The first General Session at the 2025 San Antonio Breast Cancer Symposium® included presentations on first-line tucatinib-based combination maintenance therapy in the HER2CLIMB-05 trial, primary results from the ASCENT-07 trial on sacituzumab govitecan, and the lidERA study on giredestrant. The session also spotlighted a new artificial intelligence (AI) model for predicting recurrence risk in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer.
A recording of the session, held Wednesday, December 10, is available on demand for registered SABCS® 2025 participants through March 31, 2026, on the virtual meeting platform.
GS1-01: HER2CLIMB-05: a randomized, double-blind, phase III study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2-positive metastatic breast cancer
Adding the selective HER2 inhibitor tucatinib to first-line maintenance therapy along with trastuzumab and pertuzumab delayed disease progression in patients with HER2-positive metastatic breast cancer, according to findings from the phase III HER2CLIMB-05 trial.
Currently, first-line taxane-based induction chemotherapy with dual anti-HER2 monoclonal antibody-based therapy, followed by dual anti-HER2 monoclonal antibody-based maintenance is the standard of care for HER2-positive metastatic breast cancer.
“Despite this treatment, most patients will progress and unfortunately some of these patients will not go on to receive second-line therapy,” said Erika Hamilton, MD, Director of Breast Cancer Research at Sarah Cannon Research Institute, who presented the study results.
HER2CLIMB-05 evaluated whether adding tucatinib, which targets intracellular HER2, to the cell-surface HER2-directed monoclonal antibodies improves efficacy of maintenance therapy.
HER2CLIMB-05 enrolled 654 patients with HER2-positive advanced breast cancer who had completed four to eight cycles of induction chemotherapy plus the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab, without disease progression. Patients were randomly assigned 1:1 to receive either tucatinib or placebo, alongside continued trastuzumab-pertuzumab maintenance.
At a median follow-up of 23 months, patients who received tucatinib had a median progression-free survival (PFS) of 24.9 months, compared with 16.3 months in the control arm. The PFS benefit with tucatinib was consistent across subgroups, including those with HR-positive/-negative disease and with/without brain metastases at baseline.
OS data were immature at the time of analysis, although there was a trend towards improved OS with tucatinib.
An exploratory analysis showed near doubling of median central nervous system-PFS, from 4.3 months to 8.5 months, in the 12.2% of patients with brain metastases at baseline. Dr. Hamilton cautioned that these findings were preliminary and that further study is needed to confirm central nervous system benefit.
Dr. Hamilton said that the tucatinib addition offers patients the opportunity not only to delay progression but also to extend off-chemotherapy time.
The HER2CLIMB-05 findings were simultaneously published in the Journal of Clinical Oncology.
GS1-08: Multimodal artificial intelligence models integrating image, clinical, and molecular data for predicting early and late breast cancer recurrence in TAILORx
A new AI model integrating digitized images of routine pathology slides, along with molecular and clinical features, improved recurrence risk prognostication compared to the Oncotype DX (ODX) 21-gene recurrence score in patients with HR-positive, HER2-negative breast cancer in the TAILORx trial.
Joseph A. Sparano, MD, Chief of the Division of Hematology and Oncology at the Mount Sinai Tisch Cancer Center, shared the data. Dr. Sparano and colleagues sought to develop a diagnostic test that would improve upon ODX, which is widely used in clinical practice to predict disease recurrence and guide treatment but has a limited ability to accurately predict recurrence after five years.
Digitized tissue images and molecular RNA expression data from 4,462 tumor samples and corresponding clinical data from TAILORx participants were used to train, validate, and then compare the prognostic performance of the different AI models to that of ODX.
The ICM+ multimodal AI model, which integrated pathomic imaging, clinical, and expanded molecular models, had the strongest prognostic performance, outperforming the ODX for overall 15-year distant recurrence and late recurrence after five years in the training, cross validation, and holdout validation datasets.
“The ICM+ model also provided statistically significant and clinically relevant prognostic stratification in the Oncotype [ODX] low and high genomic risk groups,” Dr. Sparano said.
GS1-09: Sacituzumab govitecan vs chemotherapy as first therapy after endocrine therapy in HR- positive/HER2-negative (IHC 0, 1+, 2+/ISH−) metastatic breast cancer: Primary results from ASCENT-07
Findings from the phase III ASCENT-07 trial showed similar PFS outcomes with sacituzumab govitecan or standard-of-care chemotherapy for patients with HR-positive, HER2-negative advanced breast cancers that were refractory to endocrine therapy.
Komal Jhaveri, MD, Patricia and James Cayne Chair for Junior Faculty; Associate Attending, Breast Medicine and Early Drug Development Services; and Section Head of the Endocrine Therapy Research Program at Memorial Sloan Kettering Cancer Center, shared the data.
“The current treatment landscape for HR-positive, HER2-negative disease in the first-line metastatic setting, for a majority of patients, includes an endocrine therapy with a CDK4/6 inhibitor,” she said.
“For endocrine-refractory disease, we often use sequential single-agent chemotherapy,” she added. Patients whose disease progresses after endocrine therapy and two lines of subsequent systemic therapy may be eligible for sacituzumab govitecan, which was approved for this population based on results from the TROPiCS-02 clinical trial that showed that sacituzumab govitecan led to improved outcomes compared with another line of chemotherapy.
ASCENT-07 compared the efficacy of sacituzumab govitecan earlier in the treatment course, as the first treatment after endocrine therapy, to that of chemotherapy.
After a median follow-up of 15.4 months in 690 patients, the median PFS was 8.3 months for both the 456 sacituzumab govitecan-treated and 234 chemotherapy-treated patients (hazard ratio of 0.85); the trial did not meet the primary endpoint of improved PFS by blinded independent central review.
OS data were immature, although preliminary analyses suggested a trend towards numerically higher OS favoring sacituzumab govitecan.
“This early numerical trend is OS was interesting, especially since 61% of the participants in the [chemotherapy] arm of ASCENT-07 did receive an antibody-drug conjugate following treatment discontinuation,” Dr. Jhaveri said.
GS1-10: Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: Results from the global phase III lidERA Breast Cancer trial
In the phase III lidERA trial, adjuvant therapy with the novel oral selective estrogen receptor degrader (SERD) giredestrant significantly improved invasive disease-free survival (iDFS) compared with standard-of-care endocrine therapy in patients with early-stage, HR-positive, HER2-negative breast cancer.
Aditya Bardia, MD, MPH, Professor of Medicine and Director of Translational Research Integration at the University of California, Los Angeles Jonsson Comprehensive Cancer Center, presented the data.
“Endocrine therapy is the mainstay of management for estrogen receptor (ER)-positive, HER2-negative disease, including early breast cancer,” he said.
However, many patients develop recurrence within five years of endocrine therapy. Also, while adding CDK4/6 inhibitors to adjuvant endocrine therapy increases efficacy, the associated toxicities can result in early cessation of treatment, thereby increasing the risk of recurrence, Dr. Bardia said.
In lidERA, 4,170 patients, 59% of whom were postmenopausal, were randomly assigned 1:1 to receive either giredestrant or physician’s choice of one of four endocrine therapies. All patients received surgery, and if indicated, adjuvant or neoadjuvant chemotherapy.
After a median follow-up of 32.3 months, giredestrant-treated patients were 30% less likely to develop invasive disease progression than patients treated with standard-of-care endocrine therapy.
Although still immature, preliminary analysis demonstrated a positive OS trend in favor of giredestrant.
Discussing safety results, Dr. Bardia pointed out that the higher rates of bradycardia with giredestrant (11.3%), compared with endocrine therapies (3.2%), was consistent with the known effects of oral SERDs and was grade 1 and asymptomatic, not requiring treatment interruption or discontinuation.
“Since approval of AIs in the 2000s, lidERA Breast Cancer is the first trial to demonstrate benefit with a novel endocrine therapy in early breast cancer [in the adjuvant setting],” Dr. Bardia concluded.
Additional abstracts presented during Wednesday’s General Session 1 included:
GS1-03: Adjuvant aromatase inhibitor or tamoxifen in patients with hormone receptor-positive/HER2-positive early breast cancer: An exploratory analysis from the ALTTO (BIG 2-06) trial
GS1-04: Tumor infiltrating lymphocytes (TILs) and pathologic complete response (pCR) in stage II/III HER2-positive breast cancer treated with taxane, trastuzumab, and pertuzumab (THP): secondary results from the ECOG-ACRIN EA1181/CompassHER2 pCR trial
GS1-05: Prognostic and predictive associations of manual, digital and AI-derived tumor infiltrating lymphocytes-scoring: A retrospective analysis from the Phase III APHINITY trial
GS1-06: Circulating tumor DNA (ctDNA) in human epidermal growth factor receptor 2-positive (HER2[+]) Early Breast Cancer (EBC): Translational analysis of PHERGain neoadjuvant tailored treatment study
