Prolonged Progression-free Survival Research Articles

State of the Art in Low-Grade Glioma Management: Insights From Isocitrate Dehydrogenase and Beyond.

Low-grade gliomas present a formidable challenge in neuro-oncology because of the challenges imposed by the blood-brain barrier, predilection for the young adult population, and propensity for recurrence. In the past two decades, the systematic examination of genomic alterations in adults and children with primary brain tumors has uncovered profound new insights into the pathogenesis of these tumors, resulting in more accurate tumor classification and prognostication. It also identified several common recurrent genomic alterations that now define specific brain tumor subtypes and have provided a new opportunity for molecularly targeted therapeutic intervention. Adult-type diffuse low-grade gliomas are frequently associated with mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), resulting in production of 2-hydroxyglutarate, an oncometabolite important for tumorigenesis. Recent studies of IDH inhibitors have yielded promising results in patients at early stages of disease with prolonged progression-free survival (PFS) and delayed time to radiation and chemotherapy. Pediatric-type gliomas have high rates of alterations in BRAF, including BRAF V600E point mutations or BRAF-KIAA1549 rearrangements. BRAF inhibitors, often combined with MEK inhibitors, have resulted in radiographic response and improved PFS in these patients. This article reviews emerging approaches to the treatment of low-grade gliomas, including a discussion of targeted therapies and how they integrate with the current treatment modalities of surgical resection, chemotherapy, and radiation.

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells wasassociated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. NCT03534453. Registered at May 23, 2018.

Molecular profiling of metastatic breast cancer and target-based therapeutic matching in an Asian tertiary phase I oncology unit

IntroductionMolecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre.MethodsPatients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014–2017) prior to institutional change to FoundationOne CDx (FM1; 2017–2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022.ResultsA total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes PIK3/AKT/PTEN affected in 62% (98/158) patients and 43% of tumours harbouring a PIK3CA alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] versus 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of PIK3/AKT/PTEN-altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment versus unmatched, with median OS (mOS) of 30.1 versus 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% versus 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75).ConclusionsBroad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS.

Interventional therapy combined with tyrosine kinase inhibitors with or without immune checkpoint inhibitors as initial treatment for hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis

BackgroundInterventional therapy, in conjunction with tyrosine kinase inhibitors (TKIs), has shown promising outcomes for treating hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). With the advent of immunotherapy, the combined use of immune checkpoint inhibitors (ICIs) has attracted great attention due to their potential effectiveness in advanced HCC. This study aims to compare the efficacy and safety of a triple therapy regimen (Interventional therapy, TKIs and ICIs, IT-TKI-ICI) with a dual therapy regimen (Interventional therapy and TKIs, IT-TKI) in the treatment of HCC and PVTT (HCC-PVTT).MethodsA comprehensive search was carried out in PubMed, Web of Science, Embase, Scopus, and the Cochrane Library databases. Primary outcome measures were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included tumor response rate, adverse event incidence as well as downstaging surgery rate. Statistical analysis was conducted using Revman 5.4 software.ResultsThe meta-analysis finally included 6 cohort studies. The triple therapy group demonstrated significantly prolonged OS and PFS compared to the dual therapy group. Meanwhile, the former exhibited significantly higher rates of objective response rate (ORR), disease control rate (DCR) and better downstaging effects with a higher salvage surgery rate without significantly increasing adverse events.ConclusionIn comparison to dual therapy, the triple therapy with interventional therapy, TKIs, and ICIs demonstrates superior efficacy and equivalent safety for HCC-PVTT.

Treatment strategy for HER2-negative advanced gastric cancer: salvage-line strategy for advanced gastric cancer.

After immune checkpoint inhibitor (ICI) comes into third-line treatment of advanced gastric cancer, the therapeutic strategy has been dramatically changed. Recent first-line regimen, which consists of ICI and chemotherapeutic agents, prolonged progression-free survival, and subsequent treatment options enabled continuous treatment beyond second-line therapy. Moreover, the advent of vascular endothelial growth factor (VEGF)-targeted agents including angiogenesis inhibitors and TKIs provides an opportunity of considering the interaction between ICI and anti-VEGF agents, and facilitating novel treatment proposal. Although clinical benefit of prolonged VEGF blockade after disease progression has not been confirmed in gastric cancer, combination therapy of cytotoxic agents and anti-VEGF agent, such as irinotecan plus ramucirumab demonstrated favorable objective response rate and progression-free survival in third- or later-line setting. In this review, we discuss recent progress and future directions of later-line treatments of HER2-negative advancer gastric cancer.

CDK4/6 inhibitors: The Devil is in the Detail.

Update on the most recent clinical evidence on CDK4/6 inhibitors (CDK4/6i) in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative breast cancer. Over the past decade, CDK4/6i have become part of the standard of care treatment of patients with both metastatic and high-risk early HR + /HER2- breast cancers. The three available CDK4/6i (palbociclib, ribociclib and abemaciclib) have been extensively studied in combination with endocrine therapy (ET) in metastatic breast cancer (mBC) with consistent prolongation of progression free survival; however, ribociclib has emerged as the preferred first line agent in mBC given overall survival benefit over endocrine monotherapy. In early BC, abemaciclib is the only currently approved agent while ribociclib has early positive clinical trial data. Toxicities and financial burden limit the use of CDK4/6i in all patients and resource-poor settings, and optimal timing of their use in mBC remains unclear. There is considerable evidence for the use of CDK4/6i in metastatic and early HR + /HER2- breast cancer, but knowledge gaps remain, and further research is necessary to better define their optimal use.

