Key takeaways:
- Vepdegestrant improved PFS for sufferers with ER-positive, HER2-negative superior breast most cancers with an ESR1 mutation.
- Vepdegestrant additionally considerably improved goal response fee.
CHICAGO — Vepdegestrant considerably improved outcomes for sure sufferers with ER-positive, HER2-negative superior breast most cancers in contrast with fulvestrant, in response to findings introduced at ASCO Annual Assembly.
Outcomes of a randomized, part 3 trial confirmed vepdegestrant (ARV-471; Arvinas, Pfizer) prolonged PFS roughly 3 months for sufferers with an ESR1 mutation.
Information derived from Hamilton EP, et al. Summary LBA1000. Offered at: ASCO Annual Assembly; Could 30-June 3, 2024; Chicago.
Nevertheless, researchers didn’t observe a big profit once they included sufferers with out the mutation.
Erika P. Hamilton
“I like to explain ESR1 mutations as a light-weight swap: As a substitute of needing estrogen to bind to the estrogen receptor, it’s like that mild swap has simply been turned on and we don’t want the estrogen anymore,” Erika P. Hamilton, MD, director of breast most cancers and gynecologic most cancers analysis at Sarah Cannon Analysis Institute, stated throughout a press briefing. “This drug actually works in these sufferers who’ve this resistance mechanism to degrade the estrogen receptor and do away with that sign for the most cancers to proceed to develop and divide.
“In comparison with a typical therapy we’ve used for a really very long time that’s given as photographs, that is an oral tablet they may take at house and means that they may have their most cancers not develop for at the very least 3 extra months,” she added.
‘Distinctive’ degrader
Sufferers with ER-positive, HER2-negative superior breast most cancers who progress after receiving first-line endocrine remedy and a CDK4/6 inhibitor do not need a consensus second-line therapy, Hamilton stated.
They usually obtain fulvestrant, a selective ER degrader (SERD), however PFS is usually 2 months or much less.
Vepdegestrant is a proteolysis-targeting chimera (PROTAC) ER degrader that targets each wild sort and mutant ER.
“SERD’s primarily bind and flag for intercellular destruction,” Hamilton stated. “What’s distinctive a few PROTAC is that it’s primarily E3 ligase that’s recruited in. The molecule binds the estrogen receptor on one facet, on the opposite facet it binds the E3 ligase, and this places E3 ligase into shut proximity with the estrogen receptor. This causes ubiquitination of the estrogen receptor and finally its proteosome degradation.”
Vepdegestrant doesn’t have FDA approval however does have fast-track standing.
Researchers evaluated vepdegestrant vs. fulvestrant for sufferers with ER-positive, HER2-negative superior or metastatic breast most cancers within the world VERITAC-2 trial.
They enrolled 624 adults (median age, 60 years; vary, 26-89).
Every participant needed to have prior endocrine remedy with a CDK4/6 inhibitor, however they may not have acquired prior chemotherapy or SERD.
Additionally they needed to have benefited from their earlier endocrine remedy for at the very least 6 months.
The researchers randomly assigned sufferers 1:1 to obtain both 200 mg oral vepdegestrant (n = 313) day by day or 500 mg intramuscular fulvestrant (n = 311) on days 1 and 15 of the primary cycle (28 days) and day 1 of every subsequent cycle.
Hamilton and colleagues stratified sufferers primarily based on ESR1 mutations and visceral illness.
In all, 43.3% of sufferers had an ESR1 mutation (136 acquired vepdegestrant; 134 acquired fulvestrant).
PFS for sufferers with ESR1 mutations, then all sufferers if optimistic, by blinded unbiased central assessment served as the first endpoint. OS, medical profit fee, goal response fee and security served as secondary endpoints.
‘Thrilling choice’
Amongst sufferers with an ESR1 mutation, those that acquired vepdegestrant had considerably longer PFS than those that acquired fulvestrant (median, 5 months vs. 2.1 months; stratified HR = 0.57; 95% CI, 0.42-0.77).
The vepdegestrant arm had a 6-month PFS fee of 45.2% in contrast with 22.7% for the fulvestrant group for these with ESR1 mutations.
Vepdegestrant additionally considerably improved the medical profit fee (42.1% vs. 20.2%; OR = 2.88; 95% CI, 1.57-5.39) and ORR (18.6% vs. 4%; OR = 5.45; 95% CI, 1.69-22.73) for these with ESR1 mutations.
Nevertheless, researchers didn’t observe a big PFS distinction between the 2 arms when evaluating all trial members.
The vepdegestrant arm skilled extra any grade (87% vs. 81%) and grade 3 or worse (23% vs. 18%) treatment-emergent adversarial occasions. Sufferers who acquired vepdegestrant additionally had a better fee of therapy discontinuation (3% vs. 1%) and dose discount (2% vs. N/A).
Fatigue was the commonest adversarial occasion in each arms (27% for vepdegestrant; 16% for fulvestrant).
No treatment-related deaths occurred through the research.
Hamilton described vepdegestrant as “properly tolerated.”
She added that restricted gastrointestinal adversarial occasions might make vepdegestrant stand aside from different degraders.
“We all know that oral SERDs have outstanding GI unwanted side effects as their most frequent facet impact,” she stated. “Throughout all-grade adversarial occasions each vomiting and diarrhea have been solely 6%. I believe [it has] a really favorable GI facet impact profile.”
ASCO professional Jane L. Meisel, MD, FASCO, co-director of breast medical oncology at Winship Most cancers Institute of Emory College College of Drugs, stated she appeared ahead to seeing OS knowledge sooner or later and the way vepdegestrant in comparison with different degraders.
“I believe this can be a very thrilling choice and positively the primary of its variety,” she added.
Perspective
Iris Zhi, MD, PhD
I’m excited concerning the rising oral endocrine remedy choices for sufferers with ESR1 mutations who progressed on prior endocrine remedy and a CDK4/6 inhibitor.
At present, elacestrant (Orserdu, Stemline Therapeutics) is the one FDA-approved oral SERD accessible as single agent, with a median PFS of three.8 months on this affected person inhabitants. A number of different oral SERDs are in medical improvement.
Given the comparatively brief PFS with single agent remedy, future research combining ER degraders with focused brokers — resembling a CDK4/6 inhibitor or PIK3CA inhibitor — might be necessary to judge each security and potential synergistic advantages.
Iris Zhi, MD, PhD
Perlmutter Most cancers Heart at NYU Langone Hospital Lengthy Island
Disclosures: Zhi studies no related monetary disclosures.
Sources/Disclosures
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Hamilton EP, et al. Summary LBA1000. Offered at: ASCO Annual Assembly; Could 30-June 3, 2024; Chicago.
Disclosures:
Hamilton studies consulting/advisory roles with Arvinas, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Gilead Sciences, Janssen, Jazz Prescribed drugs, Johnson and Johnson, Lilly, Novartis and Pfizer; and analysis funding from AbbVie, Arvinas, AstraZeneca, BeiGene, Boehringer Ingelheim; Bristol Myers Squib, Daiichi Sankyo, Genentech/Roche, Gilead Sciences, Incyte, Novartis, Seagen and several other different corporations. Please see the research for all different authors’ related monetary disclosures.
