Category: Hem/Onc Updates

Late Breaking Abstract – ASCO 2026: Adjuvant Selpercatinib Delivers Landmark Event-Free Survival Benefit in Early-Stage RET Fusion–Positive NSCLC

RR

SUMMARY: The American Cancer Society estimates that for 2026, about 229,410 new cases of lung cancer will be diagnosed and 124,990 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. The evolution of precision oncology in NSCLC continues to move beyond the metastatic setting, with targeted therapies increasingly demonstrating meaningful benefits in earlier stages of disease.

The Rationale for Targeting RET in Early Disease

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene result in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, pancreas, breast, and several hematologic malignancies.

Selpercatinib (RETEVMO®) is a highly selective and potent, CNS–penetrant RET inhibitor, designed to inhibit native RET signaling, as well as anticipated acquired resistance mechanisms. Selpercatinib selectively targets wild-type RET as well as various RET mutants and RET-containing fusion products. Additionally, Selpercatinib inhibits Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), VEGFR3, Fibroblast Growth Factor Receptor 1 (FGFR1), FGFR2, and FGFR3. This results in inhibition of cell growth of tumors that exhibit increased RET activity. This agent has already demonstrated substantial clinical benefit in advanced and metastatic RET fusion–positive NSCLC, leading to its adoption as a standard targeted treatment in that setting.

While targeted therapies directed against EGFR mutations and ALK rearrangements have transformed postoperative management of early-stage NSCLC, patients with RET fusion–positive diseases have not previously had a comparable adjuvant treatment option. Consequently, recurrence following definitive therapy has remained a major concern.

LIBRETTO-432 was designed to determine whether earlier intervention with RET-directed therapy could alter the natural history of the disease and improve long-term outcomes.

Trial Design and Patient Population

LIBRETTO-432 was a global, randomized, double-blind, placebo-controlled Phase 3 study that enrolled 151 patients across 22 countries with Stage IB–IIIA RET fusion–positive NSCLC who had completed definitive locoregional treatment. Participants were randomized in a 1:1 ratio to receive either Sselpercatinib 160 mg twice daily (N=75) or Placebo (N=76) for up to three years. Importantly, the study allowed crossover from placebo to Selpercatinib in the event of disease recurrence, providing patients access to targeted therapy while also enabling assessment of adjuvant treatment benefit. Baseline characteristics were well balanced between treatment arms, ensuring robust comparisons between groups. The Primary endpoint was investigator-assessed Event Free Survival (EFS) in patients with Stage II–IIIA disease. Secondary endpoints included EFS in the overall study population, Blinded Independent Central Review (BICR)-assessed EFS, Overall Survival, and Safety. Median follow-up was 24 months for Selpercatinib and 27 months for Placebo.

Striking Reduction in Recurrence Risk

At the prespecified efficacy analysis, Selpercatinib demonstrated a profound and statistically significant improvement in EFS among patients with Stage II–IIIA disease. The risk of recurrence, progression, or death was reduced by approximately 83% compared with placebo, with a Hazard Ratio of 0.172 (P=0.0003). Median EFS was not reached in the Selpercatinib arm, whereas patients receiving placebo experienced a median EFS of 31.8 months. Only four EFS events occurred among patients receiving Selpercatinib compared with 19 events in the placebo group, underscoring the magnitude of benefit observed.

The separation of the survival curves was reflected in the 24-month EFS rates, which reached 91.5% with Selpercatinib compared with 61.1% with placebo. Independent Central Review confirmed these findings, demonstrating a consistent treatment effect and strengthening confidence in the robustness of the results.

Benefit Extends Across the Overall Study Population

The efficacy advantage observed in the primary analysis population was mirrored in the broader cohort of patients with Stage IB–IIIA disease. In the overall study population, Selpercatinib reduced the risk of an EFS event by approximately 84%, yielding a hazard ratio of 0.165 (P=0.0002). At two years, EFS rates were 93.8% in the Selpercatinib arm compared with 69.6% in the placebo group. The consistency of benefit across both primary and secondary analyses highlights the potential of RET inhibition to become an integral component of postoperative management for RET fusion–positive NSCLC.

Early Survival Signals and Crossover Experience

Although Overall Survival data remain immature, early observations are encouraging.

After a median follow-up of approximately 25 months in the Selpercatinib group, no deaths had been reported. In contrast, three deaths occurred in the placebo arm, all attributed to disease progression.

The crossover design provided valuable insight into treatment sequencing. Sixteen patients initially assigned to placebo crossed over to Selpercatinib after recurrence, with the majority remaining on treatment at the time of analysis. While crossover may ultimately dilute differences in Overall Survival between treatment groups, the substantial EFS benefit observed emphasizes the value of introducing targeted therapy before recurrence occurs.

Manageable Safety Profile Consistent With Prior Experience

The safety findings from LIBRETTO-432 were generally consistent with the established profile of Selpercatinib in advanced RET fusion–positive NSCLC. The most commonly reported grade 3 or higher toxicities included elevations in liver enzymes, specifically ALT and AST, as well as hypertension. Most events were manageable through dose modifications and routine clinical monitoring. Treatment discontinuation due to adverse events occurred in 17.3% of patients receiving Selpercatinib, compared with 1.3% of those receiving placebo. Importantly, no deaths occurred during assigned study treatment, and all reported deaths were confined to the placebo arm as a consequence of disease progression.

These findings suggest that while long-term therapy requires careful toxicity management, the benefit-risk profile remains favorable in light of the substantial reduction in recurrence risk.

Reinforcing the Importance of Comprehensive Biomarker Testing

One of the most important implications of LIBRETTO-432 extends beyond the efficacy of Selpercatinib itself. The study reinforces the necessity of comprehensive genomic profiling at the time of NSCLC diagnosis, regardless of disease stage.

Historically, molecular testing has often been prioritized in advanced disease where treatment decisions depend heavily on biomarker status. However, the emergence of effective adjuvant targeted therapies across multiple genomic subsets, including EGFR, ALK, and now potentially RET, demonstrates that molecular characterization has become equally critical in early-stage disease. Failure to identify actionable alterations at diagnosis may result in missed opportunities to offer therapies capable of substantially reducing recurrence risk and improving long-term outcomes.

Looking Ahead

The success of LIBRETTO-432 reflects a broader transformation in thoracic oncology. Increasingly, therapies initially developed for metastatic disease are being evaluated in earlier-stage settings where the potential impact on cure is greatest. LIBRETTO-432 is the first randomized Phase 3 study to evaluate a RET inhibitor in the adjuvant setting for early-stage RET fusion–positive NSCLC, and its results represent a major advance for this patient population.

With an approximately 83% reduction in the risk of recurrence, progression, or death, Selpercatinib delivered a clinically meaningful and statistically significant improvement in Event-Free Survival while maintaining a manageable safety profile. These findings position adjuvant Selpercatinib as a potential new standard of care for patients with resected RET fusion–positive NSCLC.

Event-free survival with adjuvant selpercatinib in stage IB-IIIA RET fusion-positive NSCLC: Primary results of the phase 3 LIBRETTO-432 trial. Goldman JW, Yang X, Hochmair M, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA3)

Late Breaking Abstract – ASCO 2026: Daraxonrasib Redefines Second-Line Treatment for Metastatic Pancreatic Cancer

RR

SUMMARY: The American Cancer Society estimates that in 2026, about 67,530 people will be diagnosed with pancreatic cancer and 52,940 people will die of the disease. Pancreatic Ductal AdenoCarcinoma (PDAC) remains one of the most lethal malignancies, with most cases diagnosed at advanced stages and few modifiable risk factors identified to date. Although pancreatic cancer accounts for only about 3% of all cancer diagnoses in the United States, it is responsible for a disproportionate number of cancer-related deaths due to its aggressive biology and the fact that most patients present with advanced disease. More than half of pancreatic cancers are diagnosed after metastasis has already occurred, and outcomes remain poor despite advances in systemic therapy.

Standard second-line chemotherapy options have historically provided limited benefit, with median Progression-Free Survival (PFS) of approximately 3 to 4 months and median Overall Survival (OS) of just 6 to 7 months. While targeted therapies have transformed treatment paradigms in several solid tumors, their impact in pancreatic cancer has been restricted to relatively uncommon molecular subgroups.

The Phase 3 RASolute-302 trial may represent a turning point. Presented during the Plenary Session of the 2026 ASCO Annual Meeting, the study demonstrated that Daraxonrasib (RMC-6236), a first-in-class oral RAS(ON) multiselective inhibitor, significantly improved survival outcomes compared with standard chemotherapy in patients with previously treated metastatic PDAC.