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial

Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200mg/day for patients with bodyweight <77kg and/or platelet count <150×103/μL at baseline and 300mg/day otherwise. OS was a secondary endpoint. Totally, 265 patients were randomised to receive niraparib (n=177) or placebo (n=88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

Efficacy and safety of transarterial chemoembolization combined with targeted therapy and immunotherapy versus with targeted monotherapy in unresectable hepatocellular carcinoma: A systematic review and meta-analysis.

The application of transarterial chemoembolization (TACE) in combination with targeted therapy and immunotherapy (TACE-T-I) for unresectable hepatocellular carcinoma (HCC) has gained increasing attention. However, there are variations in the efficacy and safety outcomes between TACE-T-I versus TACE combined with targeted drugs (TACE-T). This study aims to systematically evaluate the efficacy and safety of TACE-T-I versus TACE-T in unresectable HCC. PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception to August 21, 2023, for comparative studies on TACE-T-I versus TACE-T for unresectable HCC. Outcome measures included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the incidence of treatment-related adverse events (TRAEs). OS was the primary outcome of this study. Weighted mean difference (WMD) or hazard ratio (HR) was used as the pooled statistic for OS and PFS. Relative risk (RR) was employed as the pooled statistic for ORR, DCR and the incidence of TRAEs. And 95% confidence intervals (CIs) were calculated for all effect measures. Data analysis was conducted using Stata 14.0 software. The meta-analysis included 14 studies with 2144 patients. The pooled results showed that compared with patients in the TACE-T group, patients in the TACE-T-I group had higher ORR (RR = 1.61; 95%CI: 1.38-1.89) and DCR (RR = 1.17; 95%CI: 1.09-1.26). Patients in the TACE-T-I group experienced prolonged PFS (WMD = 3.08; 95%CI: 2.63-3.53) and OS (WMD = 5.76; 95%CI: 4.68-6.84). And the risk of disease progression (HR = 0.45; 95%CI: 0.37-0.55) and death (HR = 0.43; 95%CI: 0.38-0.49) was lower in the TACE-T-I group. Common TRAEs included fever, pain, abdominal pain, nausea, vomiting, elevated ALT, elevated AST, hypertension, hand-foot syndrome, proteinuria, and diarrhea. The incidence and severity of TRAEs in the TACE-T-I group were similar to those in the TACE-T group, with no significant differences (P > .05). Current evidence suggests that, on the basis of TACE combined with targeted therapy, the addition of immunotherapy provides better clinical efficacy and survival benefits for unresectable HCC patients, with good tolerability.

Abstract PO1-19-11: Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (HER2CLIMB-05, Trial in Progress)

Abstract Background The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. NEJM 2020, Curigliano et al. Ann Oncol 2022). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS, time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a two-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in Austria, Chile, Greece, Italy, Japan, Poland, Portugal, Spain, the US, and several other European, APAC, and LATAM countries. This abstract was previously presented at ESMO-BC 2022, FPN (Final Publication Number): 415, by Veronique Dieras (reused with permission). Citation Format: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara O'Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras. Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (HER2CLIMB-05, Trial in Progress) [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 PO1-19-11.

Abstract PO2-05-05: ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC)

Abstract Background: Currently, there are no approved systemic treatment options specifically for patients with ER+/HER2- BC who have brain metastasis. The prevalence of brain metastases from ER+/HER2- BC is approximately 14% of women (Aversa, 2014). Elacestrant is a next-generation oral SERD that was evaluated in a pivotal phase 3 trial, EMERALD, as monotherapy vs. standard of care (SOC) endocrine therapy. The EMERALD trial reported significantly prolonged progression-free survival (PFS) with elacestrant vs SOC endocrine therapy in patients with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following progression on prior endocrine therapy (Bidard, 2022). Elacestrant was well tolerated with a manageable safety profile. Most adverse events, including nausea, were low-grade and consistent with other endocrine therapies. A clinical study in healthy postmenopausal women demonstrated the ability of elacestrant to cross the blood-brain barrier (Conlan, 2020). Abemaciclib, a CDK4/6i, has been shown to achieve therapeutic concentrations in brain metastases tissue (Tolaney, 2020). Given the lack of current systemic treatments, elacestrant is now being evaluated with abemaciclib in patients with ER+/HER2- BC and brain metastasis (NCT05386108). Methods: ELECTRA (NCT05386108) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib in patients with brain metastasis from ER+, HER2- BC. Eligibility are patients with ER+/HER2− locally advanced or mBC and measurable brain metastasis. For phase 1b, the presence of brain metastases is allowed but not required for eligibility. For phase 2, patients must have ≥ 1 active and measurable brain metastasis per RECIST v1.1. Patients must have received prior therapy in the metastatic setting, including ≥ 1 ET, ≤2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). The primary objectives of Phase 1b are to determine the recommended Phase 2 dose (RP2D). Phase 1b secondary objectives include safety, PK, objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), PFS, and overall survival (OS). Phase 2 primary objective is ORR per RECIST version 1.1. Phase 2 secondary objectives include intracranial response rate (RR), DoR, CBR, PFS, OS, PK, and quality of life (QoL). The phase 1b portion evaluated dose-limiting toxicities (DLTs) of the combination during the first cycle (28 days) of treatment in up to three 6-patient cohorts, starting at elacestrant 300 mg daily plus abemaciclib 100 mg twice daily. Here we report initial safety results from the phase 1b portion. Results: As of June 2023, 15 patients have been enrolled in the phase 1b portion of the trial. At dose level 1, elacestrant 300 mg QD + abemaciclib 100 mg BID, no patient experienced DLTs, and the combination was feasible. Dose level 2, elacestrant 400 mg QD + abemaciclib 100 mg BID has been completed, and no patients experienced DLTs. In dose level 1, 4/7 patients remain on treatment at cycle 5. Additional safety and PK data for the cohorts will be provided. Conclusion: In the phase 1b portion of ELECTRA, dose level 1 and dose level 2 have been completed. No patients experienced DLTs in either dose level 1 or dose level 2, and the combination was considered feasible in the respective dose levels. Dose level 3 (elacestrant 400 mg QD + abemaciclib 150 mg BID) is proceeding. Recruitment is actively ongoing, enabling oral-oral combinations to determine a RP2D. Citation Format: Nuhad Ibrahim, Sung-Bae Kim, Nancy Lin, Ahmad Awada, Eva Ciruelos Gil, Giulia Tonini, Bartomeu Piza Vallespir, Kathy Puvana Theall, Erika Hamilton. ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) [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 PO2-05-05.

