Key takeaways:
- Detection of ESR1 mutations with ctDNA earlier than development of sure superior breast cancers could enable for early intervention.
- Switching to camizestrant considerably improved outcomes after detection.
CHICAGO — Testing for ESR1 mutations throughout first-line therapy of ER-positive, HER2-negative superior breast most cancers might enable for early intervention to enhance survival, in response to outcomes of a randomized section 3 trial.
The findings, introduced at ASCO Annual Assembly and concurrently revealed in The New England Journal of Medication, confirmed sufferers who switched to camizestrant (AstraZeneca) following detection of ESR1 mutations throughout commonplace first-line therapy had a median PFS roughly 7 months longer than those that stayed on their authentic remedy.
Knowledge derived from Turner NC, et al. Summary LBA4. Introduced at: ASCO Annual Assembly; Might 30-June 3, 2024; Chicago.
“That is the proof that precision drugs is altering the apply of breast oncology,” examine writer Massimo Cristofanilli, MD, director of breast medical oncology at Weill Cornell Medication and New York-Presbyterian and affiliate director of precision oncology at Meyer Most cancers Heart, advised Healio. “I don’t suppose we will proceed to apply with out utilizing cell-free DNA testing in sufferers with hormone receptor-positive illness.”
He added, “I believe this technique can actually grow to be a brand new commonplace of care.”
‘Daring thought’
Roughly 70% of people with breast most cancers have HR-positive, HER2-negative illness, in response to examine background.
First-line commonplace of take care of these sufferers is a mix of aromatase and CDK4/6 inhibitors.
Lower than 5% of sufferers have ESR1 mutations at first of therapy, however they’re detected in roughly 40% of those that expertise illness development.
Tumors with ESR1 mutations have demonstrated resistance to aromatase inhibitors, however analysis has proven they’ve sensitivity to selective ER degraders (SERDs), equivalent to camizestrant.
Prior investigations confirmed camizestrant improved PFS for sufferers with beforehand handled ER-positive, HER2-negative superior breast most cancers with ESR1 mutations in contrast with fulvestrant, a generally used second-line therapy.
One other examine confirmed ESR1 mutations might be detected with ctDNA testing about 6 months earlier than radiological development.
These outcomes gave Cristofanilli and colleagues the “daring thought” to change one drug within the routine on the molecular emergence of ESR1 mutations, he mentioned.
The double-blind SERENA-6 trial included people with ER-positive, HER2-negative superior breast most cancers who had obtained at the very least 6 months of remedy with aromatase and CDK4/6 inhibitors.
Researchers used liquid biopsy to check for ESR1 mutations each 2 to three months, which coincided with individuals’ routine imaging.
They examined 3,256 sufferers till they found ESR1 mutations in 315 eligible individuals.
The researchers randomly assigned these people to obtain both 75 mg every day camizestrant (n = 157; median age, 61 years; vary, 29-81; 100% girls; 61.8% white) or proceed with their aromatase inhibitor (n = 158; median age, 60.5 years; vary, 35-89; 98.1% girls; 64.6% white).
All sufferers stayed on their CTK4/6 inhibitor no matter examine arm.
PFS served as the first endpoint. OS, patient-reported outcomes and security served as secondary endpoints.
‘Very excited’
After median follow-up of 12.6 months, sufferers who obtained camizestrant had a median PFS of 16 months in contrast with 9.2 months within the management group (HR = 0.44; 95% CI, 0.31-0.6).
The camizestrant arm had a considerably improved estimated 1-year PFS charge (60.7% vs. 33.4%) and 2-year charge (29.7% vs. 5.4%).
OS knowledge remained immature.
“This drug is extraordinarily efficient in sufferers with these mutations,” Cristofanilli mentioned. “We had been excited, very excited concerning the outcomes.”
Sufferers who obtained camizestrant had a considerably longer wait to deterioration in high quality of life (23 months vs. 6.4 months; HR = 0.53; 95% CI, 0.33-0.82), as effectively.
“We’re delaying the onset of disease-related signs,” Cristofanilli mentioned. “If you’re treating a affected person who has no signs as a result of there is no such thing as a radiological illness, clearly you have an effect on the standard of life.”
The camizestrant arm had a better charge of grade 3 or worse opposed occasions (60% vs. 45.8%).