Targeting a Central Driver of Pancreatic Cancer

The rationale for Daraxonrasib is rooted in the biology of pancreatic cancer itself. Aberrant activation of the RAS signaling pathway is recognized as the dominant molecular driver of PDAC, with oncogenic KRAS mutations identified in more than 90% of tumors. The majority of these alterations occur at codon 12, resulting in constitutive activation of the RAS protein and persistent downstream signaling through pathways that promote tumor growth and survival.

Although several KRAS-directed therapies have emerged in recent years, most are mutation-specific and target only a narrow subset of KRAS alterations. Daraxonrasib was designed to overcome this limitation through a broader mechanism of action.

Rather than binding directly to RAS, Daraxonrasib forms a complex with cyclophilin A that selectively engages the active GTP-bound form of RAS (active “ON” state) and suppresses downstream RAF signaling. This unique approach enables activity across multiple oncogenic RAS variants, including G12, G13, and Q61 mutations, as well as wild-type RAS. The agent also demonstrates activity across all three RAS isoforms: KRAS, NRAS, and HRAS.

This broad-spectrum activity has generated significant interest, particularly in PDAC, where dependence on RAS signaling extends beyond specific mutation subtypes and may also occur through pathway amplification or alterations elsewhere within the RAS-MAPK signaling cascade.

RASolute-302: Evaluating a New Therapeutic Strategy

RASolute-302 was a global, randomized, open-label Phase 3 trial conducted across 59 centers in North America, Europe, and Asia. The study enrolled 500 patients with previously treated metastatic PDAC and ECOG performance status 0–1. Eligible patients had received prior Fluoropyrimidine- or Gemcitabine-based therapy in the metastatic setting and were randomized 1:1 to receive either once-daily oral Daraxonrasib at 300 mg (N=248) or investigator’s choice of standard cytotoxic chemotherapy (N=252).

The trial employed dual Primary endpoints of Overall Survival and Progression-Free Survival in patients harboring RAS G12 mutations, who represented approximately 92% of the study population. Key Secondary endpoints included OS, PFS, objective response rate (ORR), and patient-reported outcomes in both the RAS G12 subgroup and the overall study population. Baseline characteristics were well balanced between treatment arms, allowing for a robust assessment of efficacy and safety.

Survival Outcomes Exceed Historical Expectations

At a median follow-up of 8.5 months, Daraxonrasib met all Primary and key Secondary endpoints, delivering results that substantially exceeded historical benchmarks for second-line treatment in metastatic pancreatic cancer.

Among patients with RAS G12-mutated disease, median Overall Survival reached 13.2 months with Daraxonrasib compared with 6.6 months for chemotherapy (HR=0.40; P<0.0001), translating into a 60% reduction in the risk of death. Progression-free survival similarly improved from 3.5 months with chemotherapy to 7.3 months with Daraxonrasib (HR=0.45; P<0.0001).

Importantly, the survival benefit extended beyond the primary analysis population. In the overall study cohort, including patients with RAS G13 mutations, RAS Q61 mutations, and those without identifiable RAS mutations, median OS remained 13.2 months with Daraxonrasib versus 6.7 months with chemotherapy (HR=0.40; P<0.0001). Median PFS was 7.2 months compared with 3.6 months, respectively (HR=0.49; P<0.0001).

These findings suggest that sustained inhibition of active RAS signaling may provide clinical benefit across a broader spectrum of pancreatic tumors than previously anticipated.

Lead investigator Brian Wolpin, MD, MPH, noted that the study addresses a major unmet need in metastatic PDAC, where no universally accepted second-line standard of care exists and available chemotherapy regimens offer modest efficacy at the cost of significant toxicity.

Response Rates and Quality-of-Life Benefits

Beyond prolonging survival, Daraxonrasib demonstrated meaningful improvements in tumor response.

The confirmed Objective Response Rate (ORR) was nearly three times higher with Daraxonrasib than with chemotherapy. In the RAS G12 population, ORR reached 33.2%, compared with 11.8% for standard treatment. Similar results were observed in the overall study population, where response rates were 31.6% and 11.2%, respectively.

Equally notable were improvements in Patient-Reported Outcomes. Patients receiving Daraxonrasib experienced a significant delay in worsening cancer-related pain and deterioration in overall health status and Quality of Life. Given the substantial symptom burden associated with metastatic pancreatic cancer, these findings underscore the clinical relevance of the survival advantages observed.

The consistency of benefit across multiple efficacy endpoints strengthens the overall therapeutic profile of the agent and suggests that gains in survival are accompanied by meaningful improvements in patient experience.

Favorable Safety Profile Supports Long-Term Use

Safety analyses further distinguished Daraxonrasib from conventional chemotherapy.

Although treatment-related adverse events occurred in nearly all patients, the overall tolerability profile favored the investigational agent. Grade 3 or higher treatment-related adverse events occurred less frequently with Daraxonrasib than with chemotherapy, as did serious treatment-related adverse events, dose reductions, and treatment discontinuations.

The most common toxicities associated with Daraxonrasib were dermatologic and gastrointestinal in nature, including rash, stomatitis, diarrhea, nausea, and vomiting. Most events were low grade and manageable with standard supportive measures and dose modifications.

Importantly, treatment discontinuation due to adverse events occurred in only 1.2% of patients receiving Daraxonrasib, compared with 11.2% among those treated with chemotherapy.

These findings are particularly compelling given the substantially longer median treatment duration achieved with Daraxonrasib, suggesting that prolonged disease control can be attained without a corresponding increase in severe toxicity.

Implications for Clinical Practice

The magnitude of benefit observed in RASolute-302 is noteworthy in the context of metastatic pancreatic cancer, where therapeutic advances have historically been incremental.

Daraxonrasib not only doubled median Overall Survival compared with chemotherapy but also produced consistent benefits across patient subgroups regardless of age, baseline CA19-9 level, prior treatment history, metastatic burden, or RAS mutation status. Such broad activity raises the possibility that targeting the active state of RAS may represent a fundamentally new therapeutic strategy for a disease long considered refractory to precision oncology approaches.

The findings also highlight the potential advantages of multiselective RAS inhibition over mutation-specific approaches. By targeting the activated RAS state rather than a single molecular variant, Daraxonrasib may address the biological heterogeneity that characterizes pancreatic cancer and other RAS-driven malignancies.

Looking Ahead

While RASolute-302 establishes a strong foundation for Daraxonrasib in previously treated metastatic PDAC, additional studies are already exploring its role in earlier disease settings. The ongoing Phase 3 RASolute-303 trial is evaluating Daraxonrasib both as monotherapy and in combination with Gemcitabine plus nab-Paclitaxel in the first-line metastatic setting. Meanwhile, RASolute-304 is investigating the agent as a post-perioperative strategy in patients with resected PDAC. Together, these studies may determine whether broad RAS inhibition can alter the treatment landscape across the continuum of pancreatic cancer care.

Key Takeaway

The Phase 3 RASolute-302 trial represents one of the most significant advances in metastatic pancreatic cancer in recent years. By delivering substantial improvements in Overall Survival, Progression-Free Survival, Response Rates, and Patient-Reported Outcomes, while maintaining a manageable safety profile, Daraxonrasib has emerged as a compelling candidate for a new standard of care in previously treated metastatic PDAC. The results not only validate RAS as a therapeutic target in pancreatic cancer but also signal the arrival of a new generation of broadly active RAS-directed therapies poised to reshape treatment paradigms across oncology.

Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer. O’Reilly EM, Wainberg ZA, Hendifar AE, et al. for the RASolute 302 Trial Investigators.  Published May 31, 2026. DOI: 10.1056/NEJMoa2605555

DATROWAY® Demonstrates Survival Advantage in First-Line Metastatic Triple-Negative Breast Cancer

RR

SUMMARY: The FDA on May 22, 2026, approved DATROWAY® (Datopotamab Deruxtecan-dlnk) for adult patients with unresectable or metastatic Triple-Negative Breast Cancer (TNBC) who are not candidates for PD-1/PD-L1 inhibitor therapy.

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.

