Chris Ryan

Eflornithine plus Gleostine was associated with superior overall survival and progression-free survival in grade 3 IDH-mutated astrocytoma.

Among patients with recurrent grade 3 IDH-mutated astrocytoma, 

he addition of eflornithine to Gleostine (lomustine) was associated with clinically meaningful overall survival (OS) and progression-free survival (PFS) benefits when compared with treatment via Gleostine alone, study results have shown.

Updated data from the phase 3 STELLAR study were presented during the 2025 Society of Neuro-Oncology Annual Meeting.

In the updated analysis, investigators reclassified patients from the original intention-to-treat (ITT) population (343 patients) using updated molecular classification to identify a subset of patients (57%) who had grade 3/4, IDH-mutated astrocytoma.

Progression-Free Survival (PFS): This measures how long a patient lives without their cancer getting worse (progressing).

Overall Survival (OS): The length of time from the start of diagnosis or treatment until a patient dies.

Karnofsky Performance Status (KPS): This is a score (from 0 to 100) that doctors use to measure a patient's general well-being and their ability to perform daily activities.

Myelosuppression: This is a side effect where a treatment, like chemotherapy or radiation, slows down or stops the production of new blood cells in the bone marrow (the soft tissue inside your bones).

Patients with grade 3 or 4 disease who received the combination (116 patients) achieved a median OS of 28.5 months compared with 22.3 months among those who received Gleostine monotherapy (119 patients). The median PFS values were 12.3 months and 7.3 months, respectively. Additionally, findings from a blinded independent central MRI review of PFS among patients with grade 3 disease revealed that the PFS benefit with eflornithine was consistent with the investigator-assessed PFS benefit.

“This updated classification based on [World Health Organization] 2021 [criteria] of the STELLAR population confirms the benefit of eflornithine in grade 3, IDH-mutant, CDK-intact population,” Dr. Howard Colman explained during the presentation. “The blinded independent review of the MRI results confirms the PFS benefit observed by investigators and the high correlation between the effect of PFS and OS in this subgroup. This is the first demonstration of a clinically significant OS and PFS benefit in a randomized study in this population.”

Colman is a Jon M. Huntsman Presidential Professor in the Department of Neurosurgery, a member of the multidisciplinary Brain Tumor Research Team and the leader of the Center for Neurologic Cancers at Huntsman Cancer Institute (HCI) at the University of Utah. He is also an HCI investigator and a member of the Experimental Therapeutics program.

STELLAR was an open-label study that enrolled patients a surgical or biopsy-proven diagnosis of WHO grade 3 anaplastic astrocytoma. Patients were also required to have experienced their first instance of disease progression or recurrence at least six months after the completion of external beam radiation therapy (ERBT). Prior treatment with ERBT and Temodar (temozolomide) plus chemotherapy prior to the first instance of disease progression or recurrence was required, as was a Karnofsky Performance Status (KPS) of at least 70 and adequate organ function.

“The STELLAR trial started in 2016 under the prior WHO diagnostic criteria, [and] this created several difficulties, but [an] extensive effort was made to gather historical archival tissue to reclassify the population based on 2021 WHO criteria,” Colman explained.

Patients were randomly assigned to receive eflornithine plus Gleostine (arm A) or Gleostine monotherapy (arm B). Patients in arm A received eflornithine at 2.8 g/m

 on a two-weeks-on, one-week-off schedule for up to 24 months in combination with Gleostine at 90 mg/m

 once on day 15 and once every six weeks during the eflornithine off weeks for up to six cycles or 12 months, whichever came first. Patients in arm B received Gleostine at 100 mg/m

 once every six weeks for up to six cycles or 12 months, whichever came first.

At baseline, the median age in the ITT population (343 patients) was 43 years. Most patients were 45 years old or younger (56%), male (60.9%), underwent one or two surgical resections (86%), and had a KPS of at least 90 (68.0%). The median time from the last dose of radiation therapy to random assignment was 26.6 months.

Previously reported data for the ITT population showed that patients treated with the combination (172 patients) achieved a median OS of 23.4 months versus 20.3 months for those given Gleostine alone (171 patients). The median PFS was 8.9 months versus 7.2 months, respectively.

What was the safety profile of the combination?

In terms of safety, patients in the combination arm experienced grade 3 (severe) or higher treatment-emergent side effects related to eflornithine or Gleostine at respective rates of 50.9% and 45.6%. Grade 3 or higher treatment-emergent side effects of relevance were reported at a rate of 63.9% and included myelosuppression (39.6%), hearing loss (23.7%) and diarrhea (9.5%). Serious treatment-emergent side effects related to eflornithine or Gleostine were reported at rates of 7.7% and 3.6%, respectively.

In the monotherapy arm, grade 3 or higher treatment-emergent side effects related to Gleostine occurred in 33.3% of patients. Grade 3 or higher TEAEs of relevance (30%) included myelosuppression (28.7%), seizure (1.3%) and nausea (0.7%). Serious treatment-emergent side effects related to study treatment were also reported (2.7%).

“[The] toxicities were consistent with prior eflornithine; gastrointestinal [side effects] and decreased hearing were the notable toxicities,” Colman said.

“Updated results of phase 3 STELLAR trial: eflornithine improves overall survival and blinded independent central review determined progression free survival in patients with recurrent WHO 2021 grade 3 IDH-mutant astrocytoma” by Dr. Howard Colman et al. Presented at: 2025 SNO Annual Meeting; November 19-23, 2025; Honolulu, HI. Abstract CTNI-58.

“Study to evaluate eflornithine + lomustine vs lomustine in recurrent anaplastic astrocytoma (AA) patients (STELLAR);” https://clinicaltrials.gov/study/NCT02796261

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Articles

The addition of eflornithine to Gleostine in patients with recurrent grade 3 IDH-mutated astrocytoma demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) compared to Gleostine alone. The phase 3 STELLAR study reclassified patients using updated molecular criteria, confirming the benefits of eflornithine in this subgroup. The combination therapy showed a median OS of 28.5 months versus 22.3 months for monotherapy. Safety profiles indicated higher rates of severe side effects with the combination, including myelosuppression and hearing loss, consistent with known eflornithine toxicities.

Eflornithine Plus Gleostine Improves Progression, Survival In Some With Astrocytoma

Voranigo plus Temodar was safe in glioma with IDH1/2 mutations.

Among patents with IDH1- or IDH2-mutant glioma, the treatment combination of Voranigo (vorasidenib) plus Temodar (temozolomide) did not lead to any serious side effects or dose-limiting toxicities (DLTs), clinical trial results have shown.

Data from the phase 1b IDHEAL-4U trial were presented at the 2025 Society for Neuro-Oncology Annual Meeting.

Findings demonstrated that, with a median treatment duration 5.5 months, all patients (seven patients) experienced any-grade treatment-emergent side effects; 28.6% (two patients) had grade 3 (severe) or higher treatment-emergent side effects, which included decreased neutrophil count (14.3%) and decreased platelet count (28.6%). No patients discontinued treatment due to treatment-emergent side effects, and all patients completed the DLT evaluation portion of the study. As of the Sept. 8, 2025, data cutoff, 85.7% (six patients) remained on treatment with both study drugs.

Increased alanine aminotransferase (ALT) levels: 

ALT is an enzyme found mostly in the liver. When ALT levels are higher than normal on a blood test, it can be a sign that the liver is irritated or damaged. 


The Karnofsky performance status is a score doctors use to describe how well a person with cancer is able to carry out daily activities. The scale goes from 0 to 100. A higher number means the person is more active and able to care for themselves; a lower number means they need more help. 

Treatment-emergent side effects led to dose reductions in 42.9% of patients; notably, 14.3% required dose reductions of only Voranigo, 28.6% needed dose reductions of only Temodar, and no patients required dose reductions of both agents. Dose reductions of Voranigo stemmed from increased alanine aminotransferase (ALT) levels (14.3%), and reductions of Temodar were due to decreased platelet count (28.6%) and decreased neutrophil count (14.3%).

Treatment-emergent side effects required study drug interruption in 57.1% of patients, including 28.6% who needed dose interruptions of both treatments, which was due to increased ALT levels (28.6%). Only Voranigo was interrupted in 14.3% of patients, and only Temodar was interrupted in 57.1% of patients. Treatment-emergent side effects leading to dose interruptions of only Voranigo included increased ALT levels (14.3%), and these included neutropenia (42.9%) and decreased platelet count (42.9%) for Temodar only.

“Based on data from the May 6, 2025, data cutoff, the safety review committee declared [Voranigo at] 40 mg as the recommended combination dose [RCD] to be given in combination with standard-of-care [Temodar],” lead study author Dr. Macarena de la Fuente and colleagues wrote in a poster presentation of the data.

de la Fuente is an associate professor of neuro-oncology, chief of the Neuro-Oncology Division, clinical service leader for Neuro-Oncology Service Line - Sylvester Comprehensive Cancer Center, chair of the Neuro-Oncology Site Disease Group, director of the Neuro-Oncology Fellowship Program, and oncology clinical service leader for Neuro-Oncology at the Miller School of Medicine of University of Miami in Florida.

Why are Voranigo and Temodar being evaluated as a combination strategy in 

Although Voranigo is approved by the FDA for the treatment of adult and pediatric patients 12 years of age and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, as detected by an FDA-approved test, following surgery including biopsy, sub-total resection, or gross total resection, treatment with IDH inhibitor monotherapy is unlikely to lead to disease control in patients with higher-grade, more aggressive gliomas.

As such, de la Fuente and colleagues hypothesized that adding Voranigo to Temodar could, “exploit the molecular vulnerabilities of higher-grade [IDH1/2-mutant] gliomas while controlling more rapidly proliferative tumor cells.”

IDHEAL-4U is a multicenter phase 1b/2 trial designed to evaluate the combination, with phase 1b focusing on safety, and the ongoing phase 2 portion looking at preliminary efficacy, safety, and tolerability for the RCD in patients with grade 4 astrocytoma harboring IDH1/2 mutations.

In phase 1b, investigators enrolled patients at least 12 years of age with grade 2 to 4 gliomas with IDH1/2 mutations who were eligible for Temodar in the adjuvant setting after radiotherapy or at first disease recurrence.

Voranigo was first evaluated at 40 mg once per day in combination with Temodar at 150 mg/m

 in cycles 2 to 12. Voranigo was continued until disease progression. After safety review committee input and analysis of DLT rate and BOIN design, investigators could dose de-escalate to evaluate Voranigo to 20 mg per day, or declare the RCD.

What were the patient characteristics in phase 1b?

The seven enrolled patients had a median age of 36 years, and 57.1% were female. Karnofsky performance status at baseline included 100 (14.3%), 90 (57.1%), 80 (14.3%) and 70 (14.3%). Patient tumor types included frontline grade 3 astrocytoma (42.9%), frontline grade 4 astrocytoma (14.3%), recurrent grade 4 astrocytoma (14.3%), frontline grade 3 oligodendroglioma (14.3%) and recurrent grade 4 oligodendroglioma (14.3%).

All patients had received prior radiation therapy. Three patients (42.9%) received prior systemic therapy, which was exclusively Temodar.

“Phase 1b safety results of vorasidenib in combination with temozolomide in patients with mutant IDH1 or IDH2 glioma” by Dr. Macarena de la Fuente et al., presented at: 2025 SNO Annual Meeting; November 19-23, 2025; Honolulu, HI. Abstract CTNI-34.

The combination of Voranigo and Temodar in IDH1/2-mutant glioma patients showed no serious side effects or dose-limiting toxicities in a phase 1b trial. All patients experienced treatment-emergent side effects, with 28.6% experiencing severe side effects. Dose reductions were necessary for 42.9% of patients, primarily due to increased ALT levels and decreased blood counts. The recommended combination dose for Voranigo was established at 40 mg. The trial aims to exploit molecular vulnerabilities in higher-grade gliomas, with ongoing evaluation of efficacy, safety, and tolerability in phase 2.

Voranigo Plus Temodar Found to Be Safe in Patients With IDH1/2+ Glioma

Alecensa achieved a 98.4% 4-year overall survival rate versus 92.4% with chemotherapy in resected ALK-positive early-stage lung cancer.

Adjuvant treatment with Alecensa (alectinib) elicited a 4-year overall survival (OS) rate of 98.4% for patients with resected ALK-positive early stage non–small cell lung cancer (NSCLC) according to an updated analysis of the phase 3 ALINA study presented at the 

At a median of 48 months of follow-up in the Alecensa arm (130 patients) and 47.4 months in the chemotherapy arm (127 patients), the 4-year OS rate was 92.4% in the comparator chemotherapy group; however, 81.7% of patients in this arm had received a subsequent ALK inhibitor after recurrence, including 58.3% who received Alecensa. The hazard ratio for OS between the two arms was 0.4. The 4-year disease-free survival (DFS) rate was 75.5% with Alecensa compared with 47% with chemotherapy, and the median DFS was not evaluable versus 41.4 months, representing a 65% reduction in the risk of disease recurrence or death.

"This slide may give you impression that you are in the wrong room. No, this is not a breast cancer session," lead investigator Dr. Rafal Dziadziuszko from the Medical University of Gdansk in Poland joked when showing the slide for OS. "This is a lung cancer session which we hoped for so many years. This is due to the activity of Alecensa and also activity of ALK inhibitors in post-chemotherapy setting in those patients who relapsed."

In the ALINA study, patients were randomly assigned one-to-one to receive adjuvant Alecensa or platinum-based chemotherapy following the surgical resection of their ALK-positive NSCLC. Alecensa was administered twice daily at 600 milligrams for two years and chemotherapy was given every three weeks for four cycles.

Adjuvant treatment: therapy given after surgery to lower the risk of the cancer returning.

ALK-positive: describes lung cancer cells with a change in the ALK gene, which drives cancer growth and can be targeted by drugs like Alecensa.

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

Disease-free survival (DFS): time after treatment during which a patient shows no signs of cancer.

Lobectomy: surgery that removes one section (lobe) of the lung containing the tumor.

ECOG performance status: scale used by doctors to measure how well a patient can perform daily activities.

Investigator-assessed DFS in the intention-to-treat population (comprising patients with stage 1B to 3A disease) as well as the subgroup of patients with stage 2 to 3A disease served as the primary end point. Central nervous system (CNS) DFS and OS were secondary end points.

Baseline patient characteristics were balanced between the arms with patients being slightly younger than in other studies of lung cancer. In the Alecensa group, 79% of patients were below the age of 65 and 65% were never smokers. The ECOG performance status was 0 (55%) and 1 (45%) and the most common stage at diagnosis was 3 (53%). N2 status was seen in nearly half of patients (49%) and most had nonsquamous histology (95%). Lobectomy was the most utilized surgical procedure (97%).

Following recurrence, 24 of 31 patients in the Alecensa arm (77.4%) and 55 of 60 in the chemotherapy arm (91.7%) received a subsequent therapy. For the chemotherapy group, 81.7% of these treatments were ALK inhibitors with 61.3% of patients receiving a subsequent ALK inhibitor in the Alecensa arm. For Alecensa, 29% of patients received subsequent chemotherapy. Radiotherapy was used for 25.8% of those in the Alecensa arm following recurrence and for 16.7% in the chemotherapy arm.

What additional data were reported in the long-term ALINA analysis?

For patients specifically with stage 2 through 3A disease, the DFS rate at 4 years was 74.5% with Alecensa compared with 46.3% with chemotherapy; the median DFS was not evaluable and 41.4 months respectively. DFS favored Alecensa across all subgroups including for stages, nodal status and race, Dziadziuszko noted.

The CNS DFS was also improved with Alecensa in the ITT population with a 63% reduction in the risk of this event occurring with the ALK inhibitor. The 4-year CNS DFS rate was 90.4% with Alecensa compared with 76.1% with chemotherapy.

"This is an important end point since ALK-positive disease has a predominance for brain dissemination," said Dziadziuszko.

Side effects were similar to prior assessments of the study, said Dziadziuszko. In the label, the most common side effects were hepatotoxicity, constipation, myalgia, COVID-19, fatigue, rash and cough.

"Alecensa continues to demonstrate a robust and durable disease-free survival benefit over chemotherapy with a hazard ratio that is consistently below 0.4 and also benefiting the reduction of risk of CNS recurrence," Dr. Marcello Tiseo, Department of Medicine and Surgery at the University of Parma in Italy, said during a discussion of the results. "OS data are still immature but the magnitude and durability of DFS improvement coupled with a well-tolerated safety profile reinforce Alecensa as a standard of care for resected ALK-positive NSCLC."

In reference to the OS data, Tiseo proposed more work should be done to examine the duration of therapy as many of the progression events occurred only after treatment was stopped at two years. "The 4-year OS [rate] of [98.4]% and in particular the trend toward improvement in OS despite [most] patients receiving a TKI at recurrence suggests the possibility of curing these patients," he said.

Based on an earlier assessment of the ALINA trial, the FDA approved adjuvant Alecensa for patients with ALK-positive NSCLC in April 2024. This approval was made under the FDA's Project Orbis initiative, the Real-Time Oncology Review program and Assessment Aid, each designed to help expedite impactful treatments for patients. The approval was granted one month ahead of schedule.

“Updated results from the phase 3 ALINA study of adjuvant Alecensa versus chemotherapy in patients with early-stage ALK-positive non-small cell lung cancer” by Dr. Rafal Dziadziuszko, et al., 

“FDA approves Alecensa as adjuvant treatment for ALK-positive non-small cell lung cancer” by Dr. Rafal Dziadziuszko, et al., 

For more news on cancer updates, research and education,

Alecensa (alectinib) demonstrated a 4-year overall survival (OS) rate of 98.4% in patients with resected ALK-positive early-stage non-small cell lung cancer (NSCLC) in the phase 3 ALINA study. Compared to chemotherapy, Alecensa significantly improved disease-free survival (DFS) and reduced the risk of central nervous system (CNS) recurrence. The study highlighted Alecensa's robust efficacy and tolerable safety profile, reinforcing its role as a standard of care. The FDA approved Alecensa for adjuvant treatment in ALK-positive NSCLC under expedited review programs in April 2024.

Alecensa Improves 4-Year Survival in Early ALK-Positive Lung Cancer

Neoadjuvant Enhertu then THP improved pathological complete response rate in patients with high-risk, HER2-positive early breast cancer.

Among patients with high-risk, HER2-positive early breast cancer, presurgical, or neoadjuvant, treatment with Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) followed by paclitaxel, Herceptin (trastuzumab) and Perjeta (pertuzumab, THP) was associated with an improvement in pathologic complete response (pCR) rate compared with dose-dense doxorubicin and cyclophosphamide plus THP (ddAC-THP), data from the phase 3 DESTINY-Breast11 trial has shown.

Findings presented at the 2025 ESMO Congress demonstrated that patients treated with Enhertu followed by THP (321 patients) experienced a pCR rate of 67.3% compared with 56.3% for those given ddAC-THP (320 patients; difference, 11.2%). Notably, the pCR benefit was observed in the hormone receptor–positive population, where the pCR rate was 61.4% in the Enhertu arm (236 patients) versus 52.3% in the ddAC-THP arm (235 patients; difference, 9.1%), as well as the hormone receptor–negative population, where the respective pCR rates for the Enhertu arm (83 patients) and ddAC-THP arm (85 patients) were 83.1% and 67.1% (difference, 16.1%).

Glossary

Pathologic complete response (pCR): this means that when the doctors look at the removed tissue under a microscope, there are no signs of remaining invasive cancer.

Event-free survival (EFS): this is the length of time a person remains alive without their cancer coming back, getting worse, or developing a second cancer.

Pharmacokinetics: this is what your body does to a drug, which includes how the drug is absorbed, distributed, changed, and eventually removed.

Invasive disease-free survival: this is the time a person lives without the return of the invasive cancer or a second invasive cancer, and without death from any cause.

Overall survival: this refers to the percentage of people in a study who are still alive after a certain period of time.

Residual cancer burden (RCB): this is a measure that estimates how much cancer is left in the breast and lymph nodes after neoadjuvant treatment (treatment given before surgery).

ECOG performance status: this is a scale that doctors use to describe a patient's general well-being and how capable they are of performing ordinary daily tasks.

Interstitial lung disease (ILD): this is a group of lung disorders that cause scarring of the lungs, which can make it hard to breathe.

Left ventricular dysfunction: this is a condition where the main pumping chamber of the heart (the left ventricle) is not working as well as it should.

Increased transaminase levels: this is a sign of liver damage or injury that is detected by blood tests measuring the levels of certain liver enzymes.

Neutropenia: this is a condition in which a person has a low number of neutrophils, which are a specific type of white blood cell important for fighting infection.

Peripheral neuropathy: this refers to nerve damage outside of the brain and spinal cord, which can cause numbness, tingling, or pain, often in the hands or feet.

Anemia: this is a condition where your body does not have enough healthy red blood cells to carry adequate oxygen to your tissues, often leading to fatigue.

Stomatitis: this is a general term for inflammation or soreness inside the mouth, which can include mouth sores.

Leukopenia: this is a condition where a person has a low overall number of white blood cells, which can put them at a higher risk of infection.

“DESTINY-Breast11 showed the highest reported pCR rate in HER2-positive early breast cancer for a registrational study in the neoadjuvant setting, despite — if you want to do cross-trial comparisons — a high prevalence of hormone receptor–positive disease and a high-risk population,” lead study author Dr. Nadia Harbeck said in a presentation of the data.

Harbeck is director of the Breast Center and chair for Conservative Oncology at the Department of OB&GYN at LMU University Hospital in Munich, Germany.

How Was the DESTINY-Breast11 Trial Designed?

Harbeck noted that current neoadjuvant standard-of-care (SOC) regimens for HER2-positive early breast cancer have remained unchanged for more than a decade. As such, investigators sought to evaluate Enhertu–based treatment in this population with the goal of improving efficacy and safety versus the current SOC.

Patients were randomly assigned to receive Enhertu followed by THP; ddAC-THP; or Enhertu alone, followed by surgery in all arms. In the first arm, 321 patients received four cycles of Enhertu followed by four cycles of THP. In the second, ddAC was administered for four cycles, followed by four cycles of THP. In the final arm, patients received Enhertu alone for eight cycles.

Notably, the Enhertu monotherapy arm was closed in March 2024, following a recommendation from the study’s independent data monitoring committee.

After surgery, study protocols called for the following treatments, irrespective of arm:

pCR: radiotherapy and concomitant Herceptin with or without Perjeta for up to one year

Non-pCR: radiotherapy and Kadcyla for up to 14 cycles

Hormone receptor–positive disease: endocrine therapy

The study’s primary end point was pCR rate. Secondary end points included event-free survival (EFS), safety, pharmacokinetics, invasive disease-free survival, overall survival and health-related quality of life. Residual cancer burden (RCB) was an additional outcome measured during the study.

At data cutoff, 16.9% of patients in the Enhertu plus THP arm discontinued a study drug, including Enhertu (2.8%) paclitaxel (14.4%) Herceptin (2.2%) and Perjeta (2.2%); 97.2% of patients in this arm proceeded to surgery. In the ddAC-THP arm, 13.8% of patients had discontinued any study treatment, including AC (2.9%) paclitaxel (12%) Herceptin (3%) and Perjeta (3.7%); 93.8% of patients in this arm underwent surgery. In the Enhertu monotherapy arm (286 patients), 18.4% of patients discontinued study treatment and 95.8% underwent surgery.

Regarding post-neoadjuvant treatments, 99.1% of evaluable patients in the Enhertu arm who achieved a pCR (226 patients) underwent any adjuvant therapy, comprising any cytotoxic chemotherapy regimen (5.8%), any Kadcyla–containing regimen (1.8%) and any Herceptin-containing regimen (94.2%). In the ddAC-THP, 98.4% of patients who achieved a pCR (190 patients) underwent any adjuvant therapy, including any cytotoxic chemotherapy regimen (5.8%), any Kadcyla–containing regimen (2.1%) and any Herceptin-containing regimen (91.6%).

For patients who did not achieve a pCR, any adjuvant therapy was administered to 89.5% of patients in the Enhertu plus THP arm (95 patients) and 82.3% of patients in the ddAC-THP arm (130 patients). In the experimental group, adjuvant therapies included any cytotoxic chemotherapy regimen (10.5%) any Kadcyla–containing regimen (52.6%) and any Herceptin-containing regimen (38.9%). These respective rates were 9.2%, 56.9% and 26.2% in the control group.

In the Enhertu plus THP and ddAC-THP arms, the median age was 50 years and 50 years, respectively. All patients in both arms were female. The highest proportion of patients in each arm was from Asia (Enhertu plus THP, 47.4%; ddAC-THP, 47.5%) and were Asian (49.8%; 49.1%). Most patients had an ECOG performance status of 0 (86.6%; 87.5%) had immunohistochemistry 3+ HER2-positive disease (87.2%; 88.4%) had cT0-2 tumors (54.8%; 58.8%) and had positive lymph nodes (89.4%; 87.8%).

What Were the Other Efficacy Outcomes for Enhertu Plus THP Versus ddAC-THP?

Findings also showed that 81.3% of patients in the Enhertu plus THP arm had no RCB (RCB-0) or minimal RCB (RCB-1) in resected breast or lymph node tissue compared with 69.1% in the ddAC-THP arm (difference, 12.2%). In the hormone receptor–positive population, the RCB-0 plus RCB-1 rates were 78% for Enhertu plus THP versus 64.7% for ddAC-THP; these respective rates were 90.4% and 81.2% in the hormone receptor–negative population.

Investigators also reported an EFS trend favoring Enhertu plus THP, with data at 4.5% maturity. Maturity for the data cutoff of the trial’s final analysis is predicted at approximately 10%. The 24-month EFS rates were 96.9% in the Enhertu plus THP arm versus 93.1% in the ddAC-THP arm.

What Is the Side Effect Profile of Enhertu Plus THP?

Any-grade side effects occurred in 98.1% of patients in the Enhertu plus THP arm compared with 98.7% of patients in the ddAC-THP arm. The respective rates of grade 3 (severe) or higher side effects were 37.5% and 55.8%. Any-grade serious side effects were reported in 10.6% and 20.2% of patients, respectively.

In the Enhertu plus THP arm, side effects led to dose any dose reduction, any drug interruption and any treatment discontinuation in 18.1%, 37.8% and 14.1% of patients, respectively. In the ddAC-THP group, these rates were 19.2%, 54.5% and 9.9%, respectively. Side effects led to death in 0.6% of patients in both arms. Side effects led to delays in surgery in 3.4% of patients in the experimental arm versus 2.6% of patients in the control arm.

Regarding side effects of special interest, any-grade drug-related adjudicated interstitial lung disease (ILD) was 4.4% in the Enhertu plus THP arm versus 5.1% in the ddAC-THP arm. The rates of grade 3 or higher ILD were 0.6% and 1.9%, respectively. Grade 5 (fatal) ILD occurred in one patient (0.3%) in both groups. Any-grade left ventricular dysfunction occurred in 1.3% of patients in the experimental arm versus 6.1% of patients in the control arm. The rates of grade 3 or higher left ventricular dysfunction were 0.3% and 1.9%, respectively, although no grade 5 events were reported in either group.

Any-grade treatment-emergent side effects reported in at least 20% of patients in either arm included nausea (Enhertu plus THP, 64.7%; ddAC-THP, 51.6%) diarrhea (58.8%; 54.2%) alopecia (47.5%; 49.0%) fatigue (41.3%; 54.8%) increased transaminase levels (34.4%; 33.7%) neutropenia (29.1%; 44.2%) constipation (29.1%; 24.4%) vomiting (28.8%; 21.2%) peripheral neuropathy (25.9%; 20.8%) anemia (22.8%; 49.7%) stomatitis (18.4%; 27.9%) and leukopenia (17.2%; 23.4%).

What Data Were Reported for Enhertu Monotherapy in HER2+ Early Breast Cancer?

In the Enhertu monotherapy arm, patients were allowed to remain on therapy or immediately switch to local SOC. If patients switched therapy, they were classified as having a non-pCR.

Findings from the monotherapy arm showed that 286 patients achieved a pCR rate of 43% at the primary analysis and 51.4% at a prespecified supplementary analysis. EFS data were similar between Enhertu monotherapy and ddAC-THP, and the 24-month EFS rate in the Enhertu monotherapy group was 94.4%.

Regarding safety, 97.5% of patients treated with Enhertu alone (283 patients) experienced any-grade side effects, 22.6% had grade 3 or higher side effects, and 10.2% had any-grade serious side effects. Side effects led to dose reduction, drug interruption and treatment discontinuation in 6.7%, 18% and 7.8% of patients, respectively. One patient (0.4%) experienced a side effect that led to death. Side effects led to surgical delay in 6.4% of patients.

The rate of any-grade drug-related adjudicated ILD was 4.9% in the Enhertu monotherapy arm, although all instances were grade 1 (mild) or 2 (moderate). Left ventricular dysfunction occurred in 0.7% of patients, all at grade 1 or 2.

Based on data from DESTINY-Breast11, the U.S. Food and Drug Administration (FDA) accepted a supplemental biologics license application seeking the approval of neoadjuvant Enhertu followed THP for the treatment of adult patients with high-risk HER2-positive (IHC 3+ or in situ hybridization–positive) stage 2/3 breast cancer.

The FDA has assigned a target action date of May 18, 2026, under the Prescription Drug User Fee Act.

“DESTINY-Breast11 results support [Enhertu plus] THP as a more effective and less toxic neoadjuvant treatment compared with ddAC-THP, and it may become the preferred regimen for patients with high-risk HER2-positive early breast cancer,” Harbeck concluded in her presentation.

“DESTINY-Breast11: neoadjuvant trastuzumab deruxtecan alone (T-DXd) or followed by paclitaxel + trastuzumab + pertuzumab (T-DXd-THP) vs SOC for high-risk HER2+ early breast cancer (eBC),” by Dr. Nadia Harbeck et al., presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 291O.

Enhertu (fam-trastuzumab deruxtecan-nxki) followed by paclitaxel, Herceptin, and Perjeta demonstrated superior pathologic complete response (pCR) rates compared to dose-dense doxorubicin and cyclophosphamide plus THP in high-risk, HER2-positive early breast cancer patients, as shown in the DESTINY-Breast11 trial. The trial highlighted significant pCR improvements in both hormone receptor-positive and negative populations. Enhertu plus THP also showed a favorable safety profile with fewer severe side effects. The FDA is reviewing a supplemental biologics license application for this regimen, with a decision expected by May 2026.

Chris Ryan

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