea (71%), neutropenia, vomiting and alopecia. Approximately 50% of patients had grade ≥3 adverse events. T-DM1 was associated with hepatotoxicity (elevated transaminases) and thrombocytopenia.

Key Safety Signal: Interstitial Lung Disease (ILD)

The most clinically significant toxicity associated with T-DXd remains ILD. The incidence was 9.6% (T-DXd) vs. 1.6% (T-DM1). They were mostly grade 1–2, but grade ≥3 events occurred and two treatment-related deaths reported. The trial incorporated proactive ILD monitoring, including serial low-dose chest CT imaging, enabling early detection. Importantly no increased ILD risk was observed with concurrent radiotherapy. Multidisciplinary evaluation is critical to distinguish ILD from radiation pneumonitis.

Clinical Context: Positioning Within Current Practice

These findings represent a clear evolution beyond the KATHERINE standard, particularly in a more contemporary, higher-risk population treated with modern neoadjuvant regimens.

Implications for Clinical Practice

  • T-DXd emerges as the preferred postneoadjuvant therapy for patients with:
    • Residual invasive disease
    • Node-positive or otherwise high-risk features
  • T-DM1 remains relevant for:
    • Lower-risk residual disease
    • Patients unable to tolerate T-DXd

Evolving Treatment Paradigms and Open Questions

DESTINY-Breast05 raises several important considerations regarding treatment sequencing and personalization:

  1. Neoadjuvant Integration of T-DXd

Emerging data suggest that incorporating T-DXd earlier in the disease course may increase pCR rates and potentially reduce treatment duration. However, optimal sequencing remains undefined.

  1. Biomarker-Driven Personalization

Future strategies may incorporate circulating tumor DNA (ctDNA) clearance, HER2 expression heterogeneity and hormone receptor co-expression, to better tailor escalation vs. de-escalation approaches.

  1. CNS Disease Prevention

Although early signals suggest reduced CNS recurrence with T-DXd, longer follow-up is required to confirm whether this translates into durable CNS protection.

  1. Duration of Therapy

With a median of ~10 cycles delivered in this study, the optimal duration of T-DXd in the curative setting remains to be defined.


Limitations

  • Open-label design
  • Relatively short follow-up for survival endpoints
  • Underrepresentation of Black patients
  • Immature Overall Survival and CNS-specific outcomes

Conclusions

DESTINY-Breast05 establishes Trastuzumab deruxtecan as a new standard of care in the postneoadjuvant management of high-risk HER2-positive early breast cancer with residual disease. The trial demonstrates a substantial and clinically meaningful improvement in Invasive Disease–Free Survival, a reduction in distant recurrence and manageable but clinically significant toxicity, particularly interstitial lung disease.

As the field moves toward increasingly personalized, response-adapted strategies, T-DXd represents a major advance, while underscoring the need for vigilant toxicity monitoring and multidisciplinary care in the curative setting.

Trastuzumab Deruxtecan in Residual HER2-Positive Early Breast Cancer. Loibl S, Park YH, Shao Z, et al. for the DESTINY-Breast05 Trial Investigators. N Engl J Med 2026;394:845-857.

ASCO Guideline Update on WBC Growth Factors

RR

SUMMARY: Neutropenia is a clinical challenge and its associated complications, such as febrile neutropenia and infection, are significant toxicities resulting from myelosuppressive chemotherapy. These complications necessitate immediate evaluation and treatment, frequently requiring empirical antibiotics and hospitalization. Hematopoietic Colony-Stimulating Factors (CSFs) are used to decrease the severity and duration of neutropenia and are recommended for patients at high risk of neutropenia due to chemotherapy regimens, age, or comorbidities, thereby reducing the risk of febrile neutropenia. Further, they are also utilized for stem-cell mobilization in transplantation (SCT). ASCO guidelines (updated in 2015) provided evidence-based guidance on the appropriate use of CSFs in adults receiving cancer treatment.

The present ASCO guideline update on use of hematopoietic Colony-Stimulating Factors (CSFs) in cancer patients was based on review of 33 randomized controlled trials and 16 meta-analyses, and systematic reviews, that addressed use of CSFs for the prevention or treatment of neutropenic events, published from September 1, 2014, to August 22, 2025.

Guideline Questions and Recommendations

Clinical Question: What factors should influence the decision to administer primary prophylaxis of febrile neutropenia with a CSF?

