Jhaveri, Komal

Abstract Background: Most patients with estrogen receptor-positive (ER+), metastatic breast cancer (mBC) treated with endocrine therapy (ET) will ultimately develop resistance. A large unmet need exists especially when resistance occurs following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), which is potentially driven by a mutation in the ERα-coding gene, ESR1. Lasofoxifene (LAS), an oral, next-generation ET and ER breast antagonist, was evaluated in two phase 2 studies of women with ER+/HER2- mBC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. In the ELAINE 1 trial, LAS monotherapy provided numerically greater progression-free survival (PFS, median 5.6 mos vs 3.7 mos; HR: 0.669 [95% CI, 0.445‒1.125], P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) compared with the ER degrader fulvestrant (fulv), with a favorable safety profile (Goetz MP et al. Ann Oncol 2023;34:1141‒51). The single-arm, ELAINE 2 trial showed that LAS combined with abemaciclib (Abema) was well tolerated with a median PFS of ∼13 mos, ORR of 56%, and CBR of 66% (Damodaran S et al. Ann Oncol 2023;34:1131‒40). The phase 3, registrational, ELAINE 3 trial was initiated based on these promising earlier-phase data. Recent results from postMONARCH confirmed superior efficacy of fulv/Abema over fulv/placebo (mPFS 6.0 mos vs 5.3 mos, HR 0.73 [0.57‒0.95], nominal P-value 0.017) in non-biomarker‒selected, mBC patients after progression on a prior CDK4/6i and aromatase inhibitor (AI), with similar HR in an ESR1-mutated cohort (Kalinsky K et al. J Clin Oncol 2025;43:1101‒12). Additionally, recent data from EMBER-3 demonstrated meaningful PFS with a novel ET combined with abemaciclib after progression on AI/CDK4/6i (Jhaveri KL et al. N Engl J Med 2025;392:1189‒202). The ELAINE 3, global trial will compare LAS/Abema with fulv/Abema in a post-CDK4/6i, ESR1-mutation‒selected, mBC population. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of LAS plus Abema versus fulv plus Abema. Patients are being enrolled at approximately 152 sites in 13 countries (Australia, Belgium, Canada, China, France, Italy, Israel, Poland, Romania, Spain, Taiwan, United Kingdom, United States). Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 yrs; ER+/HER2-, locally advanced and/or mBC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an AI plus palbociclib or ribociclib as their first hormonal treatment for advanced/mBC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive LAS 5 mg/day plus Abema 150 mg BID, or fulv 500 mg IM (days 1, 15, and 29, then once monthly) plus Abema 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS per RESIST 1.1 by blinded independent central review (BICR); key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Safety, time to cytotoxic chemotherapy, and quality of life (including vaginal health) will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected for genomic analyses at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit. Outcomes with LAS/Abema and fulv/Abema will be compared using a stratified Cox proportional hazards model and stratified logrank test with an expected PFS hazard ratio of 0.68 at final analysis. Enrollment is currently ongoing to meet the target sample size of 500 patients. Citation Format: M. P. Goetz, S. A. Wander, T. Bachelot, G. Curigliano, A. de Nonneville, E. N. Gal-Yam, K. Jhaveri, S. L. Sammons, S. Shen, C. J. Twelves, G. Gasper, P. V. Plourde, D. J. Portman, S. Damodaran. Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-30.