Triple-Negative Breast Cancer (TNBC) which accounts for roughly 10-15% of breast cancers remains one of the most biologically aggressive breast cancer subtypes, defined by the absence of estrogen and progesterone receptor expression and lack of HER2 overexpression. The disease is associated with aggressive clinical behavior, high rates of visceral and CNS metastases, early recurrence, and limited Overall Survival once metastatic. Despite therapeutic advances, metastatic TNBC carries a dismal prognosis, with 5-year relative survival rates near 15%. While immune checkpoint inhibitors and targeted therapies have improved prognosis in selected populations, nearly 70% of patients with metastatic TNBC are not candidates for immunotherapy and continue to rely on conventional chemotherapy as first-line treatment. For these individuals, response rates remain modest, disease control is often short-lived, and many patients never reach subsequent lines of therapy. Consequently, there is a critical need for therapies capable of improving outcomes earlier in the disease course.

A Potential New Standard for Patients Ineligible for Immunotherapy

 Datopotamab-deruxtecan (Dato-DXd) is an ADC composed of a TROP2-directed monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a stable tetrapeptide-based cleavable linker. Trop-2 is a transmembrane calcium signal transducer that stimulates cancer cell growth. TROP-2 is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. It has been associated with poor Overall and Disease-Free Survival in several types of solid tumors. TROP-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to TROP-2, the anti-TROP-2 monoclonal antibody is internalized and delivers the payload directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables the payload to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. The agent has already demonstrated efficacy in Hormone Receptor-positive, HER2-negative metastatic breast cancer and previously showed encouraging activity in heavily pretreated TNBC populations.

Results from the Phase III TROPION-Breast02 trial suggest that Datopotamab Deruxtecan (Dato-DXd) may offer a meaningful new treatment option for this underserved population.

Trial Design and Patient Population

TROPION-Breast02 was a global, randomized, open-label Phase III study evaluating Dato-DXd versus investigator’s choice chemotherapy in patients with previously untreated, locally recurrent inoperable or metastatic TNBC, who were not eligible for immunotherapy.

Between May 2022 and June 2024, 644 patients were enrolled and randomized in a 1:1 ratio to receive either Dato-DXd 6 mg/kg IV every three weeks (N=323) or standard chemotherapy (N=321). The study’s dual Primary endpoints were Progression-Free Survival (PFS) assessed by Blinded Independent Central Review and Overall Survival (OS). Importantly, the trial population reflected real-world clinical practice, including patients with early relapse following curative-intent therapy, short disease-free intervals, and brain metastases, groups frequently underrepresented in pivotal studies.

Significant Improvements in Progression-Free and Overall Survival

The study met both of its Primary endpoints, demonstrating statistically significant and clinically meaningful improvements in PFS and OS with Dato-DXd compared with chemotherapy.

Median PFS reached 10.8 months with Dato-DXd versus 5.6 months with chemotherapy, translating to a 43% reduction in the risk of disease progression or death (HR 0.57; P < 0.0001).

Overall Survival findings were equally compelling. Patients receiving Dato-DXd achieved a median OS of 23.7 months compared with 18.7 months for those treated with chemotherapy, representing an approximately five-month survival benefit (HR 0.79; P =0.029).

Beyond survival outcomes, Dato-DXd also demonstrated superior antitumor activity. Confirmed Objective Response Rates were higher and was 64% and 30% in the respective arms. Responses were more durable, with a longer median duration of response.

Investigators noted that efficacy benefits were generally consistent across key patient subgroups, including PD-L1 status, disease-free interval, and geographic region. Although certain regional analyses showed variability in OS hazard ratios, these findings were exploratory and likely influenced by baseline prognostic imbalances and differential use of subsequent ADC therapies.

Expanding the Role of TROP2-Directed ADCs

The positive findings from TROPION-Breast02 further strengthen the emerging role of TROP2-targeted ADCs in metastatic TNBC. The results complement observations from the Phase III ASCENT-03 study evaluating Sacituzumab govitecan in a similar first-line setting. Together, these studies provide growing evidence that TROP2-directed ADCs can outperform standard chemotherapy and potentially redefine treatment paradigms for patients with advanced TNBC.

However, important differences exist between the trials, including eligibility criteria, disease-free interval requirements, chemotherapy comparators, and access to subsequent therapies. Notably, TROPION-Breast02 enrolled patients regardless of disease-free interval, allowing inclusion of patients with particularly aggressive disease who are often excluded from clinical trials.

Manageable Safety Profile Supports Long-Term Treatment

Safety findings were consistent with the established profile of Dato-DXd and did not reveal any new safety signals. Grade 3 or higher treatment-related adverse events occurred in 33% of patients receiving Dato-DXd and 29% of those receiving chemotherapy. Importantly, treatment discontinuation due to adverse events was less frequent with Dato-DXd (4%) than with chemotherapy (7%). No treatment-related deaths were reported in either treatment arm.

The most commonly observed adverse events included stomatitis, nausea, gastrointestinal toxicities, and ocular surface events such as dry eye. Most oral and ocular toxicities were low grade and manageable with supportive care measures. Notably, no patients discontinued Dato-DXd because of stomatitis, while only a small proportion discontinued treatment due to ocular events. When treatment exposure was taken into account, overall adverse event rates, including serious toxicities and treatment discontinuations, were lower with Dato-DXd than with chemotherapy, highlighting the tolerability of prolonged treatment.

Patient-Reported Outcomes Reinforce Clinical Benefit

Beyond traditional efficacy endpoints, Patient-Reported Outcomes (PROs) provided additional evidence supporting the clinical value of Dato-DXd.

Compared with chemotherapy, patients receiving Dato-DXd experienced delayed deterioration in pain, physical functioning, breast and arm symptoms, and overall Quality of Life measures. These findings suggest that the survival improvements achieved with Dato-DXd were accompanied by meaningful preservation of day-to-day functioning and patient well-being.

Looking Ahead

Although the open-label design represents a limitation, the overall results from TROPION-Breast02 are highly encouraging. The study demonstrated robust improvements in both Progression-Free and Overall Survival while maintaining a manageable safety profile in a patient population with historically limited treatment options.

As the treatment landscape for TNBC continues to evolve, these findings position Dato-DXd as a strong candidate for first-line therapy in patients with locally recurrent inoperable or metastatic TNBC who are not eligible for immunotherapy.

For oncology clinicians, the trial marks a significant step forward in addressing one of the most challenging segments of breast cancer care and underscores the growing impact of Antibody-Drug Conjugates in transforming outcomes for patients with aggressive disease.

Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial. Dent R, Shao Z, Schmid P, on behalf of the TROPION-Breast02 investigators. Annals of Oncology, April 03, 2026. https://doi.org/10.1016/j.annonc.2026.03.008.

CheckMate-9ER primary and exploratory findings: baseline characteristics and treatment outcomes, including depth and durability of response with cabozantinib plus nivolumab

RR

CheckMate-9ER primary and exploratory findings: baseline characteristics and treatment outcomes, including depth and durability of response with cabozantinib plus nivolumab

Written by Dr Manojkumar Bupathi
Sponsored by Exelixis, Inc.

Baseline disease characteristics and tumor biology play a pivotal role in shaping outcomes for patients with advanced renal cell carcinoma (aRCC). As treatment paradigms have evolved toward combination strategies, it has become increasingly important not only to demonstrate efficacy in the overall population, but also to consider the potential for the depth, durability, and consistency of responses across clinically relevant subgroups.1,2

The Phase 3 CheckMate-9ER trial established cabozantinib plus nivolumab as a first-line option for patients with aRCC, demonstrating significant improvements in progression-free survival, overall survival, and objective response rate compared with sunitinib. However, beyond these pivotal results, additional insights from descriptive analyses on long-term outcomes and response characteristics are noteworthy to help inform real-world clinical decision-making.3

In this article, we review the key findings from the CheckMate-9ER trial, including updated 5-year follow-up data, and explore post hoc analyses evaluating baseline characteristics associated with response. In particular, we focus on patients achieving complete responses and examine the depth and durability of response to better contextualize the long-term clinical data observed with cabozantinib plus nivolumab.1,4,5

Overview of CheckMate‐9ER
Cabozantinib is a tyrosine kinase inhibitor, targeting MET, AXL, and VEGFR. Based on the results from the CheckMate-9ER trial, a Phase 3, randomized, open-label, head-to-head trial versus sunitinib, cabozantinib + nivolumab was approved for patients with previously untreated aRCC.3,4

We will begin by reviewing the results from the pivotal trial CheckMate-9ER, which enrolled 651 patients with previously untreated aRCC containing a clear-cell component. Participants were randomized 1:1 to receive cabozantinib 40 mg once daily plus nivolumab 240 mg every 2 weeks, or sunitinib 50 mg once daily administered on a 4 weeks on, 2 weeks off schedule.3,4