Recommendation:
1.1. Patients should be offered primary prophylaxis with a G-CSF when the risk of febrile neutropenia, secondary to a chemotherapy regimen, is equal to or greater than approximately 20%, unless an alternative chemotherapy regimen with comparable efficacy and safety that does not require G-CSF is available.

1.2. Among patients who receive chemotherapy with a lower risk of febrile neutropenia, primary prophylaxis with a G-CSF should be offered if a patient is at high risk of complications from febrile neutropenia based on age, comorbidities, or disease characteristics, and no alternative chemotherapy regimen with comparable efficacy and safety that does not require G-CSF is available.

1.3. If G-CSF is not affordable or available, antibiotic prophylaxis may be offered.

Qualifying statement for Recommendation 1.3: Antibiotic prophylaxis is not a preferred option due to the risk of antimicrobial resistance, disturbance of gut microbiome, Clostridioides difficile infection, and other adverse effects, which may outweigh the benefits of antibiotic use in many cases.

Clinical Question: What factors should influence the decision to administer secondary prophylaxis of febrile neutropenia with a CSF?

Recommendation:
2.1. Secondary prophylaxis with a CSF is recommended for patients who experienced a neutropenic complication from a previous cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose or treatment delay may compromise cure rates or survival outcomes. In many clinical situations, dose reduction or delay may be a reasonable alternative or additional strategy.

Clinical Question: Are there circumstances in which CSFs may be administered for the treatment of febrile neutropenia?

Recommendation:
3.1. A CSF should not be routinely used for patients with neutropenia who are afebrile.

3.2. A CSF should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia.

3.3. A CSF may be offered in patients with fever and neutropenia who are at high risk for infection-associated complications or who have prognostic factors that are predictive of poor clinical outcomes.

Clinical Question: What is the role of CSFs as adjuncts to progenitor-cell transplantation?

Recommendation:
4.1. A CSF should be used alone, after chemotherapy, or in combination with a CXCR4 inhibitor (Plerixafor or Motixafortide), to mobilize peripheral-blood progenitor cells. Choice of mobilization strategy depends in part on the type of cancer and type of transplantation.

4.2. A CSF should be administered after autologous SCT to reduce the duration of severe neutropenia.

4.3. A CSF may be administered after allogeneic SCT to reduce the duration of severe neutropenia.

Clinical Question: Should CSFs be avoided in patients receiving concomitant chemotherapy and radiation therapy?

Recommendation:
5.1. CSFs are not recommended in patients receiving concomitant chemotherapy and radiation therapy, particularly involving the mediastinum.

Note for Recommendation 5.1: There is little evidence regarding use of CSFs in patients receiving radiation therapy alone.

Clinical Question: Do CSFs differ in efficacy or safety?

Recommendation:
6.1. Filgrastim, Pegfilgrastim, Eflapegrastim, and biosimilars can be used for prophylaxis or treatment of febrile neutropenia. The choice of agent depends on cost, patient convenience, availability, accessibility, health system context, disease subtype, and treatment regimen.


The following factors increase the risk for Febrile Neutropenia in addition to chemotherapy regimen and type of malignancy

  • Age 65 years or older or frailty based on geriatric assessment
  • Advanced disease
  • Previous chemotherapy or radiation therapy
  • Preexisting neutropenia or bone marrow involvement with tumor
  • Active or recent infection
  • Colonization with multidrug-resistant organisms
  • Open wounds or recent surgery
  • Poor performance status
  • Poor nutritional status or low BMI
  • Poor renal function
  • Liver dysfunction, most notably elevated bilirubin
  • Cardiovascular disease
  • HIV
  • Multiple comorbid conditions

WBC Growth Factors: ASCO Guideline Update. Gyawali B, Bohlke K, Dickter JK, et al. J Clin Oncol. 2026; 44:812-824.

Extrapulmonary Neuroendocrine Carcinoma: Clinical Overview and Advances in DLL3 Targeted Therapy

RR

Written by: Dr. Eric Lander
Sponsored by Boehringer Ingelheim

Extrapulmonary neuroendocrine carcinomas (EP-NECs) are rare and phenotypically aggressive malignancies arising from neuroendocrine cells. While EP-NECs are currently managed with conventional chemotherapy in most cases, numerous therapies are in development which may show promise to improve disease management and prognosis for patients.