1001 Background: Imlunestrant (imlu) is a next-generation, brain-penetrant, oral selective estrogen receptor degrader. The EMBER-3 trial, in patients (pts) with ER+, HER2- ABC who had disease progression on or after aromatase inhibitor-based therapy, showed significant progression free survival (PFS) improvement with imlu vs standard therapy (SOC, fulvestrant or exemestane) in pts with ESR1 mutations ( ESR1 m), and with imlunestrant+abemaciclib (imlu+abema) vs imlu in all pts, regardless of ESR1 m. Exploratory PRO analyses are presented here. Methods: EORTC QLQ-C30 was administered at baseline (BL) and every 8 weeks until treatment discontinuation. Prespecified QLQ-C30 analysis used a longitudinal mixed model for repeated measures to calculate mean change from BL in pts with BL and ≥1 post-BL score. PRO-CTCAE (diarrhea frequency) was administered weekly, reporting 0 (never) to 4 (almost constantly). PRO-CTCAE (injection site reaction [ISR]) was administered to fulvestrant recipients weekly for 2 weeks post-injection, reporting yes/no (pain, swelling, redness). Descriptive analysis was used for PRO-CTCAE. Results: In pts with ESR1 m, imlu monotherapy was associated with many improved or maintained EORTC QLQ-C30 scores, whereas scores with SOC were declined or maintained. Specifically, pts with ESR1 m on imlu had improved global health status (GHS)/quality of life (QOL) and physical function (PF) scores, while scores with SOC declined (mean change differences between treatments: 9.9 [0.1, 19.7] and 6.2 [-0.8, 13.1], respectively). These PRO findings mirror the PFS findings in this group. In the overall population, GHS/QOL scores declined similarly with imlu vs SOC (mean change differences: 0.5 [-4.7, 5.7]), while PF scores were maintained with imlu vs a slight decline with SOC (mean change difference: 2.5 [-1.1, 6.1]). Most fulvestrant recipients (72%) reported ISR at any time while on treatment, with a mean of 31% during the first week of the first 6 cycles. Imlu+abema vs imlu showed broadly similar declines in all pts, with minimal mean change differences in GHS/QOL and PF scores (0.8 [-7.4, 5.9]; -2.2 [-6.6, 2.2], respectively). Pts reported similarly low rates of “frequent” or “almost constant” diarrhea with imlu (3%) and SOC (2%) and higher rates with imlu+abema (22%). Conclusions: PROs from EMBER-3 demonstrated that patients with ESR1 m had better GHS/QOL and PF with imlu vs SOC, mirroring efficacy results. While the frequency of CTCAE defined ISRs was low, the high rate of PRO-CTCAE ISR demonstrates that this clinically relevant adverse event is underappreciated by physicians. Additionally, all pts had generally comparable GHS/QOL and PF with imlu+abema vs imlu. Overall, these results support the efficacy and safety of imlu compared to existing SOC. Clinical trial information: NCT04975308 .

PURPOSE Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER target inhibition, including in ESR1- mutant breast cancer. This phase Ia/b trial determined the recommended phase II dose (RP2D), safety, pharmacokinetics, and efficacy of imlunestrant, as monotherapy and in combination with targeted therapy, in ER-positive (ER+) advanced breast cancer (ABC) and endometrial endometrioid cancer. The ER+/human epidermal growth factor receptor 2–negative (HER2–) ABC experience is reported here. METHODS An i3+3 dose-escalation design was used, followed by dose expansions of imlunestrant as monotherapy or in combination with abemaciclib with or without aromatase inhibitor (AI), everolimus, or alpelisib. Imlunestrant was administered orally once daily and with the combination partner per label. RESULTS Overall, 262 patients with ER+/HER2– ABC were treated (phase Ia, n = 74; phase Ib, n = 188). Among patients who received imlunestrant monotherapy (n = 114), no dose-limiting toxicities or discontinuations occurred. At the RP2D (400 mg once daily), patients (n = 51) reported grade 1-2 nausea (39.2%), fatigue (39.2%), and diarrhea (29.4%). Patients at RP2D had received previous cyclin-dependent kinase 4/6 inhibitor (CDK4/6i; 92.2%), fulvestrant (41.2%), and chemotherapy (29.4%) for ABC and achieved a median progression-free survival (mPFS) of 7.2 months (95% CI, 3.7 to 8.3). Among patients who received imlunestrant + abemaciclib (n = 42) and imlunestrant + abemaciclib + AI (n = 43), most (69.4%) were treatment-naïve for ABC; all were CDK4/6i-naïve. Patients treated with imlunestrant + everolimus (n = 42)/alpelisib (n = 21) had received previous CDK4/6i (100%), fulvestrant (34.9%), and chemotherapy (17.5%) for ABC. No new safety signals or interactions with partnered drugs were observed. The mPFS was 19.2 months (95% CI, 13.8 to not available) for imlunestrant + abemaciclib and was not reached for imlunestrant + abemaciclib + AI. The mPFS with imlunestrant + everolimus/alpelisib was 15.9 months (95% CI, 11.3 to 19.1)/9.2 months (95% CI, 3.7 to 11.1). Antitumor activity was evident regardless of ESR1 mutation status. CONCLUSION Imlunestrant, as monotherapy or in combination with targeted therapy, had a manageable safety profile with evidence of preliminary antitumor activity in ER+/HER2– ABC.

