Ashling Wahner

The addition of postsurgical Verzenio to endocrine therapy provided a benefit in HR–positive, HER2-negative breast cancer.

Among patients with hormone receptor (HR)-positive, HER2-negative, high-risk early breast cancer, postsurgical, or adjuvant, Verzenio (abemaciclib) plus endocrine therapy was associated with a 15.8% reduction in the risk of death when compared with endocrine therapy alone, clinical trial results have shown.

Findings from the primary overall survival (OS) analysis of the phase 3 monarchE trial were presented at the 2025 ESMO Congress.

At a median follow-up of 76 months (6.3 years) and a data cutoff date of July 15, 2025, all patients had stopped receiving Verzenio for at least four years. There were 301 OS events in the Verzenio arm versus 360 in the endocrine therapy–alone arm. The OS rates at 60, 72 and 84 months were 91.2%, 89.2% and 86.8% in the Verzenio arm versus 90.2%, 87.9% and 85.% in the control arm.

Overall Survival (OS): This is the length of time from diagnosis or the start of treatment that patients are still alive. It helps doctors understand how well a treatment may be working.

Invasive Disease–Free Survival (IDFS): This refers to the time after treatment during which a person has no signs of cancer coming back or spreading. It specifically focuses on more serious (invasive) cancer returning.

Distant Relapse–Free Survival (DRFS): This means how long a patient stays free from the cancer returning in other parts of the body (far from where it started), after finishing treatment.

Pharmacokinetics (PK): This is the study of how a medicine moves through the body—how it's absorbed, used, and cleared out. It helps doctors decide on the right dose and timing for treatment.

“[Verzenio] represents the first CDK4/6 inhibitor to achieve a statistically significant improvement in OS for these high-risk, node-positive patients,” Dr. Stephen Johnston stated in the presentation.

Johnston is head of the Breast Unit, a professor of breast cancer medicine, and a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in London, United Kingdom.

What Was the Impetus for Conducting the monarchE Trial?

“Improving OS and cure rates is the goal of adjuvant therapy in early breast cancer, but it's difficult to prove OS, and we often approve treatments on benefits in reducing risk of recurrence,” Johnston explained.

He summarized key findings from the past several years of investigating endocrine therapy in patients with hormone receptor–positive early breast cancer, including reductions in the risk of death conferred by the use of tamoxifen versus no treatment, the use of an aromatase inhibitor (AI) versus tamoxifen, and the use of extended AI treatment versus 5 years of endocrine therapy. He noted that unlike in prior trials, previously reported data from monarchE indicated that an OS benefit could emerge from the addition of Verzenio to endocrine therapy versus endocrine therapy alone. 

What Was the Design of the monarchE Trial?

monarchE enrolled patients with hormone receptor–positive, HER2-negative, mode-positive, high-risk early breast cancer. Cohort 1 included patients with high-risk disease based on clinical and pathological factors, including at least four positive axillary lymph nodes or one to three positive axillary lymph nodes and grade 3 disease and/or a tumor size of at least 5 cm. Cohort 2 included patients with high-risk disease based on Ki-67 score, defined as one to three positive axillary lymph nodes plus a Ki-67 score of at least 20%, as well as grade 3 or lower disease and a tumor size of less than 5 cm.

Patients in cohort 1 (5,637 patients) were randomly assigned to receive Verzenio at 150 mg twice daily plus endocrine therapy or endocrine therapy alone for the on-treatment study period of two years. During the follow-up period, patients received endocrine therapy for three to eight years as clinically indicated. Patients were stratified by prior chemotherapy, menopausal status and region.

The primary end point was invasive disease–free survival (IDFS). Secondary end points included IDFS in the high Ki-67 populations, distant relapse–free survival (DRFS), OS, safety, pharmacokinetics, and patient-reported outcomes.

What Data Have Been Previously Reported From monarchE?

The initial readout of the monarchE trial showed that patients who received two years of adjuvant Verzenio plus endocrine therapy had significant improvements in IDFS compared with those who received endocrine therapy alone. Furthermore, at the five-year landmark analysis of the trial, at a median follow-up of 54 months, the IDFS and DRFS benefits with Verzenio were sustained, and an OS trend favoring the Verzenio arm had emerged, although it had not yet reached statistical significance.

What Additional Data Were Seen in the Primary OS Analysis of monarchE?

In the primary OS analysis, the OS benefit with the addition of Verzenio was consistent across prespecified patient subgroups. However, Johnston emphasized that the point estimates for the individual subgroups should be interpreted with caution because the trial was not powered or controlled to evaluate treatment effects in individual subgroups.