Abstract PS17-02: Elacestrant vs standard-of-care in ER+/HER2- advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial

Abstract Background: The EMERALD trial reported significantly prolonged progression-free survival (PFS) and a manageable safety profile with elacestrant vs standard of care (SOC) endocrine therapy in patients (pts) with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following progression on prior endocrine therapy (ET). EMERALD is the only pivotal oral SERD clinical trial where prior CDK4/6i usage was mandated. Duration of prior CDK4/6i was shown to be a predictor of efficacy in patients with ESR1 mutations (ESR1-mut) receiving elacestrant, with median PFS (mPFS) for patients with ESR1-mut receiving at least 12 months of CDK4/6i achieved 8.61 months (elacestrant) vs 1.91 months (SOC) (SABCS 2022). This analysis evaluates the clinical benefit of single-agent elacestrant in key clinically relevant subgroups, including biomarkers, usually associated with poorer prognosis. Methods: Patients with ER+/HER2- advanced or mBC who previously had 1-2 lines of endocrine therapy, and prior CDK4/6i, were randomized 1:1 to receive elacestrant or SOC (aromatase inhibitor or fulvestrant). A subgroup analysis was performed on patients with ESR1-mut, by prior duration of CDK4/6i plus ET with at least 12 months in the advanced or metastatic setting, with concomitant presence of liver and/or lung metastases, PIK3CA mutations, TP53 mutation, and HER2 low expression. Results: Overall, 478 patients were randomized to elacestrant (n=239) or SOC (n=239), 228 pts (47.7%) had ESR1-mut, and 159 pts (71.6%) received at least 12 months of prior CDK4/6i. Out of these 159 pts, 113 pts (71%) had liver and/or lung metastases, 62 pts (39%) had a PIK3CA-mut, 61 pts (38%) had TP53m, and 77 pts (48%) had HER2 low expression. A clinically meaningful improvement in PFS favoring elacestrant compared to SOC was consistent across all relevant subgroups in pts with ESR1-mut. Conclusions: Elacestrant showed significantly greater PFS when prior treatment duration with CDK4/6i was at least 12 months, suggesting prior exposure to CDK4/6i is a surrogate marker for endocrine sensitivity. In this population, elacestrant demonstrated superior efficacy, compared to SOC, even in patients with concomitant PIK3CA or TP53 mutations, expression of HER2 low, or presence of liver and/or lung metastases. These results suggest an active ER-driven pathway for this group despite the presence of other resistance mechanisms, where single-agent oral elacestrant could be an attractive option compared to combination therapies or intravenous HER2 low-targeted ADCs. NCT number: NCT03778931 Table. a. Includes E545K, H1047R, E542K amongst others b. HER2 IHC 1+, and 2+ with no ISH amplification Citation Format: Aditya Bardia, Joyce O'Shaughnessy, Francois-Clement Bidard, Patrick Neven, José Ángel García-Sáenz, Philippe Aftimos, Javier Cortés, Janice Lu, Giulia Tonini, Kathy Puvana Theall, Alessandro Paoli, Virginia Kaklamani. Elacestrant vs standard-of-care in ER+/HER2- advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial [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 PS17-02.

Abstract PO2-05-04: ELEVATE: A phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC)

