Positive Advanced Breast Cancer Research Articles

Imlunestrant, an oral selective estrogen receptor degrader (SERD), in combination with human epidermal growth factor receptor 2 (HER2) directed therapy, with or without abemaciclib, in estrogen receptor (ER) positive, HER2 positive advanced breast cancer (aBC): EMBER phase 1a/1b study.

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 PO2-20-04: TACTIVE-U: phase 1b/2 umbrella study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER–positive advanced or metastatic breast cancer

Abstract Background: Vepdegestrant (ARV-471), an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in the first-in-human phase 1/2 study in heavily pretreated patients with ER+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer (NCT04072952). The cyclin-dependent kinase (CDK)4/6 inhibitors abemaciclib and ribociclib are approved in combination with an aromatase inhibitor or fulvestrant, or as monotherapy (abemaciclib), for ER+/HER2- advanced or metastatic breast cancer. In preclinical studies, vepdegestrant combined with abemaciclib or ribociclib showed evidence of synergistic interactions in ER+ breast cancer cells and greater tumor growth inhibition in a xenograft breast cancer model compared with fulvestrant in combination with these agents. Inhibitors targeting different CDKs, such as samuraciclib (oral CDK7 inhibitor), are in clinical development for solid tumors. The open-label, phase 1b/2 TACTIVE-U umbrella study will evaluate the safety, efficacy, and pharmacokinetics of vepdegestrant in combination with other anticancer treatments in patients with ER+ advanced or metastatic breast cancer. Vepdegestrant is being evaluated in combination with abemaciclib (sub-study A; NCT05548127), ribociclib (sub-study B; NCT05573555), and samuraciclib (sub-study C). Trial Design: Patients eligible for current sub-studies of TACTIVE-U are aged ≥18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection, and have received prior therapy for advanced or metastatic disease, including any CDK4/6 inhibitor–based regimen in any setting. In each sub-study, patients will receive vepdegestrant orally once daily (QD) continuously in a dose escalation/de-escalation approach. Abemaciclib will be given orally twice daily continuously in sub-study A, ribociclib will be given orally QD for 21 days followed by 7 days off treatment in sub-study B, and samuraciclib will be given orally QD continuously in sub-study C. For all sub-studies, the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of vepdegestrant in combination with the other anticancer treatment. Secondary endpoints of phase 1b are antitumor activity (objective response, clinical benefit rate [CBR], and duration of response [DOR]), progression-free survival (PFS), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drugs. The phase 2 portion of each sub-study will further evaluate the antitumor activity of the combinations; the primary endpoint is objective response and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Future combination sub-studies will be included in TACTIVE-U. Citation Format: Claudine Isaacs, Katarzyna Jerzak, John Hilton, José Luiz Miranda Guimarães, Rachel Layman, Dongrui Lu, Gary Mo, Anna Maria Calella, Olga Valota, Sibyl Anderson, Cynthia Ma. TACTIVE-U: phase 1b/2 umbrella study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER–positive advanced 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 PO2-20-04.

Abstract PS15-02: A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage

Abstract Background: Endocrine therapy is the mainstay treatment for estrogen receptor (ER)-positive advanced breast cancer (BC). D-0502, an orally bioavailable selective estrogen receptor degrader (SERD), has previously demonstrated antitumor activity in various ER-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer cell lines and xenograft models. The phase Ⅰ open-label study (NCT03471663) evaluated the safety, tolerability, pharmacokinetics (PK) and efficacy of D-0502 as monotherapy and in combination with palbociclib in female patients with ER+ and HER2- breast cancer. The dose escalation part of D-0502 monotherapy (phase Ⅰa) has been presented before (SABCS 2021, PS11-26 Abstract #1348). Here, we present the results of D-0502 monotherapy from the dose-expansion stage in phase Ⅰb study. Methods: In the single-agent dose-expansion stage of phase Ⅰb study, patients (n=60) received D-0502 (400 mg QD) in 28-day cycles. Eligible patients included females with confirmed ER+, HER2- locally advanced, or metastatic BC; ECOG 0-1; measurable disease (RECIST v1.1); premenopausal or postmenopausal status; adequate hematologic, hepatic and renal functions. The primary objectives are to characterize the safety of D-0502. The secondary objectives are to evaluate the preliminary anti-tumor activity and the PK characteristic. Results: As of April 07, 2023, 60 female patients were enrolled and treated with 400mg single-agent D-0502. Median age was 57 (range: 32-82) years, 55.0% had an ECOG PS of 1. Disease progression resulting in treatment discontinuation occurred in 66.7% (40/60) of patients, and 6.7% (4/60) of patients discontinued treatment because of AEs. Treatment-related adverse events (TRAEs) were reported in 57 pts (95.0%), most of which were grade 1-2. No grade 4/5 TRAE has been reported. The incidence of serious adverse events was 6.7% (4/60). The most common (≥ 15%) TRAEs included vomiting, dizziness, nausea, increased aspartate aminotransferase and alanine aminotransferase, anaemia, decreased appetite, diarrhoea, and malaise. In the 51 efficacy evaluable patients, 8 patients had partial response (PR) and 27 had stable disease (SD); objective response rate (ORR) and disease control rate (DCR) were 15.7% (8/51) and 68.6% (35/51), respectively. The clinical benefit rate (CBR: CR + PR + SD ≥24 weeks) was 47.1% (24/51). The median PFS was 5.6 months (95% Cl: 2.0, 10.0). Conclusion: D-0502 monotherapy showed promising antitumor activity and tolerable toxicity in female patients with ER+ and HER2- locally advanced or metastatic BC. Currently this treatment is being evaluated in a phase Ⅲ study for patients with ER+ and HER2- locally advanced or metastatic BC in China. Citation Format: Jiayu Wang, Tao Sun, Qingyuan Zhang, Yanxia Shi, Xu Wang, Yiding Chen, Quchang Ouyang, Kunyan Li, Manojkumar Bupathi, w. Jeffery Edenfield, Andrea L.M. Silber, Hong Zong, Erika Hamilton, Dejan Juric, Kate Lathrop, Yihong Zhang, Kathryn Stazzone, Zhe Shi, Yaolin Wang, Ling Zhang, Binghe Xu. A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage [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 PS15-02.