There were approximately 30% fewer patients living with metastatic disease in the Verzenio arm versus the control arm. In the Verzenio arm, 2.8% of patients (n = 80) had died from causes unrelated to breast cancer, 7.9% of patients (n = 221) had died due to breast cancer, and 6.4% of patients (n = 180) were alive with metastatic disease. In the control arm, these rates were 2.3% (n = 64), 10.5% (n = 296), and 9.4% (n = 266), respectively.

The addition of Verzenio to endocrine therapy reduced the risk of IDFS events by 26.6% compared with endocrine therapy alone. There were 547 and 722 IDFS events in these respective arms.

During the follow-up period, the respective IDFS rates in the Verzenio and control arms were as follows:

A consistent IDFS benefit was observed across all prespecified subgroups.

Johnston noted that most IDFS events observed in the trial were distant metastatic disease, and that the addition of Verzenio reduced the number of patients with metastases at common sites. In the Verzenio arm (2,808 patients), 18% of patients in the intent-to-treat (ITT) population had a first recurrence, consisting of distant recurrence (13.6%), local/regional recurrence (2.5%), second primary neoplasm (1.7%) and contralateral breast cancer (0.5%). The sites of initial distant recurrence in this arm included bone (5.9%), liver (3.5%), lung (2.5%), brain/central nervous system (CNS; 1.1%), lymph node (1.0%) and pleura (0.3%).

In the control arm (2,829 patients), 24.5% of patients in the ITT population had a first recurrence, consisting of distant recurrence (18.5%), local/regional recurrence (3.9%), second primary neoplasm (1.8%) and contralateral breast cancer (0.8%). The sites of initial distant recurrence in this arm included bone (9.4%), liver (4.7%), lung (2.7%), brain/CNS (1.1%), lymph node (1.6%) and pleura (1%).

Overall, investigators observed low rates of second primary neoplasms across both arms.

A sustained DRFS benefit with the addition of Verzenio was also observed, reducing the risk of DRFS events by 25.4% compared with endocrine therapy alone. There were 476 DRFS events in the Verzenio arm versus 621 DRFS events in the control arm.

During the follow-up period, the respective DRFS rates in the Verzenio and control arms were as follows:

The investigators also reported a consistent DRFS benefit with Verzenio across prespecified subgroups.

Among patients in the Verzenio arm with distant recurrence who entered the post-two-year treatment follow-up period (407 patients), 78.9% received any first systemic therapy in the first-line metastatic setting, 32.7% received chemotherapy, 46.7% received endocrine therapy, 33.2% received targeted therapy (CDK4/6 inhibitor, 30.0%; PI3K/AKT/mTOR inhibitor, 3.2%) and 5.2% received other therapy. These respective rates in the control arm (565 patients) were 83.4%, 23.7%, 58.4%, 484.8% (CDK4/6 inhibitor, 47.3%; PI3K/AKT/mTOR inhibitor, 0.7%) and 4.8%.

Differences in CDK4/6 inhibitor and chemotherapy use between the arms were predominantly seen among patients with early recurrences and were less pronounced among those with later recurrences. Among patients with early recurrences, the rates of chemotherapy and CDK4/6 inhibitor use were 43.5% and 15.2%, respectively, in the Verzenio arm (191 patients) versus 26.8% and 44.7%, respectively, in the control arm (313 patients). Among patients with late recurrences, the usage rates of these respective classes of therapy were 23.1% and 43.1% in the Verzenio arm (216 patients) versus 19.8% and 50.4% in the control arm (252 patients).

“This makes clinical sense,” Johnston reported. “Patients relapsing on their adjuvant CDK4/6 inhibitor may be more likely to be offered chemotherapy. Those who have not had it in the adjuvant setting may be offered it for their metastatic disease. Remember, this was a global trial. Investigators could treat the patients as they saw fit. Globally, not all therapies in metastatic disease are equally available around the world, so we do not believe that this analysis confounds the OS impact we've seen. If there were more CDK4/6 inhibitors [used] in the endocrine therapy–alone arm, that might diminish the OS benefit, not enhance it.”

What Were the Long-Term Safety Findings From monarchE?

Safety results from long-term follow-up were consistent with those from prior analyses, because all treated patients had completed treatment at least four years prior. Investigators observed no relevant differences in side effect–related causes of death between the two arms.