Abstract Background: ER+/HER2- breast cancer (BC) is the most prevalent BC subtype. Endocrine therapy (ET) is the mainstay of treatment; however, development of resistance to this therapeutic approach is common in the metastatic setting. After progression on first-line treatment, both ET monotherapy and combination therapy options are available. Combinations such as everolimus + exemestane and alpelisib + fulvestrant can be associated with higher efficacy, but also significant toxicity with discontinuation rates around 25%. Also, for second-line treatment, pts who did not receive prior treatment with a CDK4/6i, the combination of fulvestrant with a CDK4/6i (palbociclib, abemaciclib, and ribociclib) are among the recommended treatment options for this pt population (NCCN, 2022). However, fulvestrant has low bioavailability and an IM injection burden. The crosstalk between the three pathways ER, PI3K/AKT/mTOR and cyclin-dependent kinases (CDK4/6) provide a rationale for the combination of elacestrant, a next-generation oral SERD, with inhibitors of these pathways that are natural targets to overcome endocrine resistance. The EMERALD trial reported significantly prolonged progression-free survival (PFS) with elacestrant vs SOC ET in pts with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following disease progression on prior ET (Bidard, 2022). Elacestrant was well tolerated with a manageable safety profile. Most adverse events, including nausea, were low-grade and consistent with other endocrine therapies. The replacement of the fulvestrant backbone with elacestrant in combination with targeted agents enabling oral-oral combinations is of therapeutic interest. Methods: ELEVATE (NCT05563220) is a phase 1b/2 clinical trial that will evaluate the safety and efficacy of elacestrant combined with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib. Eligible pts must be adults with confirmed ER+/HER2− advanced or mBC, &amp;gt; 1 measurable lesion as per RECIST v1.1, and adequate bone marrow or organ function. The main objectives for Phase 1b are to determine the RP2D of elacestrant combined with other targeted agents. The RP2D of elacestrant and abemaciclib will be determined in the ELECTRA study (NCT05386108). The Phase 2 portion will evaluate the efficacy of elacestrant combined with other study drugs for PFS; secondary objectives include PK of the various combinations, ORR, DoR, CBR, PFS, and OS. Here we report the initial dosing from the Phase 1b portion. Results: As of June 2023, 11 pts were enrolled in the phase 1b portion of the trial, cohort 1 for all combinations: 5 pts in the elacestrant and everolimus (300 mg elacestrant QD/everolimus 5 mg QD) and 3 pts in the elacestrant and alpelisib (300 mg elacestrant QD/alpelisib 250 mg QD) and 2 patients for palbociclib and 1 patient in the ribociclib combinations. Further patient accrual is expected in phase 1b cohorts of various combinations during the second half of 2023; both safety and PK data will be provided. Conclusion: In the Phase 1b portion of ELEVATE, elacestrant is being combined with various targeted agents enabling oral-oral combinations to determine a RP2D. Recruitment is actively ongoing; safety and PK results will be presented at the meeting from the completed phase 1b cohorts. Citation Format: Hope Rugo, Aditya Bardia, Javier Cortés, Giuseppe Curigliano, Erika Hamilton, Sara Hurvitz, Sibylle Loibl, Sara Tolaney, Virginia Kaklamani, Giulia Tonini, Shannon Matheny, Kathy Puvana Theall, Joyce O'Shaughnessy. ELEVATE: A phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC) [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 PO2-05-04.

Abstract PO4-19-09: Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20)

Abstract Background The current standard first-line treatment in advanced or metastatic hormone receptor (HR) positive breast cancer is combination of aromatase inhibitor (AI) and cyclin D kinase-4/6 (CDK4/6) inhibitor. Emergence of ESR1 mutation is a key mechanism of resistance during first-line AI + CDK4/6 inhibitor treatment. Selective estrogen receptor downregulator (SERD) such as elacestrant or fulvestrant is suggested as second-line treatment, but the progression-free survival (PFS) outcome of second-line treatment is reported up to 3.78 months in patients who harbour ESR1 mutation. Recently, early switch of AI + CDK4/6 inhibitor to fulvestrant + CDK4/6 inhibitor at the point of rising ESR1 mutation showed prolongation of PFS up to 6 months, suggesting there may be a new strategy to overcome ESR1 mutation by modifying endocrine treatment. SWOG S0226 suggested that upfront fulvestrant + AI is feasible and associated with prolongation of PFS compared to AI alone. After CDK4/6 inhibitor has been introduced to standard treatment, there were no trials evaluating the role of AI + fulvestrant with CDK4/6 inhibitor. In this trial, we investigated triplet combination of AI + fulvestrant + CDK4/6 inhibitor as a treatment to overcome resistant mechanism such as development of ESR1 mutation when compared to current standard treatment of AI + CDK4/6 inhibitor as the first line treatment in HR positive advanced or metastatic breast cancer. Methods This study is a randomized, multicenter, open-label phase II trial comparing AI plus ribociclib versus AI, fulvestrant plus ribociclib in HR-positive advanced or metastatic breast cancer. De novo patients or patients with treatment-free interval (TFI) over 12 months after completion of adjuvant AI can be enrolled. If patients received adjuvant tamoxifen, patients with TFI less than 12 months can be also enrolled for the study. Prior endocrine treatment or cytotoxic chemotherapy at metastatic setting was not allowed. In cases of premenopausal women, gonadotropin releasing hormone agonist (GnRHa) is administered every 4 weeks with treatment. A total of 202 patients will be enrolled for 30 months, and 30 months of follow-up is planned after last-patient enrolment. Patients are randomized to 1:1, stratified based on the presence of visceral metastasis and previous administration of adjuvant AI. Study treatment of the control arm consists of letrozole 2.5mg daily with ribociclib 600mg (Day 1-Day 21 daily by month, 1 week off) until progression. In the experimental arm fulvestrant 500mg intramuscular injection is added (Day 1, Day 15, Day 29 and every 4 weeks thereafter) until progression. For exploratory analysis of ESR1 mutations, circulating tumor DNA (ctDNA) is collected at baseline, and then every 3 months thereafter. Primary endpoint is to evaluate the difference of 24-months PFS rate. Secondary endpoint included PFS, overall survival (OS), emergence and frequency of ESR1 mutation, overall response rate (ORR) and clinical benefit rate (CBR). The analysis is planned after completion of 30 months of follow-up, which provides approximately 90% power to detect superiority 24 months-PFS rate assumed by Kaplan-Meier curve of letrozole + fulvestrant + ribociclib versus letrozole + ribociclib using a log-rank test, assuming a hazard ratio of 0.64 at a two-sided alpha of 0.2. Citation Format: Jieun Lee, Su-Jin Koh, Jung Hye Kwon, Gun Min Kim, Jee Hung Kim, Ho Young Kim, Hee-Jun Kim, Keon-Uk Park, Kyong Hwa Park, Yeon Hee Park, Mi Sun Ahn, Hee Kyung Ahn, Gyeong-Won Lee, Kyoung Eun Lee, Kyung-Hun Lee, Moon Hee Lee, Sung Sook Lee, Jung Lim Lee, Kyung Hae Jung, Joo Young Jung, In Hae Park. Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20) [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 PO4-19-09.