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 PO2-04-07: Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials

Abstract Background: The numerous but conflicting first-line treatment regimens for Her-2 positive advanced breast cancer necessitate a comprehensive evaluation to inform clinical decision-making. In this study, we conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions. Methods: We systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts published by ASCO, SABCS. NMA was performed using R software, STATA and Review Manager 5.4 to calculate and analyze the primary endpoint progression free survival (PFS), as well as the secondary endpoints of overall survival (OS), objective response rate (ORR) and adverse events (AE) higher than grade 3. Results: Out of the 8,603 manuscripts retrieved, we included 30 RCTs involving 12,045 patients in our analysis. Regarding PFS, the combination of trastuzumab with TKI was more favorable than dual-target therapy (hazard ratio=0.54, 95% [CI]: 0.40–0.72), and combination chemotherapy was superior to monotherapy (HR=0.66, 0.53-0.83). It is important to note that the addition of anthracycline did not result in improved PFS (HR=1.27, 0.87-1.86). For the HR+HER2+ population, dual-target plus endocrine therapy was more effective than single-target plus endocrine therapy (HR=0.65, 0.53-0.80). Monotherapy combined with dual-target therapy significantly improved OS and ORR compared to monotherapy with single-target therapy (HR=0.69, 0.56-0.84; OR=1.89, 1.34-2.65). A comprehensive analysis of both PFS and AE higher than grade 3 indicated that monotherapy plus dual-target therapy struck a balanced approach between effectiveness and toxicity compared to other regimens. Conclusions: Monotherapy plus dual-target therapy remains the optimal choice among all first-line treatment options for advanced breast cancer. The combination of trastuzumab with TKI demonstrated a significant improvement in PFS, but further data are warranted to confirm the survival benefit. Figure 1. Network diagrams of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. Figure 2. Forest plot of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. (A): PFS of HER2+ for experimental arms. (B): PFS of HR+ and HER2+ for experimental arms. (C): OS of HER2+ for experimental arms. (D): ORR of HER2+ for experimental arms. (E): Adverse events higher than grade 3 of HER2+ for experimental arms. Figure 3. Each endpoint ranking for experimental arms. (SUCRA, surface under the cumulative ranking) (A): PFS ranking for experimental arms. (B): OS ranking for experimental arms. (C): ORR ranking for experimental arms. (D): Adverse events higher than grade 3 ranking for experimental arms. (E): Experimental arms ordered by their overall probability as the best treatment in terms of both efficacy and safety Citation Format: Junxiao Wang, Yushuai Yu, Jie Zhang, Chuangui Song. Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials [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 PO2-04-07.