  • Endpoints assessed3:
    • Primary endpoint: PFS*
    • Secondary endpoints: OS, ORR*, and safety

*Assessed by BICR.4

CheckMate-9ER studied a broad patient population, including those with a high burden of disease. Select baseline characteristics are shown in Table 1 for the cabozantinib + nivolumab arm.3

Table 13

Renal-Cell-Carcinoma-IMDC-Risk

 

†Data are for tumor sites defined at baseline by the investigators according to RECIST v1.1. The number of target or nontarget lesions at baseline was not reported for 1 patient in the CABOMETYX + OPDIVO group and for 3 patients in the sunitinib group.3

Results in the CheckMate-9ER primary analysis of the intent-to-treat population (median follow-up of 18.1 months; range: 10.6-30.6 months) were as follows3:

  • Median PFS* (mPFS) was 16.6 months with cabozantinib + nivolumab (95% CI: 12.5-24.9) vs 8.3 months  with sunitinib (95% CI: 7.0-9.7) (HR=0.51; 95% CI: 0.41-0.64; P<0.0001)4,6
  • Median OS (mOS) was not reached in either arm (HR=0.60; 98.89% CI: 0.40-0.89; P=0.001)4,6
    • Pre-planned final analysis (median follow-up: 32.9 months; range: 25.4-45.4 months): mOS was 37.7 months for the combination (95% Cl: 35.5-NR) vs 34.3 months with sunitinib (95% Cl: 29.0-NR) (HR=0.70; 95% CI: 0.55-0.90)
  • ORR* was 55.7% (95% CI: 50.1-61.2) with the combination vs 27.1% with sunitinib (95% CI: 22.4-32.3; P<0.0001)4,6
    • Complete response (CR) was 8% (n=26/323) for the combination arm vs 4.6% (n=15/328) with sunitinib
    • Partial response (PR) was 48% (n=154/323) for the combination arm vs
      23% (n=74/328) with sunitinib
  • Serious adverse reactions occurred in 48% of patients receiving cabozantinib + nivolumab (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients4
  • The most common adverse reactions (≥20%) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar‐plantar erythrodysesthesia (PPE) (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), upper respiratory tract infection (20%), and cough (20%)4

The results of the CheckMate-9ER 5-year follow-up analysis (median follow-up of 67.6 months; range 60.2-80.2 months) were as follows. No formal statistical testing was conducted at the time of the updated analysis5:

  • mPFS* was 16.4 months with the combination (95% CI: 12.5-19.3) vs 8.3 months with sunitinib (95% CI: 7.0-9.7) (HR=0.58; 95% CI: 0.49-0.70)
  • mOS was 46.5 months with the combination (95% CI: 40.6-53.8) vs 35.5 months with sunitinib (95% CI: 29.2-42.8) (HR=0.79; 95% CI: 0.65-0.96)
  • ORR* was 55.7% (95% CI: 50.1-61.2) for the combination arm vs 27.4% with sunitinib (95% CI: 22.7-32.6)
    • CR was 13.9% (n=45/323) for the combination arm vs 4.6% (n=15/328)
      with sunitinib
    • PR was 41.8% (n=135/323) for the combination arm vs 22.9% (n=75/328)
      with sunitinib
  • Safety and tolerability were similar to previous follow-ups

*Assessed by BICR.4

To further explore long-term data from the CheckMate-9ER trial, post hoc analyses were conducted to evaluate the baseline characteristics of patients who achieved CR, assess depth of response (DepOR) among those patients with PR, and examine the duration of response in patients with CR or PR.1

Depth and durability of response in patients treated with cabozantinib + nivolumab
The exploratory, post hoc analyses of the 5-year CheckMate-9ER data evaluated depth and durability of response in patients randomized to cabozantinib + nivolumab who were alive 6 months after randomization and who had available data for best overall response (BOR) and sum of diameters of target lesions.1

  • Of the 323 patients randomized to cabozantinib + nivolumab, 293 were alive at the
    6-month landmark
  • Patients were categorized into DepOR subgroups based on BOR per BICR using the maximum tumor reduction observed at any time during the study period

Baseline demographic and disease characteristics of patients receiving cabozantinib + nivolumab by DepOR subgroup are shown in Table 2, which includes patients with characteristics associated with poor prognosis.1

Table 21,7

Characteristics-Demographics

 

  • Among patients who achieved CR (n=45), the median duration of response was not reached at the time of analysis (95% CI: 30.5-NE)1*
  • Among patients who achieved PR (n=135), the median duration of response was 17.3 months (95% CI: 13.8-20.7)7*
  • Median duration of treatment with cabozantinib + nivolumab was 30.4 months for patients achieving CR, over 2 years for those with PR, and 15.3 months for those with stable disease (SD)1*
  • Safety was similar across all subgroups achieving an objective response, and the most frequently reported Grade 3/4 treatment-related adverse events included hypertension (13%), diarrhea (9%), hyponatremia (8%), and PPE (8%)1

These post hoc exploratory analyses are descriptive in nature. No statistical procedure was employed. Results should be considered hypothesis generating.

*Patients who were alive at the 6-month timepoint.1,7

Discussion
In the primary analysis cabozantinib + nivolumab doubled mPFS and demonstrated superior efficacy vs sunitinib across OS and ORR.4 Building on these results, the primary results and exploratory analyses from CheckMate-9ER provide additional context to the established efficacy of cabozantinib + nivolumab in the first-line treatment of aRCC.1,4 Notably, meaningful responses were observed among patients with baseline features traditionally associated with poorer prognosis, underscoring the broad applicability of this combination.1

The median duration of response was not reached among patients achieving complete response. The durability of responses and extended treatment exposure did not appear to be associated with a disproportionate increase in toxicity.1

These findings are derived from post hoc, descriptive exploratory analyses and should be interpreted with caution. Collectively, these data help refine our understanding of which patients may derive the greatest response and further support the role of cabozantinib + nivolumab combination as a first-line therapy option in aRCC.1

Dr Manojkumar Bupathi received a fee for participating in the development of this article, and his comments reflect his opinions and are not intended to constitute medical advice for individual patients.

AXL=AXL receptor tyrosine kinase; BICR=blinded independent central review; CI=confidence interval; HR=hazard ratio; IMDC=International Metastatic RCC Database Consortium; MET=hepatocyte growth factor receptor; NE=not estimable; NR=not reported; ORR=objective response rate; OS=overall survival; PD=progressive disease; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumors; VEGFR=vascular endothelial growth factor receptor.

INDICATION
CABOMETYX® (cabozantinib), in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: CABOMETYX can cause severe and fatal hemorrhages. The incidence of Grade 3-5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3-4 hemorrhage and before surgery. Do not administer to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, and gastrointestinal (GI) perforations, including fatal cases, each occurred in 1% of CABOMETYX patients. Monitor for signs and symptoms, and discontinue CABOMETYX in patients with Grade 4 fistulas or GI perforation.

Thromboembolic Events: CABOMETYX can cause arterial or venous thromboembolic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events have occurred. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. In CABINET (n=195), hypertension occurred in 65% (26% Grade 3) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with antihypertensive therapy or for hypertensive crisis.

Cardiac Failure: CABOMETYX can cause severe and fatal cardiac failure. Cardiac failure occurred in 0.5% of patients treated with CABOMETYX as a single agent, including fatal cardiac failure in 0.1% of patients. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue depending on the severity.

Diarrhea: CABOMETYX can cause diarrhea and it occurred in 62% (10% Grade 3) of treated patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1; resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): CABOMETYX can cause PPE and it occurred in 45% of treated patients (13% Grade 3). Withhold CABOMETYX until PPE resolves or decreases to
Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab in RCC can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. Monitor liver enzymes before initiation of treatment and periodically. Consider more frequent monitoring as compared to when the drugs are administered as single agents. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or
life-threatening hepatotoxicity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): CABOMETYX can cause ONJ and it occurred in <1% of treated patients. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution; resume at a reduced dose.

Impaired Wound Healing: CABOMETYX can cause impaired wound healing. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): CABOMETYX can cause RPLS. Perform evaluation for RPLS and diagnose by characteristic finding on MRI any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: CABOMETYX can cause thyroid dysfunction, primarily hypothyroidism, and it occurred in 19% of treated patients (0.4% Grade 3). Assess for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms during treatment.