EP-NECs originate from neuroendocrine cells located in many different organs, most commonly arising from the GI tract or pancreas, followed by genitourinary tract and gynecologic organs [1]. NECs are often confused with neuroendocrine tumors (NETs). Though both NETs and NECs arise from epithelial neuroendocrine cells expressing pan-cytokeratin, synaptophysin, and Chromogranin A, by definition NETs are well-differentiated while NECs are poorly differentiated. Though NETs can be defined as grades 1-3, they are more commonly grade 1-2 (Ki-67 <20%); NECs must be grade 3 (Ki-67 ≥20% and/or mitotic count >20 per mm2), and the Ki-67 usually exceeds 50%. The remainder of this article will focus on EP-NECs and will not include discussion about grade 3 NETs. Please reference the NCCN Guidelines or the Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society (NANETS) to learn about management strategies for G3 NETs [2].

EP-NECs most commonly result from TP53 and RB1 inactivation, similar to small cell lung neuroendocrine carcinoma (SCLC), though EP-NECs often contribute their own unique genetic mutational background (e.g. BRAF, KRAS, PIK3CA, APC, etc.) based on their site of origin, unlike most SCLC cases. If the primary site of EP-NEC origin is unknown, as occurs in up to one third of cases, encouraging pathology to perform transcription factor IHC can facilitate a site of origin assignment. Certain transcription factors (in parentheses) are unique to each organ: midgut (CDX2); pancreas (PAX6, PAX8, islet 1, or PR); rectum (SATB2); lung (OTP, TTF-1). Delineating site of origin is of particular importance as EP-NEC may be treated according to its primary site of origin at time of relapse following platinum-based chemotherapy.

Since EP-NECs are aggressive, high-grade carcinomas, patients most commonly have metastatic disease at the time of presentation. Many patients initially present for the first time to the hospital because some symptom of their disease, such as severe pain or fracture in the case of bone metastases, necessitated their presentation to the emergency room. Initial workup following tissue diagnosis should consist of imaging of the chest/abdomen/pelvis with CT or FDG-PET/CT imaging. Notably, high grade NECs have lower somatostatin receptor (SSTR) expression than NETs; therefore, FDG is preferred over SSTR-PET radiotracers [3, 4]. For EP-NECs, the incidence of brain metastases is less than 2%; thus, brain MRI should only be considered at time of diagnosis in cases of high disease burden or in symptomatic patients [5].

For molecular workup, since many EP-NECs can harbor mutations in BRAF (particularly in colorectal EP-NECs) and tumor agnostic indications for other therapies exist, NGS testing may be considered. Mismatch repair (MMR) testing or MSI testing is also recommended since 10% of NECs are deficient MMR, opening the door to immunotherapies as therapeutic options. Delta-like ligand 3 (DLL3) is an emerging target in EP-NEC; reserving tissue for DLL3 IHC is recommended in cases where patients may enroll in a clinical trial investigating a drug targeting DLL3 – which will be discussed later.

For the management of localized EP-NEC, discussion at tumor board is recommended to provide a multidisciplinary treatment approach. Data surrounding the long-term curative potential of surgery is mixed based on the tumor site of origin when surgery is often invasive, and patients remain at high risk of metastatic disease recurrence. For this reason, neoadjuvant or adjuvant platinum-based chemotherapy may be paired with surgery. Many experts will favor neoadjuvant platinum/etoposide chemotherapy to test the biology of the disease and decrease theoretical risk of micro-metastasis prior to surgery. However, many patients will present to medical oncology following tumor resection, in which case adjuvant chemotherapy may be discussed with eligible patients. Otherwise, definitive chemoradiation for organ preservation may be considered with platinum plus etoposide as the recommended radiosensitizing agents. The accruing French NEONEC trial will prospectively test neoadjuvant chemotherapy followed by surgery or chemoradiation in patients to hopefully offer clarity regarding the optimal multidisciplinary approach [6].

In the case of metastatic EP-NECs, the treatment paradigm initially parallels that of SCLC. Enrollment in clinical trial when available or platinum plus etoposide for four to six cycles remains the current first-line standard-of-care. Unlike SCLC, atezolizumab is not written into the NCCN guidelines for EP-NEC. EP-NEC patients were not included in the IMpower133 trial, and a subsequent retrospective study of a small EP-NEC patient cohort did not demonstrate a PFS or OS benefit of adding atezolizumab to platinum-based chemotherapy [7]. Larger patient numbers in a prospective trial are likely required to detect a benefit of atezolizumab—an ongoing phase II/III SWOG trial is investigating platinum/etoposide with or without atezolizumab to address this evidence gap [8].