Abstract PO1-05-06: Health-related QOL and physical activity collected via wearable device in patients with HR+/HER2− advanced breast cancer in Japan treated with palbociclib+endocrine therapy (ET) or ET alone: 6-month longitudinal study (JBCRG-26)

Abstract Background: Palbociclib (PAL) is a first-in-class cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) for the treatment of HR+/HER2− advanced breast cancer (ABC). In phase 3 clinical trials, PAL+ET prolonged progression-free survival and maintained health-related quality of life (HRQOL) compared with placebo+ET. However, few studies have evaluated the day-to-day effects of PAL+ET treatment on patients’ HRQOL and daily activities in a real-world setting. Here, we report the daily life of the patients treated with PAL+ET or ET alone evaluated with a mobile application and wearable device. Methods: This is a prospective, observational, multicenter study conducted in Japanese women with HR+/HER2- ABC initiating PAL+ET (Group 1) or ET alone (Group 2) in first- or second-line setting. HRQOL was assessed with the EORTC-QLQ-C30 at baseline and Day 15 of each cycle via a smartphone-based application for 6 treatment cycles (24 weeks). Physical activity (PA) data were collected via wearable device (CentrePoint Insight Watch®, ActiGraph LLC, the USA). Patients were instructed to wear the device at all-times, except of while bathing and sleeping, during the baseline period (at least 4 days prior to treatment initiation was recommended) and 6 cycles. PA metrics were averaged on a weekly basis. Patient data, including baseline characteristics, treatment, and adverse events, were collected via electronic case report forms. As primary endpoints, change in Global health status (GHS) of EORTC-QLQ-C30 and “sedentary time” from baseline were evaluated at each time point. No formal hypothesis testing or comparisons between groups was planned. Results: Ninety-nine patients were enrolled (Group 1: 78 patients, Group 2: 21 patients). Patients had a median age of 56/52 years (Group 1/Group 2); 51%/33% had visceral metastases; 86%/86% had ECOG performance status of 0; 76%/91% initiated first-line treatment; 36%/33% were fully employed. Seventy-four of 78 patients (95%) in Group 1 and 20 of 21 patients (95%) in Group 2 completed the 6-cycle observation period. Baseline mean GHS score was 60.9 and 64.3 in Group 1 and 2, respectively. The change from baseline to Cycle 6 in GHS score was 4.6 and 1.2 in Group 1 and 2, respectively, not reaching the deterioration-threshold of 8 points in either treatment group. Results for each functional subscale are summarized in Table 1. Baseline mean “sedentary time” was 580.7 and 565.1 min/day in Group 1 and 2, respectively. The change from baseline to Cycle 6 in “sedentary time” was —67.2 and —139.4 min/day in Group 1 and 2, respectively. Results of other PA metrics are summarized in Table. No new safety signals were identified. Conclusion: In this study, PAL+ET or ET alone did not have any significant adverse impact on HRQOL and PA measured by wearable devices in patients with HR+/HER2- ABC. (NCT04736576) Citation Format: Hiroko Bando, Mari Oba, Aya Ueda, Kaori Terata, Mihoko Doi, Shigenori Nagai, Masaya Hattori, Ken-Ichi Watanabe, Nobuko Tamura, Manabu Futamura, Kei Koizumi, Naoki Niikura, Tempei Miyaji, Yasuaki Muramatsu, Linghua Xu, Norikazu Masuda, Shigehira Saji. Health-related QOL and physical activity collected via wearable device in patients with HR+/HER2− advanced breast cancer in Japan treated with palbociclib+endocrine therapy (ET) or ET alone: 6-month longitudinal study (JBCRG-26) [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 PO1-05-06.

Abstract PO1-06-01: Clinical Efficacy of Tumor Organoid-Guided Cancer Therapy for Locally Advanced Unresectable or Metastatic Breast Cancer

Abstract Purpose: Patient-derived organoids (PDOs) may facilitate treatment selection, but the feasibility of using breast cancer PDOs to guide personalized treatment in clinical practice has not been fully investigated. This study aimed to assess the clinical efficacy of treatment guided by PDO drug sensitivity tests (OGT) versus treatment of physician’s choice (TPC) in patients with locally advanced unresectable or metastatic breast cancer (MBC) and to explore the potential of PDOs to reveal mechanisms underlying treatment resistance. Methods: Patients diagnosed with MBC were recruited between January 2020 and August 2022. PDOs were established from biopsies specimens or malignant effusion samples. The efficacy of customized drug panels was determined by measuring cell mortality after drug exposure. Patients receiving OGT were matched 1:2 by nearest neighbor propensity scores with patients receiving TPC. The primary clinical outcome was progression-free survival. Secondary outcomes included objective response rate and disease control rate. Targeted gene sequencing and pathway enrichment analysis were performed. Results: 46 PDOs (46 of 51, 90.2%) were generated from 45 MBC patients. PDO drug screening showed an accuracy of 81.1% (95% CI 67.6%-91.9%) in predicting patients' clinical responses. 36 OGT patients were matched to 69 TPC patients. OGT was associated with prolonged median progression-free survival (11.0 months vs 5.0 months; unadjusted hazard ratio 0.53 [95% CI 0.33-0.85]; P=0.01) and improved disease control (88.9% vs 63.8%; unadjusted odd ratio 4.26 [1.44-18.62]) compared with TPC. The objective response rate of both groups was similar. Pathway enrichment analysis uncovered differentially modulated pathways implicated in DNA repair and transcriptional regulation in patients less sensitive to capecitabine/gemcitabine, and pathways associated with cell cycle regulation in patients less sensitive to palbociclib. Conclusions: MBC patients treated with OGT were associated with superior progression-free survival and disease control compared with TPC. PDO-based functional precision medicine is a feasible strategy for treatment optimization and customization in MBC and may enhance our understanding of therapeutic resistance. Citation Format: Ying-Yi Lin, Hong-Fei Gao, Hong Li, Bo-Lei Du, Min-Yi Cheng, Jia-Chen Zou, Xing-xing Zheng, Teng Zhu, Ting-Ting Li, Sheng Li, Kun Wang. Clinical Efficacy of Tumor Organoid-Guided Cancer Therapy for Locally Advanced Unresectable or Metastatic Breast Cancer [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 PO1-06-01.