Abstract PO5-04-11: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) beyond progression in hormone receptor positive advanced breast cancer: a systematic review and meta-analysis

Abstract Introduction The use of CDK 4/6i (palbociclib/ribociclib/abemaciclib) with endocrine therapy (ET) is a widely adopted first line standard treatment for hormone receptor positive advanced breast cancer (HR+ABC). Data supporting incorporation of CDK 4/6i ± ET beyond progression are less clear. Recent studies have evaluated either the continuation of or switching to a different CDK 4/6i, with a change in ET after progression on 1st line CDK4/6i with varying results. A pooled analysis of this strategy could be useful for clinical decision making. Methods We reviewed reports of both observational and clinical studies that evaluated continuing the same CDK4/6i or switching to a different agent after progression on first line CDK4/6i with ET. The search included the grey literature without exclusions for publication year or language. The mean overall response rate (ORR), clinical benefit rate (CBR) and progression free survival (PFS) weighted by study sample size were calculated. Meta-regression comprising linear regression weighted by sample size (mixed effects) was performed to explore the association between disease and treatment-related factors and benefit from continuing a CDK4/6i. Quantitative significance was assessed using the Burnand criteria. Analyses were performed using SPSS version 28 (IBM Corp, Armonk NY). Results Thirteen studies (N=1006 patients) were included; 7 were prospective trials and 2 cohorts of the same retrospective study included separately). Study patients had a median age of 57.8 years and 66% had visceral metastases. Among patients whose type of first-line CDK 4/6i exposure was reported (84.5%), 81.21% received Palbociclib 3.28% received Ribociclib and 0.89% received Abemaciclib. Six patients received both Palbociclib and Ribociclib. The median duration of first line CDK 4/6i therapy was 13.8 months. In the second line,the mean ORR was 12.8%, CBR 38.8%, and median PFS was 4.6 months. The ORRs for Palbociclib, Ribociclib and Abemaciclib, irrespective of type of prior CDK 4/6i, were 7.3%, 14.7% and 18.6%, respectively. The CBR for Palbociclib, Ribociclib and Abemaciclib were 33.1%, 42.2% and 46.8%, respectively. The median PFS based the CDK 4/6i used in second line was 4.2 (Palbociclib), 5.5 (Ribociclib) and 9.2 (Abemaciclib) months. Meta-regression analysis of PFS is included in the table. Conclusion Continuing a CDK 4/6i± ET beyond progression yields modest benefits. Switching CDK4/6i offers slightly better ORR and PFS. Continuing Palbociclib beyond progression does not seem beneficial. Longer duration of CDK4i exposure in the first line appears to be associated with shorter PFS in the second line. Small number of studies with limited number of patients likely affect results. Meta-regression analysis of PFS of CDK 4/6i with or without ET in subsequent line of therapy. Citation Format: Neha Pathak, Sudhir Kumar, Diego Malon Gimenez, Massimo Di Iorio, Consolacion Molto Valiente, Danielle Cuthbert, Meredith Li, Atul Batra, Michelle Nadler, Eitan Amir, Abhenil Mittal. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) beyond progression in hormone receptor positive advanced breast cancer: a systematic review and meta-analysis [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 PO5-04-11.

Short-term efficacy and safety of neoadjuvant pyrotinib plus taxanes for early HER2-positive breast cancer: a single-arm exploratory phase II trial.

The effectiveness and safety of pyrotinib have been substantiated in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC). However, the role of pyrotinib as a single HER2 blockade in neoadjuvant setting among BC patients has not been studied. The objective of this study was to evaluate the efficacy and tolerability of pyrotinib plus taxanes as a novel neoadjuvant regimen in patients with HER2-positive early or locally advanced BC. In this single-arm exploratory phase II trial, patients with treatment-naïve HER2-positive BC (stage IIA-IIIC) received pyrotinib 400 mg once daily and taxanes [docetaxel 75 mg/m2 or nanoparticle albumin-bound (nab)-paclitaxel 260 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly] for a total of four 21-day cycles before surgery. Efficacy assessment was based on pathological and clinical measurements. The primary endpoint of this study was the total pathological complete response (tpCR) rate. The secondary endpoints included breast pCR (bpCR) rate, investigator-assessed objective response rate (ORR) and adverse events (AEs) profiles. From 1 September 2021 to 30 December 2022, a total of 31 patients were enrolled. One patient was withdrawn due to unbearable skin rash after the second cycle of neoadjuvant therapy. The majority of the intention-to-treat (ITT) population was premenopausal (54.8%), had large tumors (90.3%) and metastatic nodes (58.1%) at diagnosis and hormone-receptor positive tumors (64.5%). Most participants used nab-paclitaxel (74.2%) and received mastectomy (67.7%) after neoadjuvant treatment. The tpCR and bpCR rates were 48.4% [95% confidence interval (CI): 30.8-66%] and 51.6% (95% CI: 34-69.2%), respectively. Grade ≥3 treatment-related AEs were observed in 16.1% (5/31) of the ITT population, including diarrhea (n=2, 6.5%), hand and foot numbness (n=1, 3.2%), loss of appetite (n=1, 3.2%), and skin rash (n=1, 3.2%). AE related dose reduction or pyrotinib interruption was not required. In female patients with HER2-positive non-metastatic BC, neoadjuvant pyrotinib monotherapy plus taxanes appears to show promising clinical benefit and controllable AEs [Chinese Clinical Trial Registry (ChiCTR2100050870)]. The long-term efficacy and safety of this regime warrant further verification.