Hypocalcemia: CABOMETYX can cause hypocalcemia, with the highest incidence in DTC patients. Based on the safety population, hypocalcemia occurred in 13% of CABOMETYX patients (2% Grade 3 and 1% Grade 4).
Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume CABOMETYX at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:
CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong or Moderate CYP3A4 Inducers: If coadministration with strong or moderate CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information by clicking here.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

 References

  1. Suárez C, Motzer RJ, Powles T, et al. Characterization of depth and durability of response in patients with previously untreated advanced renal cell carcinoma who received cabozantinib plus nivolumab: long-term follow-up and exploratory analysis of CheckMate 9ER. Poster Presented at: American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026.
  2. Zarrabi KK, Lanade O, Geynisman DM. Determining front-line therapeutic strategy for metastatic clear cell renal cell carcinoma. Cancers. 2022;14;4607. doi.org/10.3390/cancers14194607.
  3. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal‐cell carcinoma. N Engl J Med. 2021;384(9):829‐841.
  4. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
  5. Motzer RJ, Escudier B, Burotto M, et al. Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2025; Published online September 23, 2025. doi:10.1016/j.annonc.2025.09.006.
  6. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with 2-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. Poster presented at: American Society of Clinical Oncology Genitourinary Cancers Symposium; February 17-19, 2022.
  7. Data on file. Exelixis, Inc.

©2026 Exelixis, Inc.    CA-3913    04/26
OPDIVO® and the related logo are registered trademarks of Bristol‐Myers Squibb Company.

Late Breaking Abstract – ASCO 2026: Sunvozertinib Demonstrates Superior First-Line Efficacy in EGFR Exon 20 Insertion–Positive Advanced NSCLC

RR

SUMMARY: The American Cancer Society estimates that for 2026, about 229,410 new cases of lung cancer will be diagnosed and 124,990 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 (Epidermal Growth Factor Receptor) mutations, and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions and occur in about 2-3% of all patients with NSCLC and  up to 12% of EGFR-mutated NSCLC . These mutations are also enriched in women, non-smokers, Asian populations, and those with adenocarcinoma.These highly heterogeneous group of mutations are typically associated with limited sensitivity to conventional EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5-year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. Further, the use of immunotherapy is detrimental in this patient population and there is therefore a clinically unmet need for this patient group.

The treatment landscape for patients with advanced NSCLC harboring EGFR exon 20 insertion (ex20ins) mutations continues to evolve, with emerging targeted therapies offering new opportunities to improve outcomes in this historically challenging patient population.

Sunvozertinib (ZEGFROVY®), a novel oral, selective, and irreversible EGFR TKI specifically designed to target EGFR exon 20 insertion mutations, has already received regulatory approval in the United States and China for previously treated patients whose disease progressed following platinum-based chemotherapy. Building on encouraging efficacy observed in the pivotal WU-KONG1B and WU-KONG6 studies, the global Phase 3 WU-KONG28 trial evaluated whether Sunvozertinib could improve outcomes when used as first-line therapy.

WU-KONG28: Evaluating a Chemotherapy-Free First-Line Approach

WU-KONG28 (NCT05668988) is a multinational, randomized Phase 3 study, comparing Sunvozertinib with standard platinum-based chemotherapy, in treatment-naïve patients with advanced nonsquamous NSCLC harboring EGFR exon 20 insertion mutations.

A total of 324 patients were randomized 1:1 to receive either oral Sunvozertinib 300 mg once daily (N=163) until disease progression, or Carboplatin plus Pemetrexed chemotherapy (N=161) administered every three weeks for up to six cycles, followed by Pemetrexed maintenance. Patients assigned to chemotherapy were permitted to cross over to Sunvozertinib following centrally confirmed disease progression. The Primary endpoint was Progression-Free Survival (PFS) assessed by Blinded Independent Central Review (BICR), while key Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DoR), and Safety.

Significant Improvement in Progression-Free Survival

At the January 16, 2026 data cutoff, Sunvozertinib demonstrated a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy. Median PFS reached 10.3 months with Sunvozertinib versus 7.5 months with chemotherapy, corresponding to a 35% reduction in the risk of disease progression or death (HR 0.65; 95% CI, 0.50–0.85; P=0.0008).

Notably, separation of the PFS curves occurred early, suggesting rapid disease control with targeted therapy. At 12 months, 46.1% of patients receiving Sunvozertinib remained progression-free compared with 26.7% of patients treated with chemotherapy. The PFS advantage was generally consistent across analyzed patient subgroups.

Higher Response Rates and More Durable Tumor Control

Beyond prolonging PFS, Sunvozertinib achieved substantially deeper and more durable responses. The confirmed ORR was 58.9% with Sunvozertinib compared with 31.1% with chemotherapy. Patients receiving Sunvozertinib also experienced greater tumor shrinkage, with a median best percentage reduction in target lesions of 42.1% versus 24.7% in the chemotherapy arm.

Response durability further favored the targeted agent, with a median DoR of 11.2 months compared with 7.1 months for chemotherapy. These findings reinforce earlier clinical observations that Sunvozertinib provides robust antitumor activity across a broad spectrum of EGFR exon 20 insertion subtypes.

Overall Survival Data Still Maturing

Overall Survival analyses remain immature, with data maturity at 38.9% at the time of analysis. Interpretation of future OS results may be influenced by the study’s crossover design, as more than 90% of chemotherapy-treated patients with confirmed disease progression subsequently crossed over to receive Sunvozertinib.

While longer follow-up is needed to determine whether the PFS and response advantages translate into an Overall Survival benefit, the current efficacy results strongly support the clinical activity of Sunvozertinib in the frontline setting.

Manageable Safety Profile Supports Long-Term Use

The safety profile observed in WU-KONG28 was consistent with previous studies of Sunvozertinib. Grade 3 or higher adverse events occurred in 75.5% of patients receiving Sunvozertinib compared with 56.7% of patients receiving chemotherapy. The most frequently reported high-grade toxicities included elevated serum creatine kinase levels, diarrhea, and anemia.

Importantly, treatment discontinuation due to drug-related adverse events occurred in only 7.4% of patients, and no treatment-related deaths were reported. Severe rash was uncommon, and although grade 3 or higher diarrhea occurred in approximately 13.5% of patients, these events were generally manageable through proactive monitoring, supportive care, and dose modifications. The majority of patients were able to maintain treatment, reflected by a median relative dose intensity of 95%.

Implications for Clinical Practice

Historically, treatment options for EGFR exon 20 insertion-positive NSCLC have been limited, with platinum-based chemotherapy delivering modest response rates and relatively short progression-free survival. While the addition of targeted antibodies such as Amivantamab has improved outcomes, these approaches still rely on intravenous chemotherapy-based regimens.

The WU-KONG28 results position Sunvozertinib as a compelling chemotherapy-free alternative. As an oral targeted therapy, Sunvozertinib offers the potential for improved convenience and quality of life while delivering superior efficacy compared with standard platinum-doublet chemotherapy.

Looking Ahead

The WU-KONG28 trial represents a significant milestone in the treatment of EGFR exon 20 insertion-positive NSCLC. Sunvozertinib demonstrated superior Progression-Free Survival, higher response rates, greater tumor shrinkage, and longer response durability compared with standard chemotherapy, while maintaining a manageable and predictable safety profile.

As Overall Survival data continue to mature, these findings provide strong evidence supporting Sunvozertinib as a potential new first-line standard of care for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations, further advancing the shift toward personalized, targeted treatment strategies in lung cancer.

First-Line Sunvozertinib in NSCLC with EGFR Exon 20 Insertion Mutations. Zhou C, Greillier L, Liu G, et al. or the WU-KONG28 Investigators. Published May 29, 2026. DOI: 10.1056/NEJMoa2604461 

Redefining First-Line Therapy in HER2-Positive Gastroesophageal Adenocarcinoma with Zanidatamab-Based Combinations

RR

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

Persistent Unmet Need in HER2-Positive Disease

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 20% of patients with GastroEsophageal Adenocarcinoma (GEA), encompassing gastric, gastroesophageal junction, and esophageal adenocarcinomas, harbor HER2-positive tumors. Despite the incorporation of HER2-directed therapy into first-line management more than a decade ago, long-term outcomes remain suboptimal. With Trastuzumab (HERCEPTIN®) plus chemotherapy, median Progression-Free Survival (PFS) has historically hovered around 10 months, and median Overall Survival (OS) around 20 months.

