Imlunestrant, an Oral Selective Estrogen Receptor Degrader, as Monotherapy and in Combination With Targeted Therapy in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Phase Ia/Ib EMBER Study.

Jhaveri KL ，Lim E ，Jeselsohn R ，Ma CX ，Hamilton EP ，Osborne C ，Bhave M ，Kaufman PA ，Beck JT ，Manso Sanchez L ，Parajuli R ，Wang HC ，Tao JJ ，Im SA ，Harnden K ，Yonemori K ，Dhakal A ，Neven P ，Aftimos P ，Pierga JY ，Lu YS ，Larson T ，Jerez Y ，Sideras K ，Sohn J ，Kim SB ，Saura C ，Bardia A ，Sammons SL ，Bacchion F ，Li Y ，Yuen E ，Estrem ST ，Rodrik-Outmezguine V ，Nguyen B ，Ismail-Khan R ，Smyth L ，Beeram M ... -  《-》

Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and combined with abemaciclib, in recurrent/advanced ER-positive endometrioid endometrial cancer: Results from the phase 1a/1b EMBER study.

Imlunestrant is a next-generation oral selective estrogen receptor degrader designed to deliver continuous estrogen receptor (ER) target inhibition. EMBER is a phase 1a/b trial of imlunestrant, as monotherapy and combined with targeted therapy, in patients with ER+ advanced breast cancer or endometrioid endometrial cancer (EEC). This report focuses on patients with ER+ EEC. EMBER used an i3 + 3 dose-escalation design to determine the recommended phase 2 dose (RP2D) followed by dose-expansion cohorts (1:1 randomization): imlunestrant monotherapy and imlunestrant plus abemaciclib (150 mg twice daily). Eligible patients had measurable disease and progression or recurrence after platinum-containing chemotherapy. Prior fulvestrant or aromatase inhibitor was not allowed. Secondary endpoints included safety, pharmacokinetics and antitumor activity. In total, 72 patients with a median of 2 prior anticancer therapies were treated. Among the 39 patients who received imlunestrant (400 mg [RP2D], n = 33; 800 mg, n = 6), the most common treatment-emergent adverse events (TEAEs) were grade 1-2 nausea (35.9 %), diarrhea (25.6 %), urinary tract infection (25.6 %), and abdominal pain (20.5 %). Overall response rate (ORR) was 10.3 %, clinical benefit rate (CBR) was 33.3 %, and median progression-free survival (mPFS) was 3.8 months (95 % CI, 1.8-6.7). Among the 33 patients who received imlunestrant (400 mg [RP2D], n = 29; 800 mg, n = 4) plus abemaciclib, the most common TEAEs were diarrhea (87.9 %), nausea (66.7 %), fatigue (48.5 %), and anemia (45.5 %). ORR was 18.2 %, CBR was 42.4 %, and mPFS was 6.8 months (95 % CI, 2.1-12). Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC.

Yonemori K ，Boni V ，Min KG ，Meniawy TM ，Lombard J ，Kaufman PA ，Richardson DL ，Bender L ，Okera M ，Matsumoto K ，Giridhar KV ，García-Sáenz JA ，Prenen H ，de Speville Uribe BD ，Dizon DS ，Garcia-Corbacho J ，Van Nieuwenhuysen E ，Li Y ，Estrem ST ，Nguyen B ，Bacchion F ，Ismail-Khan R ，Jhaveri K ，Banda K ... -  《-》

Imlunestrant with or without Abemaciclib in Advanced Breast Cancer.

Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα (ESR1). In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib. Primary end points were investigator-assessed progression-free survival with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently. Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant-abemaciclib. Among 256 patients with ESR1 mutations, the median progression-free survival was 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001). In the overall population, the median progression-free survival was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P = 0.12). Among 426 patients in the comparison of imlunestrant-abemaciclib with imlunestrant, the median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001). The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant-abemaciclib. Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status. (Funded by Eli Lilly; EMBER-3 ClinicalTrials.gov number, NCT04975308.).

Jhaveri KL ，Neven P ，Casalnuovo ML ，Kim SB ，Tokunaga E ，Aftimos P ，Saura C ，O'Shaughnessy J ，Harbeck N ，Carey LA ，Curigliano G ，Llombart-Cussac A ，Lim E ，García Tinoco ML ，Sohn J ，Mattar A ，Zhang Q ，Huang CS ，Hung CC ，Martinez Rodriguez JL ，Ruíz Borrego M ，Nakamura R ，Pradhan KR ，Cramer von Laue C ，Barrett E ，Cao S ，Wang XA ，Smyth LM ，Bidard FC ，EMBER-3 Study Group ... -  《-》

Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3.

In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3. MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint. A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed. Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.

Goetz MP ，Toi M ，Huober J ，Sohn J ，Trédan O ，Park IH ，Campone M ，Chen SC ，Manso LM ，Paluch-Shimon S ，Freedman OC ，O'Shaughnessy J ，Pivot X ，Tolaney SM ，Hurvitz SA ，Llombart-Cussac A ，André V ，Saha A ，van Hal G ，Shahir A ，Iwata H ，Johnston SRD ... -  《-》

Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.

Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. Between Aug 14, 2017, and Jul 29, 2022 (data cutoff), 127 patients with at least 18 months' follow-up were enrolled into cohort A. 119 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 21·8 months (IQR 10·8-37·6). 64 (53·8%; 95% CI 44·4-63·0) of 119 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (37 [29%] of 127 patients), rash (13 [10%]), and rash maculopapular (11 [9%]). Serious adverse events occurred in 37 (29%) of 127 patients. No treatment-related deaths were reported. BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. Novartis Pharmaceuticals.

Rugo HS ，Lerebours F ，Ciruelos E ，Drullinsky P ，Ruiz-Borrego M ，Neven P ，Park YH ，Prat A ，Bachelot T ，Juric D ，Turner N ，Sophos N ，Zarate JP ，Arce C ，Shen YM ，Turner S ，Kanakamedala H ，Hsu WC ，Chia S ... -  《-》