Abstract PO4-18-04: An exploratory study of Trastuzumab Deruxtecan neoadjuvant therapy in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy

Abstract Background The current standard of care for neoadjuvant treatment of HER2-positive early-stage breast cancer consists of dual HER2-blockade with trastuzumab (H) plus pertuzumab (P) and polychemotherapy with a pathological complete response (pCR) rate of 31%~50%. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. T-DXd significantly prolonged progression-free and overall survival vs trastuzumab emtansine in HER2-positive unresectable and/or metastatic breast cancer (mBC) previously treated with H and taxane in DESTINY-Breast03 study. HER2-low breast cancer is currently treated as HER2-negative (HER2-low and HER2-zero) breast cancer, with patients stratified according to hormone-receptor (HR) status. In DESTINY-Breast04 study, T-DXd resulted in significantly longer progression-free and overall survival than the physician’s choice of chemotherapy in HER2-low mBC. Given the efficacy of T-DXd monotherapy in HER2-positive or HER2-low mBC, we conduct an exploratory study to evaluate the efficacy and safety of T-DXd in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy, and to identify sensitive biomarkers for T-DXd neoadjuvant therapy. Methods Eligible patients were women aged 18 years to 75 years with clinical stage cT2–cT4/cN0–cN3/cM0 (stage II–III) invasive breast cancer (&amp;gt;2 cm in size) confirmed as HER2-positive (immunohistochemistry [IHC] 3+) or HER2-low (IHC2+ or IHC1+/situ hybridization-negative). Patients are required to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and baseline left ventricular ejection fraction of at least 55% (as measured by echocardiogram). Patients are also required to have adequate organ function and bone marrow function. Patients with HER2-positive breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, carboplatin, and H plus P for 2 cycles. Patients with HER2-low and HR-positive breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, and cisplatin or carboplatin for 2 cycles. Patients with HER2-low and HR-negative breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, and anthracycline (epirubicin, pirarubicin or liposomal doxorubicin) for 2 cycles. For patients who have responses of stable disease assessed by magnetic resonance imaging will receive T-DXd neoadjuvant therapy. T-DXd will be administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight for 4 cycles. Peripheral blood and biopsy tissue will be collected before neoadjuvant chemotherapy and T-DXd neoadjuvant therapy, and peripheral blood and surgical tissue will be collected after the surgery. Lipid metabolites in peripheral blood and mass spectrometry-based protein quantification in tissue will be detected to find sensitive biomarkers for T-DXd neoadjuvant therapy. The primary endpoint is pCR rate (ypT0/Tis ypN0) and identify sensitive biomarkers for T-DXd neoadjuvant therapy. Secondary endpoints include objective response rate, breast-conserving rate and invasive disease-free survival. Citation Format: Jin Zhang, Zhendong Shi, Jingjing Liu. An exploratory study of Trastuzumab Deruxtecan neoadjuvant therapy in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy [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 PO4-18-04.

Abstract PO4-16-07: Cyclin-dependent kinase inhibitor plus endocrine therapy in HR+/HER2- invasive breast cancer with bone marrow and pancytopenia: a new standard of care? Collaborative multicentric Argentinean real-world study (SUMA-02)