More recently, the addition of immune checkpoint inhibition has modestly improved outcomes in selected patients. Based on KEYNOTE-811, Pembrolizumab (KEYTRUDA®) plus Trastuzumab and chemotherapy is now standard for PD-L1–positive tumors. However, early relapse, often within the first year, remains common, underscoring the need for more effective HER2-targeted strategies.

Zanidatamab: A Next-Generation HER2-Targeted Approach

Zanidatamab (ZIIHERA®) is a novel, humanized IgG1 bispecific monoclonal antibody designed to bind two non-overlapping extracellular domains of HER2 (ECD2 and ECD4). This biparatopic binding leads to enhanced HER2 receptor clustering, internalization, and downregulation, resulting in more complete inhibition of HER2 signaling compared with single-epitope antibodies. Beyond direct signal blockade, Zanidatamab’s unique binding geometry promotes robust immune-mediated antitumor activity, including Complement-Dependent Cytotoxicity (CDC), Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP).

Preclinical and clinical data suggest greater antibody saturation on HER2-expressing tumor cells than with Trastuzumab or Pertuzumab (PERJETA®). Zanidatamab’s clinical momentum was reinforced by its FDA accelerated approval in November 2024 for previously treated, unresectable or metastatic HER2-positive biliary tract cancer, highlighting the platform’s broader relevance across HER2-driven gastrointestinal malignancies.

Rationale for Combining HER2 Blockade and Immunotherapy

The HERIZON-GEA-01 trial explored synergy between dual HER2 targeting and immune checkpoint inhibition. Tislelizumab (TEVIMBRA®), a humanized IgG4 anti-PD-1 monoclonal antibody, is engineered to minimize Fc-gamma receptor binding on macrophages, potentially reducing antibody-dependent clearance of activated T cells. Tislelizumab received FDA approval in March 2024 for previously treated metastatic esophageal Squamous Cell Carcinoma, supporting its activity in upper gastrointestinal cancers.

HERIZON-GEA-01: Trial Design and Patient Population

HERIZON-GEA-01 (NCT05152147) is a global, open-label, Phase III study evaluating Zanidatamab-based regimens versus standard Trastuzumab plus chemotherapy in the first-line setting for HER2-positive metastatic GEA (GastroEsophageal Adenocarcinoma).

A total of 914 patients with unresectable, locally advanced, recurrent, or metastatic disease were enrolled between December 2021 and February 2025. More than two-thirds had gastric primaries. Patients had received no prior systemic therapy, HER2-targeted therapy, or immunotherapy in this setting.

Participants were randomized 1:1:1 to:

  • Arm A: Trastuzumab plus chemotherapy (N=308)
  • Arm B: Zanidatamab plus chemotherapy (N=304)
  • Arm C: Zanidatamab plus Tislelizumab plus chemotherapy (N=302)

CAPOX was the chemotherapy backbone in approximately 90% of patients. Zanidatamab-based regimens in Arm B and Arm C were compared with standard Trastuzumab plus chemotherapy in Arm A. The median age was 63 yrs, about 53% were Asian, and 60% had PD-L1 status 1% or more.  The dual Primary endpoints were Progression-Free Survival (PFS) by Blinded Independent Review and Overall Survival (OS).

Efficacy Results: Clinically Meaningful and Practice-Changing

At the interim analysis (data cutoff October 2025; median follow-up 26 months), there was a clear and consistent improvement in PFS with Zanidatamab-based therapy compared with Trastuzumab plus chemotherapy. Median PFS reached 12.4 months with Zanidatamab plus chemotherapy and 12.4 months with Zanidatamab plus Tislelizumab and chemotherapy, compared with 8.1–8.2 months in the Trastuzumab control arm. These gains translated into a 35–37% reduction in the risk of disease progression or death, with Hazard Ratios of 0.65 for Zanidatamab plus chemotherapy and 0.63 for the triplet regimen (both P<0.0001). Importantly, the separation of the PFS curves was maintained over time, highlighting the durability of benefit. The estimated 18-month PFS was 38.0% with Zanidatamab plus chemotherapy and 43.9% with the triplet, versus 20.9% with Trastuzumab-based therapy. These findings mark the first time a majority of patients receiving first-line HER2-targeted therapy remain progression-free at one year, a notable advance in a disease historically characterized by early relapse.

Median OS improved from 19.2 months with Trastuzumab plus chemotherapy to 24.4 months with Zanidatamab plus chemotherapy and 26.4 months with Zanidatamab plus Tislelizumab and chemotherapy. The addition of Tislelizumab yielded a statistically significant 28% reduction in the risk of death (HR 0.72; P =0.004). While OS data for Zanidatamab plus chemotherapy alone were not yet statistically significant at this interim analysis (HR 0.80; P =0.06), the observed survival extension of more than five months suggests meaningful clinical activity, with further analyses planned as follow-up matures. The 2-year OS was 50.3% with Zanidatamab plus chemotherapy and 54.3% with the triplet, versus 38.8% with Trastuzumab-based therapy. The 30-month OS was 42.2% and 43.8%, respectively, compared with 30.0% in the Trastuzumab group.

Notably, the triplet regimen is the first HER2-directed first-line strategy to achieve median Overall Survival exceeding two years in a randomized phase III trial. Further, the benefits in both PFS and OS were consistent across key subgroups, including geographic region and PD-L1 status, an especially notable finding given that checkpoint inhibitor benefit has traditionally been restricted to PD-L1–positive tumors.

Depth and Durability of Response

Zanidatamab-based regimens also produced deeper and more durable responses. Confirmed Objective Response Rates approached 70% in both Zanidatamab arms, with Complete Response rates nearing 20% when Tislelizumab was added. Median duration of response was particularly striking, exceeding 20 months with the triplet regimen and substantially longer than the 8-month duration observed with Trastuzumab plus chemotherapy.

Safety and Tolerability

The safety profiles of Zanidatamab and Tislelizumab were consistent with their known toxicities. Grade ≥3 treatment-related adverse events occurred in approximately 74% of patients receiving Zanidatamab plus chemotherapy and 83% with the addition of Tislelizumab, compared with 74% in the Trastuzumab arm.

Diarrhea was the most common toxicity across all arms, typically occurring early and resolving within several weeks. Rates of HER2-targeted therapy discontinuation due to adverse events were higher with Zanidatamab-based regimens but remained manageable, with no new safety signals identified.

Clinical Implications and Future Directions

HERIZON-GEA-01 represents a landmark study in HER2-positive gastroesophageal adenocarcinoma. It is the first Phase III trial to demonstrate superiority of a novel HER2-targeted agent over Trastuzumab in the first-line metastatic setting, and the first to achieve median PFS beyond one year and median OS beyond two years in this population.

While cross-trial comparisons should be interpreted cautiously, outcomes with Zanidatamab plus Tislelizumab and chemotherapy compare favorably with historical results from KEYNOTE-811. The observation of benefit irrespective of PD-L1 status further broadens the potential impact of this strategy.

As longer follow-up matures and guideline bodies evaluate these data, Zanidatamab, particularly in combination with immunotherapy appears poised to redefine the standard of care for HER2-positive metastatic gastroesophageal adenocarcinoma, offering patients a meaningful extension of disease control and survival.

Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer. Shitara K, Elimova E, Liu T, et al. for the HERIZON-GEA-01 Investigators. N Engl J Med 2026;394:2002-2014.

ASCO Recommendations for Sentinel Lymph Node Biopsy (SLNB) and Axillary Management in Early-Stage Breast Cancer

RR

SUMMARY: In 2025, the American Society of Clinical Oncology updated its guidelines on sentinel lymph node biopsy (SLNB) in patients with Stage I–II breast cancer undergoing upfront breast-conserving surgery. The recommendations reflect growing evidence that SLNB may be safely omitted in selected low-risk patients without compromising oncologic outcomes.

Historically, axillary surgery was performed for locoregional control, staging, and to guide adjuvant therapy. The move toward de-escalation is largely driven by the morbidity associated with axillary surgery. Although less invasive than Axillary Lymph Node Dissection (ALND), SLNB can still result in pain, restricted arm mobility, sensory changes, and lymphedema. Clinical trials have shown higher rates of postoperative complications and persistent upper extremity symptoms in patients undergoing SLNB compared with those who avoided axillary surgery.