Most patients will achieve significant initial tumor shrinkage or disease control in response to carboplatin or cisplatin plus etoposide, especially if Ki-67 ≥ 55%, but the tumor response is not durable in most cases, and tumors are less responsive to chemotherapy upon disease progression. There is currently no standard second- or third-line treatment option for EP-NEC. When assessing patients’ treatment goals and performance status, best supportive care with hospice is a very reasonable approach in light of EP-NEC’s generally poor prognosis upon time of disease relapse.

When second-line and beyond therapy lines are being considered, enrollment in clinical trial is the preferred option for eligible patients. If patients experienced a durable response lasting at least 6 months following first-line platinum/etoposide, rechallenge may be considered. Among patients with gastrointestinal and pancreatic EP-NECs, second-line treatment with FOLFIRI has the most prospective data and lends a 6-month overall survival rate of 60% [9], while gynecologic EP-NEC has data for topotecan, taxanes, single agent irinotecan, or the combination of topotecan, paclitaxel, and bevacizumab that provided an 8-month median PFS in a small retrospective cohort [10]. For patients with dMMR/MSI-H or TMB-High disease, ipilimumab/nivolumab or pembrolizumab may be considered where dual checkpoint inhibition potentially yields a higher response rate [11]. For patients with BRAF V600E mutations, a STAR trial through SCRI is available to open at most US Oncology practices employing BRAF/MEK inhibition with dabrafenib/trametinib and includes patients with EP-NEC [12].

The most promising emerging therapies for EP-NEC remain those in clinical trials targeting DLL3—this assertion is based on extrapolation of promising data from the DeLLphi trials using tarlatamab in SCLC, and initial results investigating obrixtamig in SCLC and EP-NEC. Both tarlatamab and obrixtamig are DLL3/CD3 bispecific T-cell engagers. While DLL3 is expressed in approximately 90% of SCLC, rates of DLL3 expression in EP-NEC are lower [13]. Despite this, most patients with negative DLL3 expression in the DeLLphi-301 trial employing tarlatamab in refractory SCLC still experienced disease control with tarlatamab monotherapy [14]. Emerging therapeutics targeting DLL3 are mostly either DLL3/CD3 bispecific T-cell engagers or DLL3-targeting antibody-drug conjugates.

There are several clinical trials investigating DLL3/CD3 bispecific T-cell engagers and DLL3 antibody-drug conjugates in EP-NEC patients. At the time of writing, three different phase I studies are open and actively recruiting through US Oncology Network practices that include patients with EP-NEC, all of which require tissue for DLL3 IHC testing [15, 16, 17]. Among investigational DLL3/CD3 bispecific agents, Boehringer Ingelheim’s obrixtamig has shown promising results.  Data presented in 2025 from the phase I dose-escalation trial of obrixtamig showed that heavily-pretreated EP-NEC patients with high DLL3 expression had an overall response rate of 40% and duration of response of 7.9 months [18]. While not open in the US Oncology Network, the phase II DAREON-5 trial with obrixtamig is testing two different doses and includes patients with relapsed EP-NEC [19]. The results of ongoing obrixtamig trials will be important to follow and could potentially alter our future therapeutic approach to EP-NEC.

Standard-of-care options in EP-NEC do not yield survival much past one year in most patients. However, for the first time in decades, numerous emerging therapeutic options afford hope to significantly improve the treatment tolerability and prognosis for patients with this aggressive disease.

References:

  1. Dasari A, Mehta K, Byers LA, Sorbye H, Yao JC. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. Cancer. 2018;124(4):807-815. doi:10.1002/cncr.31124.
  2. Eads JR, Halfdanarson TR, Asmis T, et al. Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms. Endocr Relat Cancer. 2023;30(8):e220206. Published 2023 Jul 11. doi:10.1530/ERC-22-0206.
  3. Tomimaru Y, Eguchi H, Tatsumi M, et al. Clinical utility of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography in predicting World Health Organization grade in pancreatic neuroendocrine tumors. Surgery. 2015;157(2):269-276. doi:10.1016/j.surg.2014.09.011.
  4. Majala S, Seppänen H, Kemppainen J, et al. Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT. EJNMMI Res. 2019;9(1):116. Published 2019 Dec 23. doi:10.1186/s13550-019-0585-7.
  5. Alese OB, Jiang R, Shaib W, et al. High-Grade Gastrointestinal Neuroendocrine Carcinoma Management and Outcomes: A National Cancer Database Study. Oncologist. 2019;24(7):911-920. doi:10.1634/theoncologist.2018-0382.
  6. Efficacy of neoadjuvant chemotherapy in terms of DFS in patients with locally advanced, poorly differentiated digestive neuroendocrine carcinomas (NEONEC). ClinicalTrials.gov identifier NCT04268121. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT04268121
  7. Ho IW, Chiang NJ, Lai JI, et al. Efficacy of atezolizumab combined with platinum and etoposide in the treatment of extrapulmonary neuroendocrine carcinoma. Oncologist. 2025;30(3):oyae372. doi:10.1093/oncolo/oyae372.
  8. Evaluating the addition of the immunotherapy drug atezolizumab to standard chemotherapy treatment for advanced or metastatic neuroendocrine carcinomas that originate outside the lung (SWOG S2012). ClinicalTrials.gov identifier NCT05058651. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05058651
  9. Walter T, Lievre A, Coriat R, et al. Bevacizumab plus FOLFIRI after failure of platinum-etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial. Lancet Oncol. 2023;24(3):297-306. doi:10.1016/S1470-2045(23)00001-3.
  10. Frumovitz M, Munsell MF, Burzawa JK, et al. Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in recurrent small cell neuroendocrine carcinoma of the cervix. Gynecol Oncol. 2017;144(1):46-50. doi:10.1016/j.ygyno.2016.10.040.
  11. Patel SP, Mayerson E, Chae YK, et al. A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: High-grade neuroendocrine neoplasm cohort. Cancer. 2021;127(17):3194-3201. doi:10.1002/cncr.33591.
  12. ClinicalTrials.gov. Clinical study to further evaluate the efficacy of dabrafenib plus trametinib in patients with rare BRAF V600E mutation-positive unresectable or metastatic solid tumors. Identifier NCT05868629. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05868629
  13. Serrano AG, Rocha P, Freitas Lima C, et al. Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms. NPJ Precis Oncol. 2024;8(1):268. Published 2024 Nov 19. doi:10.1038/s41698-024-00739-y.
  14. Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. N Engl J Med. 2023;389(22):2063-2075. doi:10.1056/NEJMoa2307980.
  15. ClinicalTrials.gov. A study of Peluntamig (PT217) in patients with neuroendocrine carcinomas expressing DLL3 (the SKYBRIDGE study). Identifier NCT05652686. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05652686
  16. ClinicalTrials.gov. A study of IDE849 in patients with DLL3 expressing tumors including small cell lung cancer. Identifier NCT07174583. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT07174583
  17. ClinicalTrials.gov. A Phase Ib/II, open-label, multi-center study of ZL-1310 in participants with selected solid tumors. Identifier NCT06885281. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT06885281
  18. Capdevila J, Gambardella V, Kuboki Y, et al. Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: Results from an ongoing phase I trial. J Clin Oncol. 2025;43(16_suppl):3004. doi: 10.1200/JCO.2025.43.16_suppl.3004.
  19. ClinicalTrials.gov. DAREON-5: A study to test whether different doses of BI 764532 help people with small cell lung cancer or other neuroendocrine cancers. Identifier NCT05882058. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05882058

Apixaban vs Rivaroxaban in Acute VTE: Practice-Changing Insights for Oncology Clinicians

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.

Venous thromboembolism (VTE) is a frequent and clinically significant complication in patients with cancer, contributing substantially to morbidity, disruptions in systemic cancer therapy, and mortality. Direct oral anticoagulants (DOACs) have reshaped management strategies, offering efficacy comparable to vitamin K antagonists with improved convenience and safety.

Among DOACs, Apixaban (ELIQUIS®) and Rivaroxaban (XARELTO®) are widely used. However, until recently, the absence of direct comparative randomized data has limited evidence-based selection between agents, particularly in patients with elevated bleeding risk, such as those with malignancy.

Study Design and Methods

The COBRRA (Comparison of Bleeding Risk between Rivaroxaban and Apixaban) trial was an international, prospective, randomized, open-label study and represents the first randomized, head-to-head comparison of Apixaban and Rivaroxaban in patients with acute symptomatic Pulmonary Embolism or proximal Deep-Vein Thrombosis.

