2MO - Dynamics of ESR1 mutation (ESR1m) circulating tumour DNA (ctDNA) in patients (pts) with estrogen receptor (ER)+ HER2- metastatic breast cancer (mBC) receiving camizestrant or fulvestrant: Exploratory analyses from the SERENA-2 trial

Background

In the phase II SERENA-2 trial, camizestrant, the next-generation selective ER degrader and pure ER antagonist, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs fulvestrant in pts with ER+ HER2– mBC. Median PFS was similar with camizestrant regardless of ESR1m status or dose. Here, we explore suppression of ESR1m ctDNA and its relationship with PFS in pts treated with camizestrant vs fulvestrant.

Methods

Camizestrant 75 mg and 150 mg groups were pooled (N=147) and compared to fulvestrant 500 mg (N=73). ctDNA was analysed by next-generation sequencing of plasma samples collected at baseline, at Cycle 2 Day 1 (C2D1) and at disease progression.

Results

Treatment with camizestrant led to 84% of pts experiencing a ≥50% reduction in ESR1m variant allele frequency (VAF) vs baseline at C2D1; ≥50% reductions occurred in the majority of pts across ESR1m variants at both C2D1 and disease progression (Table). ESR1m remained suppressed (<100% increase in VAF vs C2D1) at progression in 56% of camizestrant-treated pts and 33% of fulvestrant-treated pts. For pts treated with camizestrant, median PFS was 11.1 m (90% CI: 4.5–13.3; n=32) for pts with a ≥50% reduction in ESR1m VAF at C2D1 vs 4.0 m (1.8–4.7; n=6) for pts with a <50% reduction; for pts treated with fulvestrant, median PFS was 3.8 m (1.9–7.6; n=17) vs 2.1 m (1.8–6.0; n=13), respectively. Table: 2MO

Cases of ESR1m VAF reduction ≥50% in ctDNA (n) among pts with paired plasma samples at baseline and C2D1/disease progression with detectable ESR1m in either sample (N)

*The total VAF frequency of all qualifying ESR1m variants in a plasma sample

Conclusions

Camizestrant showed markedly improved suppression of ESR1m ctDNA vs fulvestrant at both C2D1 and disease progression. The relationship between C2D1 suppression and median PFS suggests early changes in ctDNA may predict for better response to camizestrant treatment. The efficacy of camizestrant in pts with detectable ESR1m is being prospectively tested in the SERENA-6 trial (NCT04964934).

Clinical trial identification

NCT04214288.

Editorial acknowledgement

Medical writing support was provided by Suzanne Patel, Ph.D., from Boldscience Inc.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo / AstraZeneca, Gilead, Lilly, MSD, Relay Therapeutics, Roche, Seagen, Cureo Science, iOne, Pfizer; Financial Interests, Personal, Invited Speaker: Eisai, Gilead, Pfizer, Roche, Seagen, AstraZeneca, Lilly, Medscape, AstraZeneca, AstraZeneca; Financial Interests, Personal, Other, Educational activity: Libbs; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, GSK, Roche, Seattle Genetics, Zenith Epigenetics, Gilead, Ayala Pharmaceuticals, Pfizer; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Member of Board of Directors, Head: SOLTI Breast Cancer Research; Other, Travel Grant: Pierre Fabre, Eisai, Gilead, AstraZeneca. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, AstraZeneca, Daiichi Sankyo, Seagen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science, Theratechnologies; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana-Farber Cancer Inst, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics. C. Zamagni: Financial Interests, Personal, Advisory Board: Roche, Eisai, Novartis, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Exact Sciences, MSD, GSK, Gilead, Seagen; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, AstraZeneca, Pfizer, Seagen, Medivation, AbbVie, Array BioPharma, Morphotek, Synthon, Daiichi Sankyo, MSD, GSK, Gilead; Financial Interests, Personal, Other, Member of an Independent Data Monitoring Committee for an international clinical trial: AstraZeneca; Non-Financial Interests, Other, member of the Scientific Committee: LOTO Onlus, Susan J Komen Emilia-Romagna, Mamazone Sudtirol; Other, travel accomodation and partecipation expenses for scientific congresses: Roche, Novartis, Pfizer, Daiichi Sankyo, MSD, GSK, Gilead, AstraZeneca. M. Ajimi, I. Gioni, J. Lindemann, C. Morrow: Other, Personal, Full or part-time Employment: AstraZeneca. C. Ciardullo: Other, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. T. Klinowska, R. McEwen: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. All other authors have declared no conflicts of interest.