Time trends in real-world treatment patterns and survival in patients diagnosed with de novo HER2+ metastatic breast cancer: an analysis of the SONABRE registry

PurposeThe aim was to determine whether the real-world first-line progression-free survival (PFS) of patients diagnosed with de novo human epidermal growth factor receptor 2 positive (HER2+) advanced breast cancer (ABC) has improved since the introduction of pertuzumab in 2013. In addition to PFS, we aimed to determine differences in overall survival (OS) and the use of systemic and locoregional therapies.MethodsIncluded were patients systemically treated for de novo HER2+ ABC in ten hospitals in 2008–2017 from the SONABRE Registry (NCT-03577197). First-line PFS and OS in 2013–2017 versus 2008–2012 was determined using Kaplan–Meier analyses and multivariable Cox proportional hazards modelling. First-given systemic therapy and the use of locoregional therapy within the first year following diagnosis were determined per period of diagnosis.ResultsMedian and five-year PFS were 26.6 months and 24% in 2013–2017 (n = 85) versus 14.5 months and 10% in 2008–2012 (n = 81) (adjusted HR = 0.65, 95%CI:0.45–0.94). Median and five-year OS were 61.2 months and 51% in 2013–2017 versus 26.1 months and 28% in 2008–2012 (adjusted HR = 0.55, 95%CI:0.37–0.81). Of patients diagnosed in 2013–2017 versus 2008–2012, 84% versus 60% received HER2-targeted therapy and 59% versus 0% pertuzumab-based therapy as first-given therapy. Respectively, 27% and 23% of patients underwent locoregional breast surgery, and 6% and 7% surgery of a metastatic site during the first year following diagnosis.ConclusionThe prognosis of patients with de novo HER2 + ABC has improved considerably. Since 2013 one in four patients were alive and free from progression on first-given therapy for at least five years.

Efficacy and safety of first-line therapy in patients with HER2-positive advanced breast cancer: a network meta-analysis of randomized controlled trials

PurposeThe numerous first-line treatment regimens for human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) necessitate a comprehensive evaluation to inform clinical decision-making. We conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions.MethodsWe systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts from inception to June 1, 2023. NMA was performed to calculate and analyze progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events of grade 3 or higher (≥ 3 AEs).ResultsOut of the 10,313 manuscripts retrieved, we included 28 RCTs involving 11,680 patients. Regarding PFS and ORR, the combination of trastuzumab with tyrosine kinase inhibitors (TKIs) was more favorable than dual-targeted therapy. If only using trastuzumab, combination chemotherapy is superior to monochemotherapy in terms of PFS. It is important to note that the addition of anthracycline did not result in improved PFS. For patients with hormone receptor-positive HER2-positive diseases, dual-targeted combined with endocrine therapy showed better benefit in terms of PFS compared to dual-targeted alone, but it did not reach statistical significance. The comprehensive analysis of PFS and ≥ 3 AEs indicates that monochemotherapy combined with dual-targeted therapy still has the optimal balance between efficacy and safety.ConclusionMonochemotherapy (Docetaxel) plus dual-target (Trastuzumab and Pertuzumab) therapy remains the optimal choice among all first-line treatment options for ABC. The combination of trastuzumab with TKIs (Pyrotinib) demonstrated a significant improvement in PFS and ORR, but further data are warranted to confirm the survival benefit.

ESR1 F404 Mutations and Acquired Resistance to Fulvestrant in ESR1-Mutant Breast Cancer.

Novel F404 ESR1 mutations may be acquired to cause overt resistance to fulvestrant when combined with preexisting activating ESR1 mutations. Novel combinations of mutations in the ER ligand binding domain may cause drug-specific resistance, emphasizing the potential of similar drug-specific mutations to impact the efficacy of oral ER degraders in development. This article is featured in Selected Articles from This Issue, p. 201.

Trastuzumab Resistance in Patients With HER2-Positive Advanced Breast Cancer: Results From the SONABRE Registry