Among safety-evaluable patients in the Verzenio arm (2,791 patients), during therapy, 15 deaths occurred; the most common causes of death were infections and infestations (COVID-19, three patients) and cardiac disorders (five patients). Following treatment discontinuation in this arm, 197 patients had at least one serious side effect during late-term follow-up, regardless of causality. There were 44 deaths attributed to side effects, including infections and infestations (13 patients; COVID-19, six patients), second primary neoplasm (13 patients) and cardiac disorders (six patients).

Among safety-evaluable patients in the control arm (2,800 patients), during therapy, 11 deaths occurred; the most common causes of death were infections and infestations (five patients; COVID-19, one patient) and second primary neoplasm (one patient). Following treatment discontinuation in this arm, 213 patients had at least one serious side effect during late-term follow-up, regardless of causality. There were 30 deaths attributed to side effects, including infections and infestations (five patients; COVID-19, two patients), second primary neoplasm (seven patients) and cardiac disorders (nine patients).

“The seven-year analysis has continued to show a sustained benefit in IDFS and DRFS, and there are no new safety signals,” Johnston concluded.

“Overall survival with abemaciclib in early breast cancer” by Dr. Stephen Johnston, et al. 

“Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE)” by Dr. Stephen Johnston, et al.

“Adjuvant abemaciclib plus endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer: results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes” by Dr. Priya Rastogi et al., 

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Articles

The phase 3 monarchE trial demonstrated that adding Verzenio (abemaciclib) to endocrine therapy significantly reduced the risk of death by 15.8% in patients with hormone receptor-positive, HER2-negative, high-risk early breast cancer. The trial, with a median follow-up of 76 months, showed improved overall survival (OS) and invasive disease-free survival (IDFS) rates in the Verzenio arm compared to endocrine therapy alone. The study highlighted Verzenio as the first CDK4/6 inhibitor to achieve a statistically significant OS improvement in this patient population, with consistent benefits across subgroups.

Verzenio Plus Endocrine Therapy Benefits Survival for Some With Breast Cancer

Camrelizumab plus famitinib extended progression-free survival to 11.1 months versus 7.5 months with chemotherapy in recurrent or metastatic cervical cancer.

Camrelizumab in combination with famitinib produced superior progression-free survival (PFS) outcomes versus platinum-based chemotherapy for the frontline treatment of patients with recurrent or metastatic cervical cancer, according to data from a phase 3 trial presented during the 

At the June 10, 2025, data cutoff, at a median follow-up of 19.3 months, the median progression-free survival (PFS) per blinded independent central review (BICR) was 11.1 months in the combination arm (220 patients) compared with 7.5 months in the chemotherapy arm (223 patients). The median PFS values per investigator assessment were 11.3 months and 7.7 months, respectively.

“The chemotherapy-free regimen of camrelizumab/famitinib significantly prolonged PFS and overall survival [OS] compared with platinum-based chemotherapy with or without bevacizumab [Avastin] as first-line treatment in recurrent/metastatic cervical cancer,” Dr. Xiaohua Wu, chief physician, professor and supervisor of oncology, as well as the chairman and chief expert in the Department of Gynecologic Oncology at Fudan University Shanghai Cancer Center in China, said during the presentation. “This regimen met the dual primary end points at interim analysis.”

How was the phase 3 trial designed and what were the baseline characteristics?

The open-label, controlled, multicenter study enrolled patients with histopathologically confirmed, recurrent or metastatic squamous cell carcinoma of the cervix. Patients were required to not be amenable to curative therapy, surgery, radiotherapy or chemoradiotherapy and could not have received prior systemic therapy for recurrent or metastatic disease. Other key inclusion criteria included having at least one measurable tumor lesion according to RECIST 1.1 criteria and an ECOG performance status of 0 or 1.

Progression-free survival (PFS): time during and after treatment that a patient lives without the cancer growing or spreading.

Overall survival (OS): time from treatment start until death from any cause.

Overall response rate (ORR): percentage of patients whose cancer shrinks or disappears after treatment.

Disease control rate (DCR): percentage of patients whose cancer shrinks, disappears, or remains stable after treatment.

Duration of response (DOR): length of time a treatment keeps cancer under control after it first responds.

Time to response (TTR): time from treatment start until the cancer first shows a response.

ECOG performance status: scale used by doctors to measure how well a patient can carry out daily activities, ranging from 0 (fully active) to 5 (dead).

Patients were randomly assigned one-to-one to receive intravenous (IV) camrelizumab at 200 milligrams (mg) every three weeks for up to 35 cycles plus oral famitinib at 20 milligrams daily, or platinum-based chemotherapy every three weeks for up to 6 cycles with or without IV bevacizumab at 15 milligrams per square meter every three weeks. Stratification was performed by PD-L1 combined positive score (CPS; greater than or equal to 1 versus less than 1) and prior use of platinum (yes versus no).

The dual primary end points were BICR-assessed PFS per RECIST 1.1 criteria and overall survival (OS). Secondary end points included investigator-assessed PFS, overall response rate (ORR), disease control rate (DCR), duration of response (DOR), time to response (TTR) and safety.

At baseline, the median ages in the combination and chemotherapy arms were 55 years and 54 years, respectively. Most patients in these respective arms had a PD-L1 CPS of at least 1 (93.2% versus 92.8%), had metastatic disease (97.7% versus 97.3%), had received prior platinum-containing therapy (70.9% versus 70%) and had received prior therapy (95.5% versus 96%). At diagnosis, patients had stage 1 (15.9% versus 13.9%), 2 (32.7% versus 35.4%), 3 (38.2% versus 37.2%), 4A (0.5% versus 1.8%), 4B (8.2% versus 8.1%) or unknown (4.5% versus 3.6%) disease. Prior therapies included surgery (48.2% versus 44.8%), radiotherapy (85.5% versus 88.3%) and systemic anticancer treatment (86.8% versus 85.7%); 30.9% of patients in the chemotherapy arm received bevacizumab during the study.

What were the additional efficacy data and safety profile of the combination?

The median OS in the combination arm was 34.4 months compared with 23.4 months in the chemotherapy arm. Findings from a subgroup analysis revealed that the PFS benefit in favor of the combination arm was reported in all prespecified subgroups except for the subgroup of patients with a PD-L1 CPS of less than 1. The OS benefit with the combination was reported in all prespecified subgroups.

The BICR-assessed confirmed ORR in the combination arm was 52.3% versus 46.6% in the chemotherapy arm, including respective complete response rates of 10.9% and 8.5%. The confirmed DCRs were 81.8% and 77.6%, respectively. The median DORs were 17.9 months and 8.3 months, respectively, and the respective median TTRs were 2.2 months and 2.1 months.

In terms of safety, any-grade treatment-emergent side effects occurred in 99.5% of patients in the combination arm and 99.1% of patients in the chemotherapy arm. Patients in both arms experienced grade 3 to 5 treatment-related side effects (87.3% versus 67.1%), serious treatment-related side effects (34.5% versus 19.2%), as well as side effects leading to treatment discontinuation (13.6% versus 6.6%), dose interruption (83.6% versus 37.6%) and dose reduction (65% versus 12.2%). Patients in the combination arm experienced any-grade immune-related (38.2%) and grade 3 to 5 immune-related (7.3%) side effects; no such events were reported in the chemotherapy arm.

The most common any-grade side effects in the combination arm included decreased white blood cell count (79.5%), decreased neutrophil count (75%) and anemia (70%). These were also the most common any-grade side effects in the chemotherapy arm, occurring at respective rates of 73.7%, 70% and 75.6%.

“The safety profile was manageable. These study findings show that camrelizumab plus famitinib could serve as a novel first-line treatment option for this patient population,” Wu said in his conclusion.

“Phase 3 study of camrelizumab plus famitinib versus platinum-based chemotherapy as first-line therapy for recurrent or metastatic cervical cancer” by Dr. Xiaohua Wu, et al., 

“Camrelizumab combined with famitinib malate for treatment of recurrent/metastatic cervical cancer” by Dr. Xiaohua Wu, et al., 

For more news on cancer updates, research and education,

Camrelizumab combined with famitinib demonstrated superior progression-free survival (PFS) and overall survival (OS) compared to platinum-based chemotherapy in patients with recurrent or metastatic cervical cancer. The phase 3 trial showed a median PFS of 11.1 months for the combination versus 7.5 months for chemotherapy. The combination also achieved a median OS of 34.4 months compared to 23.4 months for chemotherapy. Despite a higher incidence of treatment-related side effects, the safety profile was deemed manageable, suggesting the combination as a potential first-line treatment option.

Camrelizumab Combo Extends Survival in Metastatic Cervical Cancer

Platinum chemo with Imfinzi, Avastin, and Lynparza improved progression-free survival versus chemo and Avastin but did not extend overall survival.

Platinum-based chemotherapy plus Imfinzi (durvalumab), Avastin (bevacizumab), and Lynparza (olaparib) showed a statistically significant and clinically meaningful improvement in median progression-free survival versus chemotherapy and Avastin for the treatment of patients with newly diagnosed non-tBRCA–mutated ovarian cancer, but did not provide a significant overall survival benefit, according to final overall survival data from the DUO-O trial presented during the 

At a median follow-up of 56 months, findings from the third data cutoff demonstrated that the median progression-free survival among patients with non-tBRCA–mutated disease in the intention-to-treat population who received chemotherapy with Imfinzi, Avastin, and Lynparza (arm 3; 378 patients) was 25.1 months compared with 19.3 months among those who received chemotherapy and Avastin (arm 1; 378 patients). Patients who received chemotherapy plus Avastin and Imfinzi (arm 2; 374 patients) had a median progression-free survival of 20.6 months, representing a benefit versus arm 1.

The 24- and 48-month progression-free survival rates were 53% and 30% in arm 3; these respective rates were 39% and 22% in arm 2 and 33% and 16% in arm 1. However, the median overall survival in arm 3 was 50.5 months compared with 49.6 months in arm 1. Similarly, the median overall survival in arm 2 was 48.5 months, which did not represent a significant benefit versus arm 1. In arm 3, the 24- and 48-month overall survival rates were 83% and 53%; these respective rates were 81% and 51% in arm 2 and 80% and 51% in arm 1.

“DUO-O met both primary end points at data cutoff 1, with a statistically significant and clinically meaningful progression-free survival improvement for arm 3 versus arm 1 in the HRD-positive and intention-to-treat populations; this benefit was maintained at data cutoff 3 with an approximate median follow-up of 56 months,” Dr. Carol Aghajanian, the chief of the Gynecologic Medical Oncology Service and the Avon Chair in Gynecologic Oncology Research at Memorial Sloan Kettering Cancer Center in New York, New York, said during the presentation. “At this final overall survival analysis, the observed progression-free survival benefits did not translate into a statistically significant overall survival improvement.”

DUO-O was a double-blind, multicenter study that examined Imfinzi plus platinum-based chemotherapy and Avastin followed by maintenance Imfinzi and Avastin or Imfinzi, Avastin, and Lynparza in patients with newly diagnosed advanced ovarian cancer. Eligible patients needed to have FIGO stage 3 to 4 ovarian, primary peritoneal, and/or fallopian-tube cancer, as well as be candidates for cytoreductive surgery. Patients also needed to be at least 18 years old, or at least 20 years old if they enrolled in Japan, have an ECOG performance status of 0 or 1, and have preserved organ and bone marrow function. Eligible patients were randomly assigned one-to-one-to-one to arms 1, 2, or 3.

During the chemotherapy phase, all patients received chemotherapy in combination with Avastin; those in arms 2 and 3 also received Imfinzi. During the maintenance phase, patients in arms 1, 2, and 3 received Avastin, Avastin plus Imfinzi, or Avastin plus Imfinzi and Lynparza, respectively. Maintenance therapy continued for up to 2 years. The primary end point was investigator-assessed progression-free survival per RECIST 1.1 criteria in arm 3 versus arm 1 in both the non-BRCA–mutated HRD-positive and intention-to-treat populations. Key secondary end points included investigator-assessed progression-free survival per RECIST 1.1 criteria in arm 2 versus arm 1 in the non-BRCA–mutated intention-to-treat population, overall survival, and safety.

Additional efficacy findings from DUO-O data cutoff 3 revealed that the median progression-free survival among patients with non-tBRCA–mutated, HRD-positive disease was 45.1 months in arm 3 (140 patients) compared with 23.3 months in arm 1 (143 patients). In arm 2 (148 patients), the median progression-free survival was 25.6 months, representing a benefit versus arm 1. In arm 3, the 24- and 48-month progression-free survival rates were 73% and 47%; these respective rates were 52% and 31% in arm 2 and 47% and 27% in arm 1.

In terms of overall survival among patients with non-tBRCA–mutated, HRD-positive disease, the median value was not reached in arms 2 and 3. When compared with the 66.8-month median overall survival in arm 1, patients in arm 3 experienced a 20% reduction in the risk of death and those in arm 2 had a 16% reduction. In arm 3, the 24- and 48-month overall survival rates were 96% and 71%; these respective rates were 92% and 71% in arm 2 and 89% and 68% in arm 1.

In terms of safety, any-grade side effects were reported in arms 1 (99.2%), 2 (99.5%), and 3 (99.2%). Grade 3 (severe) or higher side effects (62% versus 66% versus 73%), side effects leading to death (1.3% versus 2.4% versus 2.1%), serious side effects (35% versus 44% versus 40%), immune-mediated side effects (35% versus 57% versus 54%), side effects leading to dose modification (72% versus 80% versus 86%), and side effects leading to treatment discontinuation (21% versus 27% versus 35%) were reported in all three arms. Side effects of special interest associated with Lynparza that occurred in all three arms consisted of new primary malignancies (0.8% versus 0.3% versus 1.9%) and pneumonitis (0.8% versus 1.6% versus 1.9%).

“Safety continues to be generally consistent with the known profiles of each agent,” Aghajanian said in her conclusion.

“Imfinzi + paclitaxel/carboplatin + Avastin followed by Imfinzi, Avastin + Lynparza maintenance in patients with newly diagnosed non-tBRCA–mutated advanced ovarian cancer: final overall survival from DUO-O” by Dr. Carol Aghajanian, et al., Presented at the 2025 ESMO Congress

“Imfinzi treatment in combination with chemotherapy and Avastin, followed by maintenance Imfinzi, Avastin, and Lynparza in advanced ovarian cancer patients (DUO-O)” by Dr. Carol Aghajanian, ClinicalTrials.gov

The DUO-O trial evaluated the efficacy of combining platinum-based chemotherapy with Imfinzi, Avastin, and Lynparza in patients with newly diagnosed non-tBRCA–mutated ovarian cancer. The combination significantly improved median progression-free survival compared to chemotherapy and Avastin alone, but did not yield a significant overall survival benefit. The study, a double-blind, multicenter trial, involved patients with advanced ovarian cancer, assessing progression-free survival as the primary endpoint. Safety profiles were consistent with known drug profiles, with notable side effects including immune-mediated reactions and treatment discontinuations.

Imfinzi Combo Improves Progression Free Survival in Ovarian Cancer

Enhertu led to a 53% reduction in the risk of invasive disease or death versus Kadcyla in some patients with high-risk, HER2-positive breast cancer.

Among patients with high-risk, HER2-positive primary breast cancer with residual invasive disease following neoadjuvant therapy, treatment with Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) was associated with a statistically significant and clinically meaningful improvement in invasive disease–free survival (IDFS) versus Kadcyla (ado-trastuzumab emtansine; T-DM1), clinical trial results have shown.

Interim analysis findings from the phase 3 DESTINY-Breast05 trial were presented at the 2025 ESMO Congress.

Treatment with Enhertu (818 patients) led to a 53% reduction in the risk of invasive disease or death compared with Kadcyla (817 pstients). The three-year IDFS rates were 92.4% with Enhertu versus 83.7% with Kadcyla.

Glossary:

·Invasive Disease–Free Survival (IDFS): the time a patient lives without the original cancer returning, without a new invasive cancer appearing, and without dying from any cause.

·Overall Survival (OS): the total length of time, usually measured from diagnosis or the start of treatment, that a patient is still alive.

·ECOG Performance Status (PS): a simple scale doctors use to measure how a patient's cancer is affecting their daily energy and ability to perform routine activities.

·Interstitial Lung Disease (ILD): a general term for a group of chronic lung disorders that cause inflammation and scarring of the lung tissue, which can make it hard to breathe.

·Distant Recurrence-Free Survival: the time a patient lives after treatment without the cancer coming back in a part of the body far away from the original tumor site.

·Radiation Pneumonitis: a side effect that causes inflammation and irritation of the lungs, typically occurring weeks to months after receiving radiation therapy to the chest area.

·Anemia: a common condition where the blood doesn't have enough healthy red blood cells to carry adequate oxygen from your lungs to the rest of your body, often leading to fatigue.

·Increased Aspartate Aminotransferase Levels (AST): a finding on a blood test that shows a higher-than-normal amount of the AST enzyme, which is often a sign of damage or irritation to the liver or other organs like muscle or heart.

·Increased Alanine Aminotransferase Levels (ALT): a finding on a blood test that shows a higher-than-normal amount of the ALT enzyme, which is a common indicator of liver injury or inflammation.

·Arthralgia: the medical term for pain or stiffness experienced in one or more joints, such as the knees, elbows, or wrists.

“Patients benefited [from Enhertu] irrespective of age cohorts, region of accrual, hormone receptor status, disease status at presentation, post-therapy pathologic nodal status and dual or single HER2-targeted therapy, as well as irrespective of the sequence or usage of radiation therapy for that minority of patients who did not receive [radiation] treatment,” Dr. Charles E. Geyer Jr. said in the presentation.

Geyer is a professor of medicine and chief of the Division of Malignant Hematology and Medical Oncology at the University of Pittsburgh Medical Center Hillman Cancer Center.

What Was the Rationale for DESTINY-Breast05?

Previously, the phase 3 KATHERINE trial showed that Kadcyla improved IDFS and overall survival compared with Herceptin (trastuzumab) in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy. However, patients with advanced locoregional disease or positive nodal status following neoadjuvant therapy had three-year IDFS rates of 76% and 83%, respectively; the seven-year IDFS rates were 67% and 72%, respectively. These data reinforce the unmet need for improved post-neoadjuvant treatment in this population, Geyer emphasized.

This global, multicenter, randomized, open-label trial enrolled patients with residual invasive disease in the breast and/or axillary lymph nodes after neoadjuvant chemotherapy with a HER2-directed therapy. Patients needed to present with high-risk disease prior to neoadjuvant therapy, defined as inoperable early breast cancer or operable early breast cancer with axillary node–positive disease after neoadjuvant therapy. Patients also needed to have centrally confirmed HER2-positive disease and an ECOG performance status of 0 or 1. Enrolled patients were stratified by extent of disease at presentation (inoperable versus operable), type of HER2-targeted neoadjuvant therapy received (single versus dual), hormone receptor status (positive versus negative), and post-neoadjuvant therapy pathologic nodal status (positive versus negative).

Patients were randomly assigned to receive intravenous (IV) Enhertu at 5.4 mg/kg every three weeks for 14 cycles, or IV Kadcyla at 3.6 mg/kg every three weeks for 14 cycles. Treatment was followed by a 40-day safety follow-up period.

Notably, concomitant adjuvant endocrine therapy was allowed per local practice protocols. Additionally, radiotherapy, if administered, could be initiated concurrently with study therapy or completed prior to the initiation of study therapy per the investigator. An interstitial lung disease (ILD) monitoring program was required for patients who received radiotherapy.

IDFS served as the primary end point, with disease-free survival (DFS) as a key secondary end point. Other secondary end points included OS, distant recurrence–free interval (DRFI), brain metastasis–free interval (BMFI) and safety.

What Did the DESTINY-Breast05 Patient Population Look Like?

In total, 1635 patients were randomly assigned to receive Enhertu (818 patients) or Kadcyla (817 patients). In the Enhertu arm, 806 patients received treatment. A total of 27.7% of patients in this arm discontinued treatment due to side effects (17.9%), patient withdrawal (7.4%), disease recurrence (0.2%), physician decision (1.9%) and protocol deviation (0.2%). In total, 72.3% of patients in this arm completed study treatment, and the median study duration was 29.9 months.

In the Kadcyla arm, 801 patients received treatment. A total of 23.7% of patients in this arm discontinued treatment due to side effects (12.7%), patient withdrawal (6.2%), disease recurrence (3.7%), physician decision (0.6%), protocol deviation (0.1%) and other reasons (0.1%). In total, 76.3% of patients in this arm completed study treatment, and the median study duration was 29.7 months.

In the Enhertu arm, the median age was 50.3 years, Asian patients were the most predominant race (48.8%), and most patients had HER2 3+ disease by immunohistochemistry (IHC) (82.6%), hormone receptor–positive disease (71%), inoperable disease (52.7%), positive nodal status (80.7%), received dual HER2-targeted therapy with Herceptin plus Perjeta (pertuzumab) (77.9%), prior anthracycline use (51.7%) and received prior adjuvant radiotherapy (93.4%). In the Kadcyla arm, the median age was 50.6 years, Asian patients were the most predominant race (47.2%), and the highest proportions of patients had HER2 3+ disease by IHC (82.%), hormone receptor–positive disease (71.4%), inoperable disease (51.9%), positive nodal status (80.5%), received dual HER2-targeted therapy with Herceptin plus Perjeta (78.5%), prior anthracycline use (48.8%), and received prior adjuvant radiotherapy (92.9%).

What Additional Efficacy Outcomes Were Observed in DESTINY-Breast05?

Overall, investigators observed lower rates of distant and local recurrences, including central nervous system (CNS) recurrences, with Enhertu versus Kadcyla. The numbers of patients with recurrences in these respective arms were as follows:

Distant recurrence: 42 (non-CNS, 25; CNS, 17); 77 (non-CNS, 52; CNS, 25)

A DFS benefit was observed with Enhertu versus Kadcyla. The three-year DFS rates were 92.3% with Enhertu versus 83.5% with Kadcyla.