A total of 2,760 patients with acute symptomatic Pulmonary Embolism or proximal Deep-Vein Thrombosis were randomized 1:1 to:

  • Apixaban: 10 mg twice daily for 7 days, followed by 5 mg twice daily
  • Rivaroxaban: 15 mg twice daily for 21 days, followed by 20 mg once daily

The Primary endpoint was clinically relevant bleeding (major or clinically relevant nonmajor bleeding) over 3 months. Secondary outcomes included all-cause mortality and recurrent VTE.

Notably, patients with cancer-associated thrombosis were excluded, reflecting historical standards at the time of trial design.

Key Results: Significant Reduction in Bleeding with Apixaban

At 3 months, Apixaban demonstrated a significant reduction in clinically relevant bleeding:

  • 3.3% (Apixaban) vs 7.1% (Rivaroxaban)
  • Relative Risk (RR): 0.46 (95% CI, 0.33–0.65; P<0.001)

This represents a 54% reduction in bleeding risk with Apixaban.

  • Clinically relevant nonmajor bleeding:
    • 2.9% (Apixaban) vs 4.9% (Rivaroxaban)
  • Major bleeding was also lower with Apixaban (notably rare overall)

Common bleeding events included vaginal and gastrointestinal bleeding, with consistently lower rates observed in the Apixaban arm.

Comparable Efficacy

  • Recurrent VTE rates were similar between groups (~1%)
  • The improved safety profile of Apixaban did not compromise antithrombotic efficacy

Safety

  • No deaths due to bleeding were reported
  • Non-bleeding serious adverse events were comparable between groups

Relevance to Oncology Practice

Although cancer patients were not included, the findings have important indirect implications for oncology:

  1. Bleeding Risk Is Paramount in Cancer

Patients with malignancy often have:

  • Tumor-related mucosal bleeding (e.g., GI, GU cancers)
  • Treatment-related thrombocytopenia
  • Drug–drug interactions with systemic therapies

In this context, the lower bleeding risk observed with Apixaban is highly clinically meaningful, particularly for patients at elevated hemorrhagic risk.

  1. Alignment with Emerging Oncology Data

Subsequent cancer-specific trials (e.g., CARAVAGGIO) have already demonstrated that Apixaban is effective and relatively safe in cancer-associated thrombosis, with a favorable bleeding profile compared with other DOACs in certain settings.

The COBRRA findings reinforce a growing body of evidence suggesting that Apixaban may be the preferred DOAC when bleeding risk is a major concern.

  1. Practical Treatment Considerations
  • Dosing strategy matters: The extended 21-day high-dose phase with Rivaroxaban may contribute to early bleeding risk
  • Pharmacokinetics: Higher peak drug levels with once-daily Rivaroxaban may increase mucosal bleeding, relevant in GI or GU malignancies
  • Adherence: Despite slightly lower adherence with Apixaban in the trial, efficacy remained preserved

Limitations and Applicability to Oncology

  • Exclusion of cancer-associated thrombosis limits direct generalizability
  • Short follow-up (3 months) does not address extended anticoagulation
  • Underrepresentation of diverse populations
  • Not powered for efficacy differences

Despite these limitations, the biologic and pharmacologic insights are highly translatable to oncology populations

Clinical Takeaways

  • Apixaban significantly reduces clinically relevant bleeding compared with Rivaroxaban in acute VTE
  • Efficacy remains equivalent, supporting its use as a first-line agent
  • For oncology patients, particularly those with high bleeding risk, Apixaban may represent a more favorable therapeutic option
  • These findings may help inform DOAC selection in cancer-associated thrombosis, alongside existing oncology-specific trial data and guidelines

Conclusion

The COBRRA trial provides the first randomized evidence demonstrating a clear safety advantage of Apixaban over Rivaroxaban in acute VTE. For oncology clinicians, where balancing thrombosis prevention with bleeding risk is critical, these data support prioritizing Apixaban in appropriate patients, while awaiting further dedicated studies in cancer-associated thrombosis populations.

Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism. Castellucci LA, Chen VM,  Kovacs MJ, et al.for the COBRRA Trial Investigators. N Engl J Med 2026;394:1051-1060

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

RR

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

Evolving Treatment Paradigms in CLL            

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

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

Trial Design and Patient Population

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

Fixed-duration Venetoclax plus Obinutuzumab (N=303)

Fixed-duration Venetoclax plus Ibrutinib (N=305)

Continuous Ibrutinib monotherapy (N=301)

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

Efficacy Outcomes: Noninferiority Achieved

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

81.1% with Venetoclax–Obinutuzumab

79.4% with Venetoclax–Ibrutinib

81.0% with continuous Ibrutinib

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

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

Depth of Remission and MRD Dynamics

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

73.3% of patients treated with Venetoclax–Obinutuzumab

47.2% of those receiving Venetoclax–Ibrutinib

0% of patients on continuous Ibrutinib

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

Safety and Tolerability Considerations

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

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

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

Subgroup Insights and Clinical Implications

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

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

Positioning CLL17 in the Current Treatment Landscape

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

Conclusions

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

Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia. Al-Sawaf O, Stumpf J,  Zhang C, et al. for the CLL17 Trial Investigators. N Engl J Med 2026;394:1084-1096.

Reassessing the Role of Carboplatin in Neoadjuvant Therapy for HER2-Positive Breast Cancer: Insights from the neoCARHP Trial

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

Human epidermal growth factor receptor 2–positive (HER2+) breast cancer accounts for approximately 15%–20% of all breast malignancies and historically has been associated with aggressive disease biology. Over the past decade, the integration of dual HER2 blockade with Trastuzumab (HERCEPTIN®) and Pertuzumab (PERJETA®) alongside cytotoxic chemotherapy has substantially improved outcomes. In patients with Stage II–III disease, neoadjuvant therapy has become the standard treatment approach, enabling early assessment of treatment response and guiding postoperative therapy.

The combination of a Taxane, Carboplatin, Trastuzumab, and Pertuzumab (TCbHP) is widely endorsed by treatment guidelines as a preferred neoadjuvant regimen. However, the inclusion of Carboplatin, originally incorporated as an anthracycline-sparing strategy to mitigate cardiotoxicity, remains a subject of ongoing debate. While platinum agents may enhance antitumor activity through DNA-damaging mechanisms and potential synergy with HER2-targeted therapy, Carboplatin is also associated with increased hematologic and gastrointestinal toxicities that frequently necessitate dose reductions or treatment interruptions.

Several earlier studies have questioned the incremental benefit of Carboplatin in HER2-positive disease. Trials in both metastatic and early-stage settings have suggested that the addition of platinum compounds may not significantly improve response outcomes, while contributing to higher rates of treatment-related toxicity. At the same time, multiple investigations evaluating chemotherapy de-escalation strategies have demonstrated promising activity with taxane-based regimens combined with dual HER2 blockade alone.

Against this evolving backdrop, the Phase III neoCARHP study sought to determine whether Carboplatin could be safely omitted from neoadjuvant therapy without compromising efficacy.

Study Design and Treatment Approach

The neoCARHP trial was a multicenter, open-label, randomized Phase III noninferiority study, conducted across 15 institutions. The study enrolled women aged 18 years or older with previously untreated Stage II or III HER2-positive invasive breast cancer. Patients with metastatic disease, inflammatory breast cancer, bilateral tumors, or prior systemic therapy for breast cancer were excluded.

Participants were randomly assigned in a 1:1 ratio to receive six cycles of either the standard TCbHP regimen or a Carboplatin-free regimen consisting of a Taxane plus Trastuzumab and Pertuzumab (THP). Taxane selection, including Docetaxel, Paclitaxel, or nab-Paclitaxel, was left to investigator discretion. Importantly, Docetaxel dosing differed between arms, with a higher dose used in the THP arm to maintain treatment intensity in the absence of Carboplatin.

All patients received Trastuzumab and Pertuzumab every three weeks. Surgery was scheduled within six weeks following completion of neoadjuvant therapy. Postoperative treatment followed standard guidelines: patients achieving a pathologic Complete Response (pCR) typically continued Trastuzumab with or without Pertuzumab to complete one year of HER2-targeted therapy, while those with residual disease were eligible to receive adjuvant Trastuzumab emtansine (KADCYLA®).

Between April 2021 and August 2024, 774 patients were randomized, and 766 who received at least one dose of study therapy were included in the efficacy analysis. Baseline characteristics were well balanced between the treatment arms, with most patients presenting with Stage II disease and approximately one-third being node-negative.

The Primary endpoint of the trial was the rate of pathologic Complete Response in the breast and axilla (ypT0/is ypN0) in the modified intention-to-treat population.

Efficacy Outcomes

Pathologic Complete Response was achieved in 64.1% of patients treated with the Carboplatin-free THP regimen compared with 65.9% in the TCbHP group. The absolute difference of –1.8% fell well within the prespecified noninferiority margin, confirming that THP was statistically noninferior to the standard Carboplatin-containing regimen.