BackgroundThis study aims to explore whether first-line pertuzumab use modifies the effect of prior use of (neo-) adjuvant trastuzumab on the PFS of first-line HER2-targeted therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). MethodsPatients diagnosed with HER2-positive ABC in 2008 to 2018 in 9 Dutch hospitals were derived from the SONABRE Registry (NCT03577197). Patients diagnosed with de novo metastatic breast cancer were excluded. Patients receiving first-line trastuzumab-based therapy for ABC were selected and divided into trastuzumab naïve (n = 113) and trastuzumab pretreated (n = 112). Progression-free survival (PFS) was compared using multivariable Cox proportional hazard models. The interaction effect of first-line pertuzumab was tested using the likelihood-ratio test. ResultsThe median follow-up time was 47 months (95% confidence interval [CI]: 42-52). When comparing trastuzumab pretreated with trastuzumab naïve patients, the hazard ratio for first-line progression was 2.07 (CI:1.47-2.92). For trastuzumab pretreated patients who received first-line trastuzumab without pertuzumab, the hazard ratio for progression was 2.60 (95% CI:1.72-3.93), whereas for those who received first-line trastuzumab with pertuzumab the hazard ratio was 1.43 (95% CI: 0.81-2.52) (P interaction = .10). ConclusionsPrior use of trastuzumab as (neo-)adjuvant treatment had a negative impact on PFS of first-line HER2-targeted therapy outcomes. Adding pertuzumab to first-line trastuzumab-based therapy decreased the negative impact of prior (neo-)adjuvant trastuzumab use on first-line PFS. Further studies are needed to assess the effect of prior (neo-)adjuvant pertuzumab use on the outcomes of first-line pertuzumab-based therapy.

Inetetamab combined with pyrotinib and oral vinorelbine for patients with human epidermal growth factor receptor 2 positive advanced breast cancer: A single-arm phase 2 clinical trial

BackgroundHuman epidermal growth factor receptor 2 (HER2)-targeted agents have significantly improved the outcomes of patients with HER2-positive breast cancer; however, a large proportion of patients still develop resistance to trastuzumab. In this study, we investigated the efficacy and safety of inetetamab, another anti-HER2 antibody, combined with pyrotinib and oral vinorelbine in patients with HER2-positive advanced breast cancer so as to provide new ideas for the treatment. MethodsIn this prospective, single-arm, phase 2 trial, patients with HER2-positive advanced breast cancer with disease progression after trastuzumab were recruited. Patients received a combination of inetetamab (loading dose of 8 mg/kg and subsequent doses of 6 mg/kg intravenously once every 3 weeks), pyrotinib (400 mg orally once daily), and vinorelbine (60 mg/m2 orally once weekly) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), disease control rate (DCR), and safety. ResultsBetween February 13, 2022 and December 25, 2022, 30 patients were screened and enrolled in this study. The median age of the patients at enrollment was 54 years, 12 patients (40.0 %) had hormone-receptor-positive disease and 23 patients (76.7 %) had visceral metastasis. The median PFS was 8.63 months (95 % confidence interval [CI] 4.15–13.12 months). The median OS was not reached. The ORR was 53.3 % (16/30) and the DCR was 96.7 % (29/30). The most common Grade III/IV adverse events were leukopenia (n = 5, 16.7 %), neutropenia (n = 4, 13.3 %), and diarrhea (n = 3, 10 %). No treatment-related serious adverse events or deaths occurred. ConclusionsThe combination regimen of inetetamab, pyrotinib, and oral vinorelbine showed encouraging efficacy and favorable safety in patients with HER2-positive advanced breast cancer and could be considered as an alternative treatment option for the patients. Trial registrationNo.NCT05823623; https://www.clinicaltrials.gov/.

A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone

Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. No direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs in patients commencing T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd. Patients with human epidermal growth factor receptor 2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinicopathological information, prior treatment, the presence or absence of central nervous system (CNS) disease, outcomes and treatment-emergent adverse events (TEAEs) were recorded. Twenty-nine female patients, with a median age of 52 years (interquartile range 44-62 years), were identified; the prevalence of BM was 41%. Median number of lines of prior therapy was 2 (range 2-6). At a median follow-up of 13.8 months, median progression-free survival (PFS) for the overall population was 13.9 months [95% confidence interval (CI) 12.4 months-not estimable (NE)], 16.1 months (95% CI 15.1 months-NE) for active BMs and 12.4 months (95% CI 8.3 months-NE) for progressive extracranial disease alone. The 12-month overall survival (OS) rate was 74% (95% CI 59% to 95%) in the overall population, and 83% (95% CI 58% to 100%) and 66% (95% CI 45% to 96%) for active BMs and extracranial disease only, respectively. Most common TEAEs were fatigue, alopecia, and constipation. In nine patients (31%, including two deaths), pneumonitis occurred. In this real-world population, we demonstrate T-DXd to be effective in patients with active BMs and those with progressive extracranial disease alone. PFS and OS were numerically longer in those with active BMs. These data demonstrate that patients with active BM treated with T-DXd have at least comparable outcomes to those with extracranial disease alone. The high rate of pneumonitis warrants further consideration.

