51P ctDNA analyses at baseline in patients with ER-positive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC) treated with imlunestrant in the EMBER phase I study

The EMBER trial (NCT04188548) demonstrated that the next generation oral SERD, imlunestrant, had favourable safety and pharmacokinetics profiles with a clinical benefit rate (CBR) of 42% in 114 patients (pts) with ER+, HER2- aBC. Here we explore the association between ctDNA results at baseline and CBR in pts treated with imlunestrant. Baseline plasma samples from ER+, HER2- aBC pts treated with single agent imlunestrant (at doses ranging from 200-1200 mg QD) were sequenced using the Guardant360 assay. The association between ctDNA positivity and alterations at baseline with CBR (CR or PR, or stable disease ≥24 weeks) were assessed with the Fisher's test. At data cutoff (August 14, 2023), 109 pts had evaluable baseline plasma samples. Median number of prior therapies for aBC was 2 (range, 0-8), including: prior CDK4/6 inhibitor (93%), fulvestrant (52%), or chemotherapy (25%). Most pts (90%, 98/109) had detectable ctDNA at baseline, while 11 (10%) pts did not. Commonly altered genes included ESR1, PIK3CA, and TP53. In total, 43% of pts had an activating PI3K/AKT/PTEN pathway alteration and 20% had concomitant ESR1 and PIK3CA alterations. Overall, single agent imlunestrant achieved a CBR of 42% [95%CI 32 - 52] in pts (n=109) with evaluable samples. Subgroup analyses based on ctDNA results did not identify any significant difference in CBR across subgroups (Table). However, a numerically higher CBR was observed in pts (n=11) without baseline detectable ctDNA vs pts (n=98) with detectable ctDNA: 64% vs 40%, p = 0.2. D = Gene alteration detected, ND = Gene alteration not detected.Table: 51PCBR (%, 95 CI)pDNDctDNA39/98 (40, 30-50)7/11 (64, 31-89)0.20AKT12/5 (40, 5-85)44/104 (42, 33-52)1.00ARID1A2/7 (29, 4-71)44/102 (43, 33-53)0.70ATM0/5 (0, 0-52)46/104 (44, 34-54)0.07BRCA20/4 (0, 0-60)46/105 (44, 34-54)0.14ESR125/53 (47, 33-61)21/56 (38, 25-51)0.34GATA38/14 (57, 29-82)38/95 (40, 30-51)0.26KRAS2/7 (29, 4-71)44/102 (43, 33-53)0.70PIK3CA14/40 (35, 21-52)32/69 (46, 34-59)0.32PTEN0/5 (0, 0-52)46/104 (44, 34-54)0.07RB10/4 (0, 0-60)46/105 (44, 34-54)0.14SMAD41/4 (25, 1-81)45/105 (43, 33-53)0.64TP537/26 (27, 12-48)39/83 (47, 36-58)0.11ESR1 & PIK3CA10/22 (45, 24-68)36/87 (41, 31-52)0.81PIK3CA or AKT1 or PTEN16/47 (34, 21-49)30/62 (48, 35-61)0.17 Open table in a new tab Exploratory ctDNA analyses of ER+, HER2- aBC pts treated with imlunestrant in the EMBER trial demonstrated no significant impact on clinical benefit in pts harboring common genomic alterations. These findings will be further explored in the ongoing phase III EMBER-3 trial.