In ESR1-mutant, ER+, HER2– superior breast most cancers, vepdegestrant improved PFS versus Faslodex: © inventory.adobe.com.
When put next with versus fulvestrant (Faslodex), vepdegestrant (ARV-471) remedy elicited a statistically vital and clinically significant enchancment in survival with out development by blinded impartial central overview (BICR) in pretreated sufferers with ESR1-mutant estrogen receptor (ER)-positive, HER2-negative superior or metastatic breast most cancers.
These findings had been garnered from the part 3 VERITAC-2 trial, information from which had been shared on the 2025 ASCO Annual Assembly.
Of the 136 sufferers within the vepdegestrant arm, and the 134 sufferers within the Faslodex arm, at a median follow-up of seven.4 months and 6.0 months, respectively, the median progression-free survival was 5.0 months and a pair of.1 months. On the time of the evaluation, 58% of progression-free survival occasions had occurred within the vepdegestrant arm versus 71% within the Faslodex arm; remedy was ongoing in 33% and 12% of sufferers, respectively. The 6-month progression-free survival charges with vepdegestrant and Faslodex had been 45.2% and 22.7%, respectively.
BICR-assessed progression-free survival didn’t present a considerable enchancment with vepdegestrant versus Faslodex within the all-comer inhabitants.
“Vepdegestrant is the primary PROTAC [proteolysis targeting chimera] to be evaluated in a part 3 research,” lead research creator Dr. Erika Hamilton, mentioned in a press briefing forward of the assembly. “These outcomes assist vepdegestrant as a possible remedy possibility for beforehand handled [patients with] ESR1-mutant ER-positive, HER2-negative superior breast most cancers.”
Setting the Stage for VERITAC-2
There is no such thing as a agreed-upon normal of take care of sufferers with ER-positive, HER2-negative superior breast most cancers following development on frontline endocrine remedy. Faslodex is a selective estrogen receptor degrader, often known as SERDs, that’s sometimes given within the second line although it’s related to modest progression-free survival profit following development on CDK4/6 inhibition and endocrine remedy.
Since January 2023, Orserdu (elacestrant) has grow to be an possibility for postmenopausal ladies or grownup males with ER-positive, HER2-negative, ESR1-mutated superior or metastatic breast most cancers with illness development following no less than one line of endocrine remedy. Nevertheless, median progression-free survival stays restricted.
Vepdegestrant is a selective, oral PROTAC ER degrader that targets the mutant and wild-type ER. Within the first-in-human part 1/2 trial, vepdegestrant was effectively tolerated and lively, with a scientific profit charge of 51.2% in closely pretreated sufferers with ESR1-mutant ER-positive, HER2-negative superior breast most cancers who had obtained a median of three (vary, 0-7) prior strains of remedy within the metastatic setting.
Glossary:
General survival (OS): the size of time from both the date of analysis or the beginning of remedy for a illness that sufferers recognized are alive.
Development-free survival (PFS): the size of time throughout and after the remedy {that a} affected person lives with the illness nevertheless it doesn’t worsen.
General response charge (ORR): the proportion of sufferers who’ve a partial or full response to remedy.
In February 2024, the FDA granted quick observe designation to vepdegestrant for the remedy of sufferers with ER-positive, HER2-negative domestically superior or metastatic breast most cancers beforehand handled with endocrine-based remedy.
Searching for affirmation of profit within the VERITAC-2 trial, investigators enrolled sufferers no less than 18 years of age with ER-positive, HER2-negative superior or metastatic breast most cancers that developed radiological development throughout or after the final line of remedy. Prior remedy consisted of 1 line of endocrine remedy and a CDK4/6 inhibitor, and not more than 1 further line of endocrine remedy. Sufferers should have been uncovered to the latest line of endocrine remedy for no less than 6 months, and prior chemotherapy for superior or metastatic illness or a selective estrogen receptor degrader like Faslodex or Orserdu was not allowed.
In whole, 313 eligible sufferers had been randomly assigned to obtain 200 miligrams (mg) of oral vepdegestrant as soon as every day or 500 mg of intramuscular Faslodex on days one and 15 of cycle one, and day certainly one of subsequent cycles. Remedy cycles had been 28 days. Sufferers had been stratified by ESR1 standing (mutated versus not) and visceral illness (sure versus no).
The first finish level was BICR-assessed progression-free survival within the ESR1-mutant and all-comer populations. Secondary finish factors had been general survival, scientific profit charge and goal response charge by BICR, and unwanted effects.
Hamilton famous that roughly 80% of sufferers had obtained 1 prior line of remedy and round 20% had obtained 2 prior strains of remedy within the superior or metastatic setting.
Vepdegestrant Sails By way of Secondary Finish Level Verification of Profit
With respect to the secondary finish factors of the trial, vepdegestrant (121 sufferers) greater than doubled the scientific profit charge in contrast with Faslodex (119 sufferers) within the ESR1-mutant inhabitants, at 42.1% versus 20.2%, respectively. The general response charge was 18.6% with vepdegestrant (97 sufferers) versus 4.0% with Faslodex. The median period of response was not reached.
Security was evaluated in all-treated sufferers who obtained vepdegestrant (312 sufferers) and Faslodex (307 sufferers) and was usually effectively tolerated.
“Vepdegestrant demonstrated a good security profile, evidenced by few unwanted effects [< 5%] resulting in dose discount or discontinuation,” Hamilton mentioned.
Any-grade treatment-emergent unwanted effects occurred in 87% of sufferers on vepdegestrant (grade 3 or greater, 23%) versus 81% of these on Faslodex (grade 3 or greater, 18%). Severe unwanted effects occurred in 10% and 9% of sufferers on vepdegestrant and Faslodex, respectively. Remedy-emergent unwanted effects resulting in discontinuation and dose discount occurred in 3% and a pair of% of instances, respectively, within the vepdegestrant arm. Only one% of sufferers within the Faslodex arm required remedy discontinuation due to a treatment-emergent facet impact. Remedy-related unwanted effects additionally occurred within the vepdegestrant (any grade, 57%; grade 3 or greater, 8%) and Faslodex (any grade, 40%; grade 3 or greater, 3%) arms.
Any-grade treatment-emergent unwanted effects that occurred in no less than 10% of sufferers within the vepdegestrant and Faslodex arms, respectively, had been fatigue (27%; 16%), alanine aminotransferase enhance (14%; 10%), aspartate aminotransferase enhance (14%; 10%), nausea (13%; 9%), anemia (12%; 8%), neutropenia (12%; 5%), again ache (11%; 7%), arthralgia (11%; 11%) and decreased urge for food (11%; 5%).
No treatment-related deaths occurred.
“General survival analyses stay immature, and follow-up is ongoing,” Hamilton concluded.
Placing the Leads to Context
“This can be a very thrilling research,” Dr. Jane L. Meisel, professor within the Departments of Hematology and Medical Oncology and Gynecology & Obstetrics, and codirector of Breast Medical Oncology at Emory College College of Medication in Georgia, mentioned. “This drug is one thing that we predict goes to be a really thrilling possibility doubtlessly for sufferers with beforehand handled, ESR1-mutant ER-positive, HER2-negative superior breast most cancers. There are quite a lot of thrilling issues occurring on this area, so seeing what the general survival analyses present will likely be attention-grabbing and the way this compares with a few of the different issues that we [have]. All of us stay up for that. This can be a very thrilling possibility, and the primary of its form by way of being a PROTAC versus different mechanisms of motion, so [there’s] loads to consider, and thrilling information to see.”
References
- Hamilton E, De Laurentiis M, Jhaveri Ok, et al. Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal development issue receptor 2 (HER2)–adverse superior breast most cancers: outcomes of the worldwide, randomized, part 3 VERITAC-2 research. J Clin Oncol. 2025;43(suppl 17):LBA1000. doi:10.1200/JCO.2025.43.17_suppl.LBA1000
- Schott AF, Hurvitz S, Ma C, et al. GS3-03 ARV-471, a PROTAC estrogen receptor (ER) degrader in superior ER-positive/human epidermal development issue receptor 2 (HER2)-negative breast most cancers: part 2 growth (VERITAC) of a part 1/2 research. Most cancers Res. 2023;83(suppl 5):GS3-03. doi:10.1158/1538-7445.SABCS22-GS3-03
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