DARPP-32 and t-DARPP in the development of resistance to anti-HER2 agents. Pre-clinical evidence from the STEP study

The therapeutic scenario of Human Epidermal Growth Factor Receptor 2 positive advanced breast cancer (ABC) has been recently enriched by a number of innovative agents, which are reshaping treatment sequence. While randomized trials have documented an advantage in terms of efficacy, for the newly available agents we lack effectiveness and tolerability evidence from the real-world setting. Similarly, the identification of predictive biomarkers might improve clinical decision. We herein describe the outline of a prospective/retrospective study which aims to explore the optimal sequence of treatment in HER2+, pertuzumab pre-treated ABC patients treated in II line with anti-HER2 agents in clinical practice. As part of the pre-clinical tasks envisioned by the STEP study, in vitro cell models of resistance were exploited to investigate molecular features associated with reduced efficacy of HER2 targeting agents at the transcript level. The aggressive behavior of resistant cell populations was measured by growth assessment in mouse models. This approach led to the identification of DARPP-32 and t-DARPP proteins as possible predictive biomarkers of efficacy of anti-HER2 agents. Biomarkers validation and the clinical goals will be reached through patients’ inclusion into two independent cohorts, i.e., the prospective and retrospective cohorts, whose setup is currently ongoing.

Pyrotinib plus capecitabine for trastuzumab-resistant, HER2-positive advanced breast cancer (PICTURE): a single-arm, multicenter phase 2 trial

BackgroundPatients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer and primary resistance to trastuzumab have a poor clinical outcome and lack good evidence to inform clinical decision. This study investigated the efficacy and safety of pyrotinib plus capecitabine in this population.MethodsThis phase 2 trial was conducted at 16 sites in China. Patients received oral pyrotinib 400 mg once daily and capecitabine 1000 mg/m2 twice a day on days 1–14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).ResultsBetween June 2019 and September 2021, 100 patients were enrolled with a median age of 51 years (range, 24–69). All patients had been treated with trastuzumab and 21 (21.0%) patients had prior use of pertuzumab. As of August 31, 2022, the median follow-up duration was 20.1 months (range, 1.3–38.2). The median PFS was 11.8 months (95% confidence interval [CI], 8.4–15.1), which crossed the pre-specified efficacy boundary of 8.0 months. The objective response rate was 70.0% (70/100), with a median duration of response of 13.8 months (95% CI, 10.2–19.3). The disease control rate was 87.0% (87/100). The median overall survival was not reached. The most common grade ≥ 3 treatment-emergent adverse event was diarrhea (24 [24.0%]). No treatment-related deaths occurred.ConclusionsPyrotinib plus capecitabine can be considered to be a treatment option in HER2-positive advanced breast cancer patients who have shown primary resistance to trastuzumab. Even in the era of modern anti-HER2 treatments, this clinical setting warrants more investigations to meet unmet needs.Trial registrationClinicalTrials.gov, NCT04001621. Retrospectively registered on June 28, 2019.

Fulvestrant with or without anti-HER2 therapy in patients in a postmenopausal hormonal state and with ER-positive HER2-positive advanced or metastatic breast cancer: A subgroup analysis of data from the Safari study (JBCRG-C06).

The role of endocrine therapy in the treatment of patients in a postmenopausal hormonal state and with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer (AMBC) is unclear. We analyzed the data from 94 patients with ER-positive HER2-positive AMBC enrolled in the Safari study (UMIN000015168), a retrospective cohort study of 1072 ER-positive AMBC patients in a postmenopausal hormonal state who received fulvestrant 500 mg (F500): (1) to compare time to treatment failure (TTF) and overall survival (OS) by treatment group, and TTF by treatment line; (2) in patients who received endocrine therapy (including F500) or anti-HER2 therapy as initial systemic therapy before chemotherapy, to investigate relations between TTF for the first-line therapy or time to chemotherapy (TTC) and OS; (3) to investigate factors associated with OS. The TTF was longer in the patients treated with F500 as first- or second-line therapy (n = 20) than in those who received later-line F500 therapy (n = 74) (6.6 vs. 3.7 months; HR, 1.98; p = 0.014). In the 59 patients who received endocrine therapy or anti-HER2 therapy as initial systemic therapy before chemotherapy, those with TTC ≥3 years had longer median OS than those with TTC <3 years (10.5 vs. 5.9 years; HR, 0.32; p = 0.001). Longer TTC was associated with prolonged OS. In patients with ER-positive HER2-positive AMBC enrolled in the Safari study, TTF was longer in patients who received F500 as first- or second-line therapy. In patients who received chemotherapy-free initial systemic therapy, the prolonged OS in those with TTC ≥3 years suggests that this value may be a helpful cut-off for indicating clinical outcomes.

FS-1502 in HER2-positive advanced breast cancer: Results from an open-label, phase 1 study.