Per-protocol analyses yielded nearly identical results, with both treatment groups demonstrating a pCR rate of 68.5%. Importantly, subgroup analyses showed consistent outcomes across clinically relevant populations, including both Hormone Receptor–positive and Hormone Receptor–negative disease. Among patients with Hormone Receptor–negative tumors, pCR rates approached 78% in both treatment arms.

Safety and Tolerability

A key finding of the neoCARHP study was the improved safety profile associated with the Carboplatin-free regimen. Grade 3 or 4 adverse events occurred in 20.7% of patients receiving THP compared with 34.6% in those treated with TCbHP. Serious adverse events were also less frequent in the THP arm (1.3% vs 4.7%).

Hematologic toxicities were notably reduced with Carboplatin omission. Rates of neutropenia and leukopenia were significantly lower in the THP group, and gastrointestinal toxicities such as diarrhea occurred less frequently. Overall toxicity rates were similar between groups, but the majority of events were low grade. No treatment-related deaths were reported.

These findings suggest that eliminating Carboplatin may substantially reduce treatment-related morbidity while preserving efficacy.

Clinical Context and Emerging Evidence

The results of neoCARHP align with a growing body of evidence supporting chemotherapy de-escalation strategies in HER2-positive breast cancer. Multiple prior trials, including NeoSphere, WSG-ADAPT, COMPASS-HER2-pCR, and DAPHNe, have demonstrated that taxane-based regimens combined with dual HER2 blockade can achieve high pCR rates, particularly in Hormone Receptor–negative tumors.

Collectively, these studies suggest that approximately half of patients with Stage II–III HER2-positive breast cancer may achieve pCR after four cycles of THP, with response rates exceeding 60% after six cycles. For patients with Hormone Receptor–negative disease, pCR rates may approach 80%. Importantly, omitting Carboplatin appears to improve tolerability without compromising early efficacy outcomes, raising the possibility that selected patients with low- or intermediate-risk disease may safely receive less intensive chemotherapy.

Future Directions and Biomarker-Guided Treatment

Despite these encouraging results, several important questions remain. Long-term outcomes, including Event-Free Survival, invasive Disease–Free Survival, and Overall Survival, are still maturing in the neoCARHP trial. Because pCR is not universally validated as a surrogate for survival across all breast cancer subtypes, extended follow-up will be critical to confirm the durability of these findings.

Advances in biomarker-driven treatment selection may also play a key role in refining neoadjuvant strategies. Emerging tools such as PET-guided response assessment, genomic assays like HER2DX, and intrinsic subtype classification may help identify patients most likely to benefit from treatment de-escalation while ensuring that higher-risk individuals continue to receive optimal therapy.

Meanwhile, antibody–drug conjugates are rapidly entering the early-stage setting and could further reshape treatment paradigms. Agents such as Trastuzumab deruxtecan (ENHERTU&reg;) are currently being investigated in neoadjuvant and adjuvant trials and may eventually offer additional Carboplatin-free therapeutic options.

Clinical Takeaway

The Phase III neoCARHP trial demonstrates that a neoadjuvant regimen consisting of a taxane combined with Trastuzumab and Pertuzumab achieves pathologic Complete Response rates comparable to the standard TCbHP regimen while significantly reducing high-grade toxicities.

These findings support the potential omission of Carboplatin in selected patients with Stage II–III HER2-positive breast cancer and represent another step toward individualized, toxicity-conscious treatment strategies in early HER2-positive disease.

Neoadjuvant Taxane Plus Trastuzumab and Pertuzumab With or Without Carboplatin in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: The Randomized Noninferiority Phase III neoCARHP Trial. Gao H-F, Ye G-L, Lin Y, et al. J Clin Oncol. DOI: 10.1200/JCO-25-02176

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

RR

SUMMARY: The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer will be diagnosed in 2026 and about 10,740 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Background

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

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

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

Study Design and Patient Population

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

Participants were randomized to one of three chemotherapy regimens:

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

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

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

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

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

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

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

The median PFS follow-up was 24.1 months.

Neurotoxicity Outcomes

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

Grade 2–4 neurotoxicity occurred in:

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

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

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

Efficacy Results

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

Median Progression-Free Survival was:

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

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

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

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

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

Safety and Adverse Events

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

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

Clinical Implications

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

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

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

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

Key Takeaway for Oncology Practice:

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

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