TPS1127 Background: Patients with estrogen receptor-positive (ER+) metastatic breast cancer (mBC) may develop resistance to endocrine therapy (ET), particularly following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), potentially driven by a mutation in the ERa-coding gene, ESR1. Lasofoxifene (LAS), an oral, next-generation ET and ER breast antagonist, was evaluated in two phase 2 studies of women with ER+/HER2- mBC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. The ELAINE 1 trial showed numerically greater progression-free survival (PFS, median ~6 vs 4 mos; P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) with LAS monotherapy versus the ER degrader fulvestrant (fulv), with a favorable safety profile (1). The single-arm, ELAINE 2 trial demonstrated that LAS plus abemaciclib (Abema) was well tolerated with a median PFS of ~13 mos, ORR of 56%, and CBR of 66% (2). Based on these data, the phase 3, registrational, ELAINE 3 trial was initiated. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of LAS plus Abema versus fulv plus Abema. Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 yrs; ER+/HER2-, locally advanced and/or mBC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal treatment for advanced/mBC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive LAS 5 mg/day plus Abema 150 mg BID, or fulv 500 mg IM on days 1, 15, and 29, then once monthly plus Abema 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS; key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Time to cytotoxic chemotherapy, quality of life, and safety will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected for genomic analyses at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit. Outcomes with LAS/Abema and fulv/Abema will be compared using a stratified Cox proportional hazards model and stratified logrank test. Expected PFS is ≥10.3 mos for LAS/Abema and 7 mos for fulv/Abema (PFS hazard ratio of 0.68 at final analysis). The target sample size is 400, to achieve 90% power with a one-sided type I error rate of 0.025 after 285 PFS events. Full recruitment is expected to occur over 18 mos at approximately 125 global sites. 1. Goetz MP, et al. Ann Oncol. 2023;34:1141-1151. 2. Damodaran S, et al. Ann Oncol. 2023;34:1131-1140. Clinical trial information: NCT05696626 .

1027 Background: Imlunestrant is a next-generation, oral SERD designed to deliver continuous ER-target inhibition. In the first-in-human Phase 1a/b EMBER study (NCT04188548), imlunestrant demonstrated favourable safety, PK, and clinical benefit when administered as monotherapy or with targeted therapy in ER+, HER2- aBC. Here we present clinical data of imlunestrant with HER2 targeted therapy, in patients (pts) with ER+, HER2+ aBC enrolled in EMBER. Methods: Pts were randomized to imlunestrant (400mg po daily) + trastuzumab (H), with or without (±) abemaciclib (Part C) or received maintenance treatment with imlunestrant + H + pertuzumab (P) (Part E), at standard doses in 21-day cycles. Key eligibility (Part C): ≥ 2 prior HER2 directed regimens, no prior CDK4/6i or fulvestrant; (Part E): received 1st line induction taxane chemotherapy (any duration) + H + P, without disease progression and ≤1 prior therapy for aBC. Key endpoints included safety, PK, ORR, CBR and PFS. Results: Overall, 45 pts with ER+/HER2+ aBC received the following combinations: imlunestrant + H (n=18), imlunestrant + H + abemaciclib (n=21; 1 pt received 800 mg imlunestrant), and imlunestrant + H + P (n=6). Baseline characteristics, safety, and preliminary efficacy are presented below (Table). Most TEAEs were grade 1-2. Common TEAEs with imlunestrant + H were fatigue (33%) and nausea (28%); with imlunestrant + H + abemaciclib were diarrhea (100%), neutropenia (57%), fatigue (52%) and nausea (48%); and with imlunestrant + H + P were diarrhea (50%) and arthralgia (50%). Imlunestrant PK was consistent with those previously reported with no drug-drug interactions observed with the combinations. From Part C, sequencing of baseline plasma ctDNA samples (n=37) identified prevalent mutations in TP53 (49%), PIK3CA (30%), ESR1 (24%), and GATA3 (14%). Clinical activity of imlunestrant in this ER+/HER2+ population, while based on small numbers, is promising. Conclusions: Imlunestrant in combination with trastuzumab ± abemaciclib or pertuzumab was well tolerated, showed no drug-drug interactions, and demonstrated preliminary antitumor activity in pts with ER+/HER2+ aBC. Clinical trial information: NCT04188548 . [Table: see text]

Abstract Background: Patients with estrogen receptor-positive (ER+) metastatic breast cancer (BC) may develop resistance to endocrine therapy (ET), particularly following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), potentially driven by a mutation in the ERa-coding gene, ESR1. Lasofoxifene, an oral, next-generation ET and ER breast antagonist, had potent activity in mBC xenograft models expressing ESR1 mutations, either as a single agent or combined with a CDK4/6i. Subsequently, two phase 2 studies evaluated lasofoxifene in women with ER+/HER2- metastatic BC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. The ELAINE 1 trial showed numerically greater progression-free survival (PFS, median ~6 vs 4 months; P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) with lasofoxifene monotherapy versus the ER degrader fulvestrant, with a favorable safety profile (Goetz MP, et al. Ann Oncol. 2022;33:S1387). The single-arm, ELAINE 2 trial demonstrated that lasofoxifene combined with abemaciclib was well tolerated with a median PFS of ~13 months, ORR of 56%, and CBR of 66% (Damodaran S, et al. J Clin Oncol. 2023;41:suppl 16; abstr 1057). Based on these data, the phase 3, registrational, ELAINE 3 trial was initiated. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of lasofoxifene plus abemaciclib versus fulvestrant plus abemaciclib. Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 years; ER+/HER2-, locally advanced and/or metastatic BC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal treatment for advanced/metastatic BC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive lasofoxifene 5 mg/day plus abemaciclib 150 mg BID, or fulvestrant 500 mg IM on days 1, 15, and 29, then 4 weekly plus abemaciclib 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS; key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Time to cytotoxic chemotherapy, quality of life, and safety will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit for genomic analyses. Outcomes with lasofoxifene/abemaciclib and fulvestrant/abemaciclib will be compared using a stratified Cox proportional hazards model and stratified logrank test. Expected PFS is ≥10.3 months for lasofoxifene/abemaciclib and 7 months for fulvestrant/abemaciclib (PFS hazard ratio of 0.68 at final analysis). The target sample size is 400, to achieve 90% power with a one-sided type I error rate of 0.025 after 285 PFS events. Full recruitment is expected to occur over 18 months at 125 global sites. Citation Format: Matthew Goetz, Seth Wander, Thomas Bachelot, Gerald Batist, Javier Cortés, Massimo Cristofanilli, Giuseppe Curigliano, Alexandre de Nonneville, Einav Nili-Gal Yam, Komal Jhaveri, Cynthia Ma, Heather Parsons, Hope Rugo, Sarah Sammons, Daniel Stover, Chris Twelves, Aditya Bardia, Paul V. Plourde, David J Portman, Senthil Damodaran. Trial in progress: Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating locally advanced or ER+/HER2- metastatic breast cancer with an ESR1 mutation [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-12.

Abstract Background: Adjuvant ET has been the standard of care for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) EBC. A significant proportion of patients with increased risk still experience disease relapse despite available ET and more optimum ET is needed to prevent patients developing incurable metastatic cancer. Distant recurrence risk ranges from 20% to 40% after 5 years of adjuvant ET, depending on clinicopathological (clin-path) features at diagnosis. Consequently, there is a need to further optimize adjuvant treatment, particularly in those patients who are at increased risk of recurrence. Imlunestrant is an orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties and the potential to overcome ET resistance. In early phase trials, imlunestrant monotherapy showed favorable safety with pharmacokinetic (PK) exposures exceeding fulvestrant and preliminary efficacy in ER+, HER2- advanced breast cancer patients (EMBER, Jhaveri 2022) along with robust biological/pharmacodynamic activity and tolerability in EBC (EMBER-2, Neven). Trial Design: EMBER-4 is a randomized, open-label, global phase 3 study comparing imlunestrant versus physicians’ choice of ET, in patients who are at an increased risk of recurrence based on clin-path features and who have received 2 to 5 years of standard adjuvant ET. Approximately 6,000 patients will be randomized 1:1 to receive imlunestrant (400 mg daily) for 5 years or physicians’ choice of adjuvant ET (tamoxifen or an aromatase inhibitor, AI, dosed per label). Study treatment duration is 5 years. Males and pre-/peri-menopausal women will receive concomitant treatment with a GnRH agonist if receiving imlunestrant or an AI. Stratification factors include time from initial adjuvant ET, use of prior adjuvant cyclin dependent kinase 4/6 inhibitors, nodal status, menopausal status, and geographic region. Eligibility criteria: Eligible patients are adult males and females (pre-, peri- or postmenopausal) with ER+, HER2- EBC who have completed definitive locoregional therapy and have received 2 to 5 years of prior adjuvant ET without disease recurrence, but who are at increased risk of recurrence based on clin-path features at diagnosis. Prior (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor is permitted. Study endpoints: The primary endpoint is invasive disease-free survival (IDFS), excluding second non-breast primary invasive cancers. Key secondary endpoints include distant relapse-free survival, overall survival, IDFS including second non-breast primary invasive cancers, safety, PK and patient reported outcomes. Recruitment for EMBER-4 begins globally in Q4 2022. Citation Format: Komal Jhaveri, Joyce O’Shaughnessy, Fabrice Andre, Matthew P. Goetz, Nadia Harbeck, Miguel Martín, Francois-Clement Bidard, Zachary M. Thomas, Suzanne Young, Roohi Ismail-Khan, Lillian M. Smyth, Michael Gnant. EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-01-02.

Abstract HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2-mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (NCT01953926). The primary objective of the BTC cohort was objective response rate (ORR). Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers), the ORR was 16%. The most common HER2 mutations were S310F (n = 11; 48%) and V777L (n = 4; 17%). Outcomes appeared worse for ampullary tumours or those with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations were identified at progression in one responder. Neratinib demonstrated anti-tumour activity in patients with refractory BTC harbouring HER2 mutations. Future studies of rational combinations are warranted.