3044 Background: FS-1502 is an anti-HER2 antibody-drug conjugate that was well tolerated and showed good antitumor activity in patients (pts) with advanced HER2 -expressing solid tumors in the dose-escalation stage of the current Phase 1 study. The results were presented at SABCS 2022. The recommend Phase 2 dose (RP2D) was 2.3 mg/kg IV once every 3 weeks. Here, we report the efficacy and safety of HER2-positive breast cancer (BC) pts treated with FS-1502 at the RP2D. Methods: This open-label Phase 1 trial was conducted at 9 hospitals in China. Heavily pretreated HER2-positive (IHC 3+ or 2+/FISH+) BC pts who had failed prior anti-HER2 therapy were recruited in the dose-expansion stage. All HER2-positive BC pts treated at the RP2D were pooled for analysis. Efficacy endpoints included objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1. Safety endpoints included treatment-emergent adverse events (TEAEs) and the laboratory data. Results: As of cutoff date, December 24, 2022, the median study follow-up duration was 5.2 months. A total of 70 female HER2-positive BC pts, with a median age of 51.8 (range: 31-76) years, were enrolled and received at least one dose of FS-1502. The median prior therapy line was 3 (range: 1-16), and 91.4% (64/70) of pts had previously received at least 2 therapy lines. The most common metastasis organs were lung 55.7% (39/70), lymph node 54.3% (38/70) and bone 50% (35/70). 81.4% (57/70) of pts had at least 3 metastatic lesions. All pts had previously received anti-HER2 therapy, among which trastuzumab ± pertuzumab (n = 67, 96%) and pyrotinib (n = 52, 74%) were the most common. Among 68 efficacy-evaluable pts, the best ORR of 52.9% (36/68) (95% CI, 40.45-65.17) was achieved with 2 complete responses and 34 partial responses. DCR was 88.2% (60/68), median progression-free survival was 15.5 months (95% CI, 4.57,-), and median duration of response was 12.9 months (95% CI, 5.72,-). FS-1502 was well tolerated. No related interstitial lung disease occurred in any grade. Eye toxicity was mostly Grade 1 or 2 of dry eye and keratitis. Grade ≥ 3 study-related TEAEs were reported in 27 (38.6%) pts, in which the most common events (≥ 5%) were hypokalemia (18.6%), platelet count decreased (7.1%), and neutrophil count decreased (5.7%). One (1.4%) patient experienced adverse events leading to drug discontinuation (hemoptysis). Adverse events leading to death were reported in 2 (2.9%) pts (bacterial pneumonia and hemoptysis, respectively). Bacterial pneumonia was not related to FS-1502, while hemoptysis was possibly related to the drug. Conclusions: FS-1502 demonstrated very promising antitumor activity and was well tolerated in heavily pretreated HER2-positive BC, with mild eye toxicity and no related interstitial lung disease reported. A Phase 3 clinical trial is under planning to further confirm efficacy and safety of FS-1502 in pts with advanced HER2-positive BC. Clinical trial information: NCT03944499 .

Combination of eribulin with trastuzumab and pertuzumab for HER2 positive advanced or recurrent breast cancer: JBCRGM03.

e13031 Background: Pertuzumab (P) was an effective first-line treatment for HER2 positive metastatic breast cancer (MBC) in the CLEOPATRA study, improving both overall and progression-free survival (PFS). However, it is challenging to provide intravenous docetaxel to MBC patients over long term at a dosage of 75 mg/m2 every three weeks. Eribulin (E) is a well tolerated cytotoxic agent. In a multicenter, open-label phase II research (UMIN000012232), we have shown the effectiveness and safety of E combined with trastuzumab (T) with P as first- and second-line treatment for metastatic or advanced BC. Methods: The study included HER2 positive MBC patients with no or one previous treatment, including advanced or recurrent chemotherapy. All patients were administered with T and taxane as perioperative or first-line chemotherapy. E (1.4 mg/m2) along with T (8 mg/kg loading dosage &gt; 6 mg/kg), and P (840 mg loading dose &gt; 420 mg) was administered intravenously on days 1 and 8 of a 21-day cycle, once every three weeks. The primary end point was PFS and the secondary endpoints were the response rate (RR) based on RECIST ver1.1. Overall patient survival effectiveness following P administration, E compliance, and success of follow-up therapies were observed. Results: A total of 50 patients were enrolled, with 49 of them qualifying for the safety analysis. However, the full analysis set (FAS) consisted of 46 individuals. The average patient age was 56 years old (range 23–70), and 9 (18%) and 40 (82%) patients received care in first- and second-line settings, respectively. The median PFS for patients who received main therapy was 20.5 months, whereas the median PFS for patients who received subsequent treatment was 8.6 months. Thirty-five patients (76.1%) were able to receive concomitant E until the end of protocol treatment. The overall RR was 56.5% among the 46 patients in the FAS. Nine patients (19.5%) responded completely, whereas 17 patients (37.0%) responded partially. There were 13 cases of stable disease (28.2%), six cases of progressing disease (13.0%), and one case was not evaluable (1.2%). The median survival of the primary treatment population was not reached; however, the median survival of the secondary treatment population was 42.4 months. Twenty three patients received T-DM1 as a follow-up treatment, 13 patients received TP plus chemotherapy, and five patients received additional therapies. The average duration of treatment with T-DM1 as a consequent therapy was approximately four months, whereas the average duration of treatment with HP plus chemotherapy was 11 months. Conclusions: For HER2positive MBC, E in combination with T plus P was well tolerated and may be an alternative to docetaxel-based combination therapy. Results from the JBCRG M06 trial research, which compares taxanes combination with T plus P with E combined with T plus P in first-line therapy, are still pending. Clinical trial information: UMIN000012232 .

