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

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. 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. 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: 2MOCases 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)ESR1m variantBaseline to C2D1Baseline to disease progressionCamizestrant; n/N (%)Fulvestrant; n/N (%)Camizestrant; n/N (%)Fulvestrant; n/N (%)Summed VAF*32/38 (84)17/30 (57)17/27 (63)8/28 (29)Y537C/N/S31/35 (89)12/20 (60)18/24 (75)6/26 (23)D538G19/23 (83)9/18 (50)11/17 (65)6/17 (35)L536H/P/R7/11 (64)4/7 (57)5/10 (50)1/7 (14)E380Q9/10 (90)3/4 (75)5/6 (83)2/5 (40)*The total VAF frequency of all qualifying ESR1m variants in a plasma sample Open table in a new tab *The total VAF frequency of all qualifying ESR1m variants in a plasma sample 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).