Neutropenia was the commonest opposed occasion in each teams, with sufferers who obtained camizestrant experiencing a better charge of any-grade (54.8% vs. 44.5%) and grade 3 or worse (45.2% vs. 34.2%) occasions.
Bradycardia (5.2%) and sinus bradycardia (2.6%) solely occurred within the camizestrant arm.
Nonetheless, the camizestrant arm had a decrease charge of great opposed occasions (10.3% vs. 12.3%) and people who led to therapy discontinuation (1.3% v. 1.9%).
“This therapy may be very well-tolerated,” Cristofanilli mentioned. “You might be prolonging the time to chemotherapy or extended time to an infusion remedy with related unwanted side effects.”
Cristofanilli and colleagues wish to examine which sufferers profit probably the most and discover different mutations that emerge throughout therapy.
“Having cell-free DNA monitoring within the minimal residual illness setting, with detection of mutations within the detection of illness earlier than having a recurrence, could have even a bigger affect on these kind of sufferers,” Cristofanilli mentioned.
Worth might be a limitation to begin.
“When camizestrant is permitted, will probably be permitted particularly together with the surveillance for detecting rising ESR1 mutations,” lead writer Nicholas C. Turner, MD, PhD, FRCP, professor and director of medical analysis and growth at The Royal Marsden NHS Basis Belief and Institute of Most cancers Analysis, mentioned throughout a press briefing. “The present assay is comparatively pricey with first surveillance, however we’re working actively on growing proof with cost-effective methods.”
Nonetheless, molecular monitoring might be cost-effective in the long term.
“Imaging each 3 months may be modified to doing blood exams and cell-free DNA or molecular exams,” Cristofanilli mentioned. “Imaging may be executed solely when the blood exams recommend a change within the state of the illness. I believe that might be a cheap technique, altering the best way we monitor illness, the best way we use commonplace imaging and the best way we assess response.
“There’s been some dialogue about the best way cell-free DNA offers not solely the mutation standing, but additionally that it may be used to measure tumor burden in response to therapy. I believe we’ll see rather more use of cell-free DNA and fewer imaging total. The price will go down, and the best way we apply shall be streamlined in a approach that we will present one of the best care to our sufferers.”
ASCO skilled Eleonora Teplinsky, MD, head of breast and gynecologic medical oncology at Valley-Mount Sinai Complete Most cancers Care, described SERENA-6 as an “unimaginable” examine with important implications throughout a press briefing.
“When sufferers progress unscanned, we’re already behind,” she mentioned. “We’re switching remedy, and we’ve already misplaced management. An early swap method earlier than we see illness development on imaging permits us to basically keep forward of the curve. Permitting sufferers to stay on first-line endocrine remedy for hormone receptor-positive, HER2-negative superior breast most cancers is crucial as a result of we all know that outcomes worsen with subsequent strains of remedy. Permitting that longer time on first-line endocrine remedy is important and it additionally improves high quality of life, as we’ve seen. That’s’ an enormous a part of dwelling with metastatic breast most cancers.”
As a result of camizestrant just isn’t presently FDA permitted, a serious query for this method is whether or not different accessible SERDs might be substituted as an alternative.
“This can be a query that everybody’s excited about, however we don’t have that knowledge,” Teplinsky mentioned. “Not all oral SERDs are the identical, and we don’t know if utilizing the accessible oral SERDs on this setting goes to have the identical outcomes. That is actually going to evolve as we now have this knowledge.”
References:
For extra data:
Massimo Cristofanilli, MD, may be reached at mac9795@med.cornell.edu.
Sources/Disclosures
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Turner NC, et al. Summary LBA4. Introduced at: ASCO Annual Assembly; Might 30-June 3, 2024; Chicago.
Disclosures:
AstraZeneca funded the examine. Cristofanilli experiences no related monetary disclosures. Turner experiences consultancy or advisory for AstraZeneca, Precise Sciences, Gilead Sciences, GlaxoSmithKline, Guardant Well being, Inivata, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Relay Therapeutics, Repare Therapeutics and Roche; and analysis funding from AstraZeneca, Guardant Well being, Inivata, InVitae, Merck Sharpe and Dohme, Natera, Personalis, Pfizer and Roche. Please see the summary for all different authors’ related monetary disclosures.