Real world evidence of systemic therapy in hormone receptor positive advanced breast cancer (HR+ ABC) in Australia: ARORA Registry.

e13054 Background: The last decade has seen a rapid increase in systemic treatment options for patients with HR+ ABC. The incorporation of CDK4/6 inhibitors in first line (1L) is now standard practice leading to improved survival. However, there is a paucity of data on uptake of standard therapies and associated toxicities in the real-world setting. Methods: ARORA is a secondary data use study of Australian patients with HR+ ABC capturing prospective data on patient characteristics, systemic therapy sequencing and treatment outcomes in routine clinical practice. Patients aged &gt; 18 diagnosed after 1 Jan 2020 are eligible. Results: Data from 294 patients at 16 sites was analysed with a median follow up of 15 months. Mean age was 63 years; 23% &gt; 75 years. 64% were ECOG 0, 5.4% had a familial syndrome, 61% had relapsed metastatic disease and 19.4% had bone only metastases at diagnosis. Of patients who relapsed, 14.6% and 52.8% received neoadjuvant and adjuvant chemotherapy respectively, and 77.5% received adjuvant endocrine therapy (ET). 41% relapsed on or within 12 months of stopping adjuvant ET. 5 patients (1.7%) did not receive any systemic therapy for ABC. Of those on 1L therapy, 223 (77%) received CDK4/6i + ET, 38 (13.1%) received ET alone and 26 (9%) received chemotherapy. Choice of 1L CDK4/6i was palbociclib (50.7%), ribociclib (34.5%) and abemaciclib (9.9%). Patients who received 1L ET alone were older (mean age 75 vs 62 years; 68.4 vs 16.6% &gt; 75 years) with poorer performance status (34.2 vs 6.3% ECOG ≥2) and more comorbidities (76.3 vs 36.8% Charlson index &gt; 2) compared to those who received 1L CDK4/6i + ET. Conversely, those on 1L chemotherapy were younger (mean age 54, 96.2% &lt; 75years), with better performance status (69.2% ECOG 0-1) and fewer comorbidities (88.5% Charlson index &lt; 2). Patients receiving 1L chemotherapy were more likely to have visceral metastases compared to those on CDK4/6i + ET (69.2 vs 43.1%, p = 0.01). The most common reported toxicities in patients receiving CDK4/6i were diarrhea (59% abemaciclib vs 3.9% ribociclib vs 2.7% palbociclib), neutropenia (38.1% palbociclib vs 32.5% ribociclib vs 22.7% abemaciclib) and nausea/vomiting (27.3% abemaciclib vs 22.1% ribociclib vs 12.4% palbociclib). Abnormal LFTs occurred in 9.1% of patients on abemaciclib (vs 3.9% ribociclib and &lt; 1% palbociclib). 2 patients (1.8%) on palbociclib had pneumonitis whilst 1 (1.3%) on ribociclib had QTc prolongation. Survival data is immature. Conclusions: Despite CDK4/6i + ET being gold standard treatment in 1L HR+ ABC, only 3/4 of patients received this combination, with a substantial minority receiving ET alone or chemotherapy. Age, ECOG status, comorbidity burden and presence of visceral disease appear to be major determinants of treatment choice. Toxicity profile of the CDK4/6i agents were mostly in line with clinical trial results, although longer follow up is needed to confirm this.

Cardiac function of long-responders to dual anti-HER2 antibodies amongst patients with HER2 positive advanced breast cancer.

1043 Background: Dual anti-HER2 antibodies pertuzumab (P) and trastuzumab (T) in combination with taxane (D), followed by PT maintenance, is the standard first line treatment for HER2 positive advanced breast cancer (HER2+ ABC). Treatment associated cardiotoxicity necessitates regular cardiac function surveillance, which is a burden particularly for treatment long-responders. Data for cardiac safety of prolonged P+T exposure is scarce. We investigate the real-world impact on cardiac function in long-responders to treatment with dual anti-HER2 antibodies. Methods: We identified consecutive patients with HER2+ ABC who received the CLEOPATRA regimen (PT-D) