Two new therapy options have demonstrated significant advances in survival outcomes for select patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Both studies were presented today at the 2025 ASCO Annual Meeting in Chicago and simultaneously published in The New England Journal of Medicine. (1) (2)
MSK recruited most American patients in both phase 3 international studies. Highlights of the results were as follows:
The triplet therapy of inavolisib plus palbociclib-fulvestrant showed the first-ever overall survival (OS) benefit for patients with PIK3CA-mutated ER+/HER2- locally advanced or metastatic breast cancer. (1)
Vepdegestrant, an oral proteolysis targeting chimera (PROTAC) ER degrader, significantly improved progression-free survival (PFS) in patients with ESR1-mutated ER+/HER2- advanced breast cancer. (2)
ER+/HER2- breast cancer accounts for about 70% of all breast cancer cases. (3)
“Most patients develop treatment resistance and experience disease progression on current doublet regimens of endocrine therapy plus CDK4/6 inhibitors,” said breast medical oncologist and early drug development specialist Komal Jhaveri, MD, FACP, Section Head of the Endocrine Therapy Research Program and Clinical Director of the Early Drug Development Service at MSK. “It’s exciting that these treatment options provide clinically meaningful survival benefits for patients with hormone receptor-positive advanced disease.”
Inavolisib Plus Palbociclib-Fulvestrant for PIK3CA-mutated ER+/HER2- Breast Cancer
About 35% to 40% of hormone receptor-positive breast cancers have activating PIK3CA mutations, which indicate a poor prognosis in advanced disease and serve as a predictive biomarker of response to PI3K inhibitors. (4) (5) (6) (7) (8) (9) (10)
The ER, CDK4/6, and PI3K pathways are three oncogenic pathways that drive hormone-receptor breast cancer. (11) Existing doublet regimens of endocrine therapy with CDK4/6 inhibitors, such as palbociclib, or with PI3K inhibitors, often result in treatment resistance. (12) (13)
Inavolisib is an oral, highly selective PI3K-alpha inhibitor that also facilitates mutant-specific degradation of p110-alpha, a subunit that plays an essential role in cellular growth, division, and survival. Fulvestrant is a synthetic estrogen receptor agonist.
The international phase 3 trial INAVO120 (NCT04191499) evaluated the triplet regimen of inavolisib plus palbociclib-fulvestrant compared with placebo plus palbociclib-fulvestrant.
The study enrolled 325 patients between January 2020 and September 2023. Eligible patients included women of any menopausal status or men with PI3KCA-mutated ER+/HER2- locally advanced or metastatic breast cancer with disease recurrence or progression during or within 12 months of completing adjuvant endocrine therapy. (1)
Randomization assigned 161 patients to the inavolisib group and 164 patients to the placebo group. Patients received inavolisib or placebo daily on days 1 to 28 of each 28-day cycle in combination with oral palbociclib once daily on days 1 to 21 of each 28-day cycle plus intramuscular fulvestrant on days 1 and 15 in cycle 1 and about every four weeks thereafter, until disease progression, unacceptable toxicity, withdrawal of consent, or death. (1)
After 34 months of follow-up, the median OS was 34 months with inavolisib versus 27 months with placebo (hazard ratio (HR) = 0.67, p = 0.0190). (1)
The objective response rates (ORR) were 63% and 28%, respectively (p < 0.0001). PFS rates were 17.2 months and 7.3 months, respectively (HR = 0.42), and the duration of response (DOR) was 19.2 months for the inavolisib group versus 11.1 months for the placebo group. (1)
ORR, PFS, and DOR rates were higher than or in line with the primary analysis reported previously.(14) The U.S. Food and Drug Administration (FDA) approved the inavolisib plus palbociclib-fulvestrant regimen for this patient population in October 2024. The National Comprehensive Center Network updated the Guidelines for Breast Cancer in November 2024.
“Both PFS and OS curves showed an early clinical benefit for inavolisib starting at about two months,” said Dr. Jhaveri, who was first author of the paper and a member of the Steering Committee for the international trial. “The results for this triple blockade strategy also underscored the benefits of optimizing first-line therapy for these patients, as there was a significant delay to chemotherapy in the triplet arm.”
Read ASCO 2025 Abstract 1003. The study was sponsored and funded by F. Hoffman-LaRoche. Access disclosures for Dr. Jhaveri.
Vepdegestrant Provides PFS Benefit in ESR1-Mutated ER+/HER2- Breast Cancer
Most patients with ER+/HER2 breast cancer develop resistance and experience disease progression after treatment with standard endocrine therapy plus CDK4/6 inhibitors.(9) (12) (13) (15) (16) ESR1 mutations drive resistance in about 40% to 50% of patients. (9) (12) (17) (18) (19) Treatment decisions in the second line and beyond setting are determined by previous treatment history, patient preference, and tumor genomics. The optimal sequencing of therapies is evolving dynamically.
Elacestrant is currently the only approved drug for patients with ESR1-mutated advanced breast cancer that progressed on endocrine therapy. As research efforts continue to further improve its safety and therapeutic index, (20) a significant unmet need remains for a treatment that can further improve outcomes with an improved safety profile, particularly in the second-line setting.
The international, phase 3 trial VERITAC-2 (NCT05654623) evaluated vepdegestrant versus fulvestrant in patients with ER+/HER2- advanced breast cancer who received one prior line of CDK4/6 inhibitor plus endocrine therapy. (2)
Vepdegestrant is an oral proteolysis targeting chimera (PROTAC) ER degrader. It is the first PROTAC to be evaluated in a phase 3 trial and the first to be assessed in patients with breast cancer. (2)
The study took place at 213 sites in 26 countries. A total of 624 patients were randomized to receive oral vepdegestrant once daily continuously in each 28-day cycle or fulvestrant intramuscularly on days 1 and 15 of cycle 1 and on day one of each subsequent cycle. There were 313 patients in the vepdegestrant group and 311 in the fulvestrant group. Results were stratified by ESR1 mutation status and the presence or absence of visceral disease. (2)
Among 270 patients with ESR1 mutations, the median PFS was five months for the vepdegestrant group versus 2.1 months for those in the fulvestrant group (HR = 0.57, p < 0.001). No significant difference in PFS was found in the all patient population: PFS was 3.7 months with vepdegestrant and 3.6 months with fulvestrant (HR=0.83, p=0.07). (2)
Grade 3 adverse events occurred in 23% and 18% in the vepdegestrant and fulvestrant groups, leading to treatment discontinuation in 2.9% and 0.7% of patients, respectively. (2)
Overall, vepdegestrant prolonged median PFS by about three months compared with fulvestrant among patients with ESR1 mutations, with a clinical benefit rate of 42% versus 20% and an ORR of 19% versus 4%, respectively. (2)
“These results add to the body of evidence demonstrating that novel endocrine agents can work well as monotherapy in the metastatic setting for patients with ESR1 mutations but not wild-type disease,” said Dr. Jhaveri, a co-author on the paper. “Vepdegestrant has the potential to be a clinically meaningful new treatment option with a differentiated mechanism of action and safety profile for patients who currently have limited treatment options.”
Vepdegestrant received fast track designation from the FDA on February 6, 2025. Dr. Jhaveri anticipates the manufacturer will file for full approval based on the strength of these phase 3 trial results.
Read ASCO Abstract LBA1000. The study was sponsored by Pfizer, Inc. in collaboration with Arvinas Estrogen Receptor, Inc. Access disclosures for Dr. Jhaveri.
More ASCO 2025 Conference News on Targeted Therapies for Advanced Breast Cancer
At ASCO 2025, Dr. Jhaveri gave a talk called “What’s on the Horizon: Emerging Agents for Second Line and Beyond in Hormone Receptor-Positive Disease,” part of the education session After a CDK4/6 Inhibitor: State of the Art in Hormone Receptor-Positive Metastatic Breast Cancer.
Dr. Jhaveri also co-authored a summary of results from the RETRACT survey of U.S. oncologists, which collected opinions of real-world clinicians regarding the visceral crisis in ER+/HER2- metastatic breast cancer. Read ASCO Abstract e13081. Access the full paper published in The Breast.
MSK medical oncology fellow Jimmitti Teysir, MD, gave a poster presentation of her study on treatment patterns in ER+/HER2- metastatic breast cancer (MBC) with co-occurring PIK3CA and ESR1 mutations, looking at MSK-IMPACT® and MSK-ACCESS® data from patients treated at MSK with SERDs and PI3K inhibitors. Read ASCO Abstract 1082.