Breast cancer–related lymphedema remains a significant long-term complication that can impair physical function, quality of life, and psychosocial well-being. Avoiding axillary surgery altogether is the most effective strategy for reducing this risk. As a result, the decision to omit SLNB should be individualized, balancing the value of nodal staging against surgical morbidity, patient preferences, and the likelihood that nodal findings would meaningfully alter adjuvant treatment decisions.

The updated ASCO guideline identifies clinical scenarios in which SLNB can be safely omitted because nodal involvement is unlikely to affect overall management.

1.Omission of Sentinel Lymph Node Biopsy (SLNB)

1.1 Criteria for Omitting SLNB

SLNB may be safely omitted in carefully selected patients with small (≤2 cm), clinically node-negative breast cancer when the results would not alter postoperative treatment decisions. Eligible patients should meet all of the following criteria:

  • Postmenopausal and aged ≥50 years
  • Unifocal invasive ductal carcinoma measuring ≤2 cm
  • Nottingham grade 1 or 2 disease
  • Hormone receptor–positive, HER2-negative tumors in patients planned for adjuvant endocrine therapy
  • No suspicious lymph nodes identified on axillary ultrasound, or only one suspicious node with benign and concordant biopsy findings
  • Undergoing breast-conserving surgery followed by whole-breast irradiation in patients younger than 65 years

Additional consideration:
For patients older than 70 years, current Choosing Wisely recommendations do not require axillary ultrasound when considering omission of SLNB.

1.2 Patients Aged ≥65 Years

Axillary surgery is not routinely required in patients aged ≥65 years who satisfy the criteria for SLNB omission. Evidence from prospective studies indicates that the likelihood of nodal involvement is very low in the following group:

  • Postmenopausal women
  • Tumors ≤2 cm
  • Nottingham grade 1–2 disease
  • Hormone receptor–positive, HER2-negative tumors
  • Candidates for endocrine therapy
  • Normal axillary ultrasound findings or a single suspicious node with benign concordant biopsy results

2. Impact of SLNB Omission on Adjuvant Therapy

2.1 Radiation Therapy

In patients meeting the criteria for SLNB omission, decisions regarding radiation therapy should remain unchanged. Omission of SLNB alone should not influence radiation treatment recommendations.

2.2 Systemic Therapy

Similarly, genomic assay testing and subsequent systemic treatment recommendations should not be modified solely because SLNB was omitted in appropriately selected patients.

Clinical note:
When chemotherapy decisions are being considered, genomic assays such as the 21-gene recurrence score may still be utilized to guide adjuvant treatment planning in the setting of omitted SLNB.

3. Axillary Lymph Node Dissection (ALND)

3.1 Breast-Conserving Surgery Patients          

Completion ALND is generally not recommended for patients with early-stage, clinically node-negative breast cancer who undergo breast-conserving surgery and are found to have one or two positive sentinel lymph nodes, provided they will receive whole-breast radiation therapy.

Additional considerations:

  • Completion ALND after positive SLNB may not be necessary when patients already meet criteria for treatment with CDK4/6 inhibitor or olaparib based on tumor biology.
  • In a patient with 1-2 positive nodes on SLNB, and not otherwise eligible for CDK4/6 inhibitors or olaparib based on tumor biology, completion ALND can be considered.
  • The rate of 4 or more nodal metastases with completion ALND after 1-2 positive SLNB is low (13%) and given the significantly higher morbidity of completion ALND compared with SLNB, treatment decisions should incorporate shared decision-making between physician and patient. to reduce treatment-related morbidity.

4.1 ALND in Patients Undergoing Mastectomy with Limited Nodal Disease

ALND may be omitted in patients with clinically node-negative invasive breast cancer measuring ≤5 cm who undergo mastectomy and are found to have one or two positive sentinel lymph nodes, provided that postmastectomy radiation therapy (PMRT) with Regional Nodal Irradiation (RNI) is planned.

4.2 ALND in Patients Not Receiving PMRT or RNI

For patients with pT1–T2, pN1 breast cancer undergoing mastectomy without planned PMRT or regional nodal irradiation, completion ALND is recommended.

4.3 ALND Prior to PMRT in Patients with Extensive Nodal Involvement

Patients undergoing mastectomy who are found to have four or more positive lymph nodes should undergo completion ALND followed by postmastectomy radiation (PMRT)

Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer: ASCO Guideline Clinical Insights. Park KU, Vega RBM, Shams S, et al. JCO Oncol Pract. 2026; 22:748-754

Beyond TNM Staging: How ctDNA Is Reshaping Risk Stratification in Stage III Colon Cancer

RR

SUMMARY: Adjuvant treatment decisions in stage III colon cancer (CC) have traditionally relied on TNM staging to classify patients as low risk (T1-3N1) or high risk (T4 and/or N2) following surgery. However, outcomes remain highly variable despite standard adjuvant treatment with CAPOX or FOLFOX. The IDEA collaboration highlighted this heterogeneity, with 5-year disease-free survival (DFS) ranging from nearly 90% in T1N1a tumors to approximately 31% in T4N2b disease.

Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for detecting molecular residual disease (MRD) after surgery. Detectable postoperative ctDNA may identify patients harboring persistent microscopic disease and refine recurrence risk beyond conventional staging alone.

N0147 Trial Highlights Prognostic Value of ctDNA

A recent analysis of the Phase III Alliance/NCCTG N0147 trial evaluated postoperative plasma samples from 2,260 patients with resected Stage III colon cancer using Guardant Reveal, a tissue-free epigenomic ctDNA assay.

Approximately 20% of patients were ctDNA-positive after surgery. ctDNA positivity was more common in tumors with adverse pathologic features, including:

  • T4 disease
  • N2 nodal involvement
  • High-grade histology
  • Bowel obstruction or perforation
  • BRAFV600E mutations

The highest ctDNA positivity rates were observed in patients with bowel perforation.

ctDNA Positivity Strongly Predicts Recurrence and Survival

At a median follow-up exceeding six years, postoperative ctDNA positivity was associated with significantly worse outcomes across all major endpoints:

  • Shorter Disease-Free Survival (DFS) – Hazard Ratio=5.03
  • Reduced Time To recurrence (TTR) – Hazard Ratio=5.96
  • Poorer Overall Survival (OS) – Hazard Ratio=4.45

Five-year DFS was 27.7% in ctDNA-positive patients versus 77.1% in ctDNA-negative patients, while 5-year OS was 50.4% versus 86.8%, respectively. Importantly, ctDNA remained an independent prognostic factor after adjustment for clinicopathologic variables:

These findings suggest ctDNA may more accurately identify patients with persistent residual disease following surgery than TNM staging alone.

Redefining “Low-Risk” Disease

The adverse prognostic impact of ctDNA positivity was particularly pronounced in patients traditionally considered lower risk, including:

  • T1/T2 tumors
  • N1 disease
  • Clinically “low-risk” Stage III disease
  • Deficient MisMatch Repair (dMMR) tumors

These findings highlight limitations of conventional staging and suggest that molecular residual disease can exist even in anatomically favorable tumors.

Epigenetic Tumor Fraction Adds Prognostic Precision

Investigators also evaluated epigenetic Tumor Fraction (TF), a quantitative measure of residual tumor burden. Among ctDNA-positive patients, higher TF levels correlated with:

  • Increased recurrence risk
  • Shorter DFS
  • Inferior Overall Survival

These results align with findings from studies such as DYNAMIC and GALAXY, supporting the concept that ctDNA quantity, not simply detectability, may further refine recurrence risk assessment.

Molecular Profiling and Patterns of Recurrence

ctDNA-positive patients were more likely to develop liver metastases, while ctDNA-negative relapses more commonly involved locoregional or peritoneal recurrence.

Genomic profiling of ctDNA-positive samples identified recurrent mutations in FLT1 (VEGFR1), PREX2, KRAS, BRAF, ATM, BRCA2 and PIK3CA.

Notably, FLT1 and PREX2 demonstrated strong associations with recurrence risk, highlighting potential future opportunities for MRD-directed precision therapies.

Is ctDNA Ready to Guide Treatment Decisions?

Despite its strong prognostic value, ctDNA is not yet fully established as a treatment-directing biomarker. Trials evaluating ctDNA-guided treatment escalation have produced mixed results, and persistent ctDNA positivity after standard chemotherapy remains common, indicating that current adjuvant regimens may be insufficient to eradicate molecular residual disease in many patients.

Currently, ctDNA appears most valuable as a complementary risk stratification tool integrated with TNM staging, Mismatch repair status, Molecular profiling  and traditional high-risk clinicopathologic features.

Ongoing studies, including CIRCULATE-US and other MRD-directed trials, aim to clarify whether ctDNA-guided treatment strategies can improve outcomes.

Looking Ahead

ctDNA testing has the potential to reshape postoperative colon cancer management through:

  • Personalized adjuvant therapy selection
  • Risk-adapted surveillance strategies
  • Earlier relapse detection
  • Integration with precision oncology approaches

Tissue-free assays may further support broader clinical adoption by eliminating the need for tumor tissue sequencing and streamlining workflow.

Conclusion

The N0147 analysis represents one of the largest evaluations of tissue-free MRD assessment in resected Stage III colon cancer. Postoperative ctDNA positivity emerged as a powerful independent predictor of recurrence and survival, refining prognostic assessment beyond traditional TNM staging.

Although ctDNA is not yet ready to direct treatment decisions independently, it is increasingly positioned as an important complementary biomarker in precision oncology and may ultimately play a central role in individualized postoperative management of colon cancer.

Tissue-Free Circulating Tumor DNA Assay and Patient Outcome in a Phase III Trial of FOLFOX-Based Adjuvant Chemotherapy (Alliance N0147). Sinicrope FA,  Segovia D,  Sharma N, et al. J Clin Oncol. 2026;44:1401-1415

FDA Approves ENHERTU® for Neoadjuvant Therapy in High-Risk HER2-Positive Early Breast Cancer

RR

SUMMARY: The FDA on May 15, 2026, approved fam-Trastuzumab deruxtecan-nxki (T-DXd, ENHERTU®), followed by a taxane, Trastuzumab, and Pertuzumab (THP) for the neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer, as determined by an FDA-authorized test. FDA also approved two companion diagnostic devices, the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the VENTANA HER2 Dual ISH DNA Probe Cocktail, both for identifying HER2-positive (IHC3+ or ISH+) patients for treatment with T-DXd, consistent with the approved drug labeling.

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 present FDA approval was based on DESTINY-Breast11 trial, which explored whether Antibody-Drug Conjugate (ADC)-based therapy, could improve efficacy, while reducing the toxicity burden associated with traditional Anthracycline and Carboplatin containing regimens.

Trial Design and Patient Population

DESTINY-Breast11 was a global, multicentre, open-label Phase III study conducted across 147 sites in 18 countries. The trial enrolled patients with high-risk, locally advanced, or inflammatory HER2-positive early-stage breast cancer, defined by lymph node-positive disease (N1-3) or primary tumors staged T3-4.

A total of 927 female patients were randomized across three treatment arms:

Patients assigned to the investigational combination arm received T-DXd 5.4 mg/kg intravenously every 3 weeks for four cycles followed by Paclitaxel 80 mg/m² weekly, Trastuzumab 6 mg/kg every 3 weeks and Pertuzumab 840 mg loading dose followed by 420 mg every 3 weeks for 4 cycles (T-DXd followed by THP; N=321)

The comparator arm received Dose-dense Doxorubicin 60 mg/m² every 2 weeks, Cyclophosphamide 600 mg/m² every 2 weeks for four cycles, followed by Paclitaxel 80 mg/m² weekly with concurrent Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks Pertuzumab 840 mg loading dose, followed by 420 mg every 3 weeks for 4 cycles. (Dose-dense AC followed by THP (ddAC-THP; N=320)

The T-DXd monotherapy arm evaluated eight cycles of T-DXd at 5.4 mg/kg every 3 weeks; however, enrollment into this cohort was discontinued early following an Independent Data Monitoring Committee (IDMC) review (T-DXd monotherapy; N=286)

Median patient age was 50 years, 88% had an ECOG performance status of 0, and approximately 72% had Hormone Receptor (HR)-positive disease. HER2 expression was strongly positive in most patients, with 88% classified as IHC 3+.

Primary Endpoint Met with Significant pCR Improvement

The Primary endpoint was centrally assessed pathological Complete Response (pCR), defined as ypT0/is ypN0 following surgery.

Results demonstrated 67.3% pCR rate with T-DXd-THP vs 56.3% with ddAC-THP. This translated into an absolute improvement of 11% (95% CI: 4.0%-18.3%; P=0.003). Importantly, benefit was observed across hormone receptor subgroups:

  • HR-positive disease: 61.4% vs 52.3%
  • HR-negative disease: 83.1% vs 67.1%

The magnitude of benefit in the HR-negative cohort was particularly notable, with an absolute pCR improvement exceeding 16%. Investigators also reported improved Residual Cancer Burden (RCB) outcomes with T-DXd-THP, with RCB-0/I rates reaching 81.3% compared with 69.1% for the standard regimen.

Early EFS Signal and Safety Advantages

While Event-Free Survival (EFS) data remain immature, early findings favored the investigational approach. At 4.5% maturity, the Hazard Ratio for EFS comparing T-DXd-THP with ddAC-THP was 0.56 (95% CI: 0.26-1.17). Equally important for clinical practice, the ADC-based regimen demonstrated a more favorable toxicity profile than the anthracycline-containing comparator.

Grade ≥3 adverse events occurred in 37.5% of patients receiving T-DXd-THP vs 55.8% with ddAC-THP. Serious adverse events were also reduced and occurred in 10.6% with T-DXd-THP vs 20.2% with ddAC-THP. Cardiac toxicity rates were lower with the investigational regimen, with all-grade left ventricular dysfunction reported in only 1.3% of patients receiving T-DXd-THP compared with 6.1% in the ddAC-THP arm.

Given ongoing concerns regarding anthracycline-associated cardiotoxicity, these findings may be particularly relevant when selecting therapy for patients with baseline cardiovascular risk factors.

Interstitial lung disease (ILD)/pneumonitis, an established toxicity associated with T-DXd, was infrequent and comparable across treatment groups, occurring in approximately 4%-5% of patients. Three treatment-related deaths were reported overall.

Closure of the T-DXd Monotherapy Arm

Although the T-DXd monotherapy arm passed a predefined futility analysis, enrollment was halted early after IDMC review. Investigators cited multiple contributing factors, including lower pCR rates, reduced likelihood of superiority over standard therapy, and timing considerations surrounding surgery. Observed pCR rates were 43.0% with T-DXd alone, 67.3% with T-DXd-THP, and 56.3% with ddAC-THP. Interpretation of the monotherapy cohort was further complicated by protocol-directed transitions to local standard-of-care therapy after enrollment closure.

Clinical Implications

DESTINY-Breast11 introduces compelling evidence supporting ADC-based neoadjuvant therapy in high-risk HER2-positive early breast cancer. The combination of T-DXd followed by THP not only improved pCR rates compared with an anthracycline-based standard but also reduced severe toxicities and cardiac adverse events.

The findings are especially notable given the trial’s predominantly HR-positive and high-risk patient population, where pCR rates are historically more difficult to achieve. As clinicians continue to balance efficacy against long-term toxicity risks, DESTINY-Breast11 raises the possibility that Anthracycline- and Carboplatin-free regimens may emerge as a new treatment paradigm for selected patients with HER2-positive early-stage disease. Longer follow-up will be essential to determine whether the substantial pCR gains observed in DESTINY-Breast11 ultimately translate into durable improvements in Event-Free and Overall Survival.

Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial. Harbeck N, Modi S, Pusztai L, et al., for the DESTINY-Breast11 Trial Investigators. Annals of Oncology, 2025; 37:166-179.

FDA Approves ENHERTU® in Postneoadjuvant Care for High-Risk HER2-Positive Early Breast Cancer

RR

SUMMARY: The FDA on May 15, 2026, approved fam-Trastuzumab deruxtecan-nxki (T-DXd, ENHERTU®) for the adjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant treatment with Trastuzumab (with or without Pertuzumab) and taxane-based treatment.

FDA also approved two companion diagnostic devices, the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the VENTANA HER2 Dual ISH DNA Probe Cocktail, both for identifying HER2-positive (IHC3+ or ISH+) patients for treatment with T-DXd, consistent with the approved drug labeling.

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®) 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®), 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

The present FDA approval was based on DESTINY-Breast05, which 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 receive T-DXd (5.4 mg/kg) every 3 weeks (N=818) or T-DM1 (3.6 mg/kg) every 3 weeks (N=817) for up to 14 cycles. The Primary endpoint was invasive DFS (IDFS), 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: About 52% presented with inoperable disease at disease presentation, about 81% had node-positive disease after neoadjuvant therapy and approximately 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

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.