DRFI, BMFI and OS benefits were also seen with Enhertu versus Kadcyla. The respective three-year DRFI rates were 93.9% and 86.1%. The respective three-year BMFI rates were 97.6% and 95.1%. The respective three-year OS rates were 97.4% and 95.7%.

Regarding on-study treatment exposure, in the Enhertu arm, the median study treatment duration was 9.8 months, and 72.3% of patients completed the planned 14 cycles of therapy. In the Kadcyla arm, the median study treatment duration was 9.7 months, and 76.3% of patients completed the planned 14 cycles of therapy. Notably, patients who discontinued the study before receiving 14 cycles of study treatment were permitted to receive an additional HER2-targeted therapy per standard of care (SOC) guidelines to complete 14 total cycles of HER2-targeted adjuvant therapy.

What Was the Safety Profile of Enhertu vs Kadcyla in DESTINY-Breast05?

In the Enhertu arm, any-grade treatment-emergent side effects were reported in 99.5% of patients, and 50.6% of patients experienced grade 3 (severe) or higher treatment-emergent side effects. Serious treatment-emergent side effects (17.4%) and those associated with drug discontinuation (17.9%; drug-related ILD/pneumonitis, 10.8%), drug interruptions (49.6%), dose reductions (26.4%) and deaths (0.4%; ILD/pneumonitis, two patients; respiratory tract infection adjudicated as not ILD, one patient) also occurred.

In the Kadcyla arm, any-grade treatment-emergent side effects were reported in 98.4% of patients, and 51.9% of patients experienced grade 3 or higher treatment-emergent side effects. Serious treatment-emergent side effects (13.6%) and those associated with drug discontinuation (12.9%; drug-related ILD/pneumonitis, 2.5%), drug interruptions (41.1%), dose reductions (26.6%) and deaths (0.6%; leiomyosarcoma of the uterus, aneurysm, non-neutropenic sepsis, ovarian cancer and traumatic pneumothorax, one each) also occurred.

The most commonly reported treatment-emergent side effects in the Enhertu and Kadcyla arms, respectively, were nausea (71.3%; 29.3%), constipation (32.0%; 16.2%), decreased neutrophil counts (31.6%; 14.4%), vomiting (31.0%; 9.0%), decreased white blood cell counts (29.7%; 13.0%), fatigue (29.5%; 20.2%), radiation pneumonitis (28.8%; 27%), anemia (28.3%; 17.0%), increased aspartate aminotransferase levels (25.6%; 50.2%), increased alanine aminotransferase levels (23.7%; 45.3%), diarrhea (23.2%; 8.6%), decreased platelet counts (21.2%; 49.8%), decreased appetite (20.0%; 10%), headache (15.8%; 20.7%), and arthralgia (10.3%; 20.5%).

The rates of adjudicated drug-related ILD in the Enhertu and Kadcyla arms were as follows:

No differences in adjudicated drug-related ILD instances were observed based on adjuvant radiotherapy timing (sequential or concurrent). Investigators observed similar distributions of any-grade adjudicated drug-related ILD events with sequential (Enhertu arm, 10.7%; Kadcyla arm, 2.6%) and concurrent (9.6%; 1%) radiotherapy.

The rates of left ventricular dysfunction in the Enhertu and Kadcyla arms were as follows:

“Adjuvant [Enhertu] demonstrated superior efficacy with manageable safety in patients with high-risk, HER2-positive early breast cancer and residual invasive disease after neoadjuvant therapy, which represents a potential new SOC in this post-neoadjuvant setting,” Geyer concluded.

“Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with high-risk human epidermal growth factor receptor 2–positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy (tx): interim analysis of DESTINY-Breast05,” Dr. Charles E. Geyer et al., presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA1.

Kadcyla. Prescribing information. Genentech; revised May 2025; https://www.gene.com/download/pdf/kadcyla_prescribing.pdf

Enhertu (fam-trastuzumab deruxtecan-nxki) demonstrated a significant improvement in invasive disease-free survival (IDFS) compared to Kadcyla (ado-trastuzumab emtansine) in patients with high-risk, HER2-positive primary breast cancer with residual invasive disease post-neoadjuvant therapy. The DESTINY-Breast05 trial showed a 53% reduction in the risk of invasive disease or death with Enhertu. Enhertu's efficacy was consistent across various patient subgroups, and it showed benefits in disease-free survival, distant recurrence-free interval, and overall survival. Enhertu's safety profile was manageable, with notable side effects including interstitial lung disease.

Ashling Wahner

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