Abstract Introduction Bone marrow involvement is a rare occurrence in patients with advanced breast cancer (ABC), and the prognosis in this context is generally poor. Prompt initiation of treatment to improve the patient's hematological status is crucial. However, this condition is often excluded from clinical trials, making it challenging to determine the effectiveness of new drugs. Limited data and evidence are available to guide treatment decisions, but guidelines recommend starting with chemotherapy for the need of a rapid response. This study aims to analyze the real-world efficacy of cyclin-dependent kinase inhibitors (CDKis) in HR+/HER2- ABC with bone marrow infiltration. Methods Retrospective multicenter cohort study including HR+/HER2- ABC patients from public and private facilities in Argentina. Patients with confirmed bone marrow involvement (blood smear or histological biopsy analysis) and treated with CDKi were eligible. Bone marrow response was defined as an increase in at least one of the previously abnormal blood series to Hb &amp;gt;10.0, platelets &amp;gt;100,000, and leukocytes &amp;gt;4,000. Results A total of 22 patients from different medical centers in Argentina were included. The median age was 55.5 (IQR 46.25-65). Histological confirmation of bone marrow involvement was reported in 81.8% (18) of patients. Among them, 54.5% (12) had initial diagnosis at an early stage, and 13.6% (3) experienced relapse during or within 1 year of completing adjuvant hormonal treatment. Bone-only metastasis was observed in 50% (11) of patients, while the remaining 50% (11) had both visceral and bone disease. Anemia, thrombocytopenia, and leukopenia were present in 95.5% (21), 90.9% (20), and 40.9% (9) of patients, respectively. In 68.2% (15) of patients, bone marrow involvement was detected at the first-line treatment setting. The selected CDKis were palbociclib in 40.9% (9) of patients, ribociclib in 31.8% (7), and abemaciclib in 27.3% (6). The bone marrow response rate was 68.2% (15), with a median of 2 cycles (range 1-5) required for a response. Dose reduction was necessary in 31.8% (7) of patients. Discussion Managing patients with uncommon sites of metastasis, such as bone marrow, poses significant challenges for oncologists. Bone marrow infiltration leads to hematopoietic alterations that adversely affect the quality of life, resulting in increased risk of infections, bleeding, and other comorbidities with fatal consequences. While chemotherapy is the standard treatment in such cases, our study demonstrates that CDKis are a safe and effective option for managing these complications. Conclusion The findings of this study support the evaluation of CDKis as a standard treatment for HR+/HER2- ABC patients. Our results are in line with the recently published phase 2 clinical trial RIGHT CHOICE, which showed a prolonged progression free survival in patients treated with ribociclib and HT with HR+/HE2- ABC and visceral crisis. Citation Format: Alexis Ostinelli, Pablo Mandó, Carolina Almada, Melina Winocur, M. Agustina Ipiña, Viviana Paez, Silvia Aparicio, Sergio Rivero, Federico Waisberg, Laura Sabina Lapuchesky, Cristian Micheri, M. Belen Montenegro, Cristina Rusz Maidana, Carolina Reinhardt, Evelina Rovera, Gonzalo Gómez Abuin, Santiago Bella, Florencia Perazzo, Adrian Nervo, Andrea Aguilar, Matías Chacón, Victoria Costanzo, Valeria Caceres, Jorge Nadal. Cyclin-dependent kinase inhibitor plus endocrine therapy in HR+/HER2- invasive breast cancer with bone marrow and pancytopenia: a new standard of care? Collaborative multicentric Argentinean real-world study (SUMA-02) [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 PO4-16-07.

Abstract PO4-27-07: A Phase 3, randomized, open-label study of upfront camizestrant vs standard endocrine therapy as adjuvant treatment for ER-positive/HER2-negative early breast cancer with intermediate-high or high risk of recurrence (CAMBRIA-2)

Abstract Background: Camizestrant is a next-generation oral selective estrogen receptor (ER) degrader and pure ER antagonist being investigated in early and advanced breast cancer (BC). In postmenopausal women with advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative BC and disease recurrence or progression on or after ≤1 endocrine therapy (ET) in the advanced setting, camizestrant significantly prolonged progression-free survival compared with fulvestrant in the Phase 2 SERENA-2 trial. Camizestrant may also provide benefit in the early BC setting. Following locoregional therapy (surgery ± radiotherapy), standard adjuvant treatment of ET with or without chemotherapy and/or a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has shown significant benefit in decreasing the risk of recurrence of stage I–III ER-positive/HER2-negative BC. However, BC recurrence as incurable metastatic disease is still common. Thus, adjuvant therapeutic options with improved clinical outcomes are needed. The CAMBRIA-2 study (NCT05952557) aims to assess whether upfront camizestrant can improve outcomes compared with standard ET as adjuvant treatment in patients with ER-positive/HER2-negative early BC with an intermediate-high or high risk of recurrence after definitive locoregional therapy. Trial design: This ongoing Phase 3, randomized, open-label study is enrolling women (pre-, peri-, or postmenopausal) and men with ER-positive/HER2-negative (HER2-negative status defined as immunohistochemistry 0, or 1+, or in situ hybridization-negative) early BC who are at intermediate-high or high risk of recurrence (as defined in the protocol) after having completed definitive locoregional therapy (surgery ± radiotherapy) ± (neo)adjuvant systemic chemotherapy, and who have no evidence of disease. Patients may have received up to 12 weeks of (neo)adjuvant ET prior to randomization. Patients are randomized (1:1) to receive camizestrant 75 mg ± abemaciclib ± luteinizing hormone-releasing hormone (LHRH) agonist or standard ET of the investigator’s choice (any aromatase inhibitor or tamoxifen) ± abemaciclib ± LHRH agonist for up to 7 years. The primary endpoint is invasive BC-free survival (IBCFS) (Standardized Definitions for Efficacy End Points [STEEP] 2.0 criteria). Secondary endpoints include invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) (STEEP 2.0 criteria), overall survival, safety, and health-related quality of life. Primary endpoint analysis will use a stratified log-rank test adjusting for stratification factors, assuming a two-sided significance level of 5%. Approximately 5500 patients will be randomized. Clinical trial identification: NCT05952557 Editorial acknowledgment: Writing assistance was provided by Clare Davis of BOLDSCIENCE Inc., funded by AstraZeneca. Legal entity responsible for the study: AstraZeneca Funding: This study was supported by AstraZeneca. Citation Format: Sibylle Loibl, Yeon Park, Sara Tolaney, Ioanna Gioni, Simon Johnston, Teresa Klinowska, Ingrid A. Mayer, Raquel Nunes, Barbara Pistilli, Mary Stuart, Angela Quintana, Andrew Walding, Michael Gnant. A Phase 3, randomized, open-label study of upfront camizestrant vs standard endocrine therapy as adjuvant treatment for ER-positive/HER2-negative early breast cancer with intermediate-high or high risk of recurrence (CAMBRIA-2) [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 PO4-27-07.

Abstract PO4-04-06: Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study

Abstract Background Trastuzumab emtansine (T-DM1) is the established standard second-line treatment for HER2-positive metastatic breast cancer (MBC) patients who have previously received trastuzumab. However, there is ongoing debate regarding the subsequent therapeutic options following T-DM1 failure. This study aimed to evaluate the efficacy and safety of tyrosine kinase inhibitors (TKIs)-based therapy in HER2-positive MBC patients with resistance to T-DM1. Methods During the period from September 2018 to October 2021, a multicenter real-world study was conducted, enrolling a total of 53 patients diagnosed with HER2-positive metastatic breast cancer (MBC). These patients underwent TKIs-based therapy following the failure of T-DM1 treatment. The primary focus of the study was on evaluating progression-free survival (PFS) as the main endpoint. Secondary endpoints encompassed objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and safety assessments. Results A total of 53 patients received TKIs-based therapy as a second-line or later treatment. The median progression-free survival (PFS) for TKIs-based therapy was 11.9 months (95% CI 7.9-15.9). The objective response rate (ORR) and clinical benefit rate (CBR) were found to be 19.6% and 72.5%, respectively. Among patients with brain metastasis (n=12), a median PFS of 10.5 months (95% CI 7.5-13.5) and an intracranial ORR of 33.3% were observed. Patients treated with pyrotinib (n=21) showed improved PFS compared to those treated with lapatinib (n=30), as well as patients who had derived favorable benefit from T-DM1 (PFS ≥ 6 months). Hormone receptor status (HR) and response to T-DM1 were identified as independent factors affecting the effectiveness of TKIs-based therapy. The most frequently reported adverse events included thrombocytopenia (23.6%), diarrhea (15.7%), leucopenia (15.7%), and hand-foot syndrome (15.7%). Conclusion TKIs-based therapy demonstrated favorable effectiveness and safety in HER2-positive metastatic breast cancer (MBC) patients who had previously received T-DM1 but experienced treatment failure. This includes patients with brain metastases. Notably, individuals who derived favorable benefits from prior T-DM1 treatment displayed significantly prolonged progression-free survival (PFS) when undergoing subsequent TKIs-based therapy. Citation Format: Yongmei Yin, Chunxiao Sun, Yijia Hua, Nan Jin, Wei Li, Xiang Huang. Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study [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 PO4-04-06.

Abstract PO2-18-09: A phase 3 randomized open-label study of extended adjuvant therapy with camizestrant vs standard endocrine therapy in patients with ER+/HER2– early breast cancer and an intermediate or high risk of recurrence (CAMBRIA 1)

Abstract Background: Definitive locoregional (surgery ± radiotherapy) and standard adjuvant endocrine therapy (ET) (± chemotherapy or cyclin-dependent kinase 4/6 inhibitor [CDK4/6i]) can achieve cure in many patients (pts) with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2–) early breast cancer (BC). Nevertheless, a significant proportion of pts with stage I–III disease will experience recurrence to metastatic, incurable disease (5- and 10-year cumulative incidences of recurrence of 8.3% and 14.0%, respectively). There is evidence that incorporating a more effective endocrine therapy after 2 years of standard adjuvant ET can result in clinical benefit for high-risk individuals. Camizestrant is a next-generation oral selective ER degrader and pure ER antagonist. In SERENA-2, camizestrant 75 mg and 150 mg significantly prolonged progression-free survival vs fulvestrant in postmenopausal women with ER+/HER2– advanced BC with disease recurrence or progression after ET. The CAMBRIA-1 study (NCT05774951) is evaluating the potential of extended adjuvant therapy with camizestrant to improve outcomes in pts with ER+/HER2– early BC with an intermediate or high risk of recurrence after definitive locoregional therapy and standard adjuvant ET. Trial design: This phase 3 randomized, open-label study is enrolling women (pre- or postmenopausal) and men with ER+/HER2– (immunohistochemistry 0/1+/2+/in situ hybridization-negative) early BC who have completed definitive locoregional therapy and standard adjuvant ET (± CDK4/6i) for ≥2 and ≤5 years (+ 3 months) without disease recurrence. Pts must be considered at intermediate or high risk of recurrence based on clinical, biological, and genomic factors. Pts are randomized (1:1) to continue standard ET of the investigator’s choice (tamoxifen or aromatase inhibitor ± luteinizing hormone-releasing hormone [LHRH] agonist) or camizestrant ± LHRH agonist for up to 60 months. The primary endpoint is invasive BC-free survival (STEEP 2.0 criteria). Secondary endpoints include invasive disease-free survival and distant relapse-free survival (STEEP 2.0 criteria), overall survival, safety, and health-related quality of life. Primary endpoint analysis will use a stratified log-rank test adjusting for stratification factors, assuming a two-sided significance level of 5%. Approximately 4300 pts will be randomized; enrollment is ongoing. Clinical trial identification: NCT05774951 Editorial acknowledgment: Writing assistance was provided by Alison Lovibond, PhD, of BOLDSCIENCE Inc., funded by AstraZeneca. Legal entity responsible for the study: AstraZeneca Funding: This study was supported by AstraZeneca. Citation Format: Erika Hamilton, Sibylle Loibl, Naoki Niikura, Priya Rastogi, Kamal S. Saini, Ioanna Gioni, Teresa Klinowska, Ingrid A. Mayer, Mary Stuart, Emilia Syta, Andrew Walding, Thomas Bachelot. A phase 3 randomized open-label study of extended adjuvant therapy with camizestrant vs standard endocrine therapy in patients with ER+/HER2– early breast cancer and an intermediate or high risk of recurrence (CAMBRIA 1) [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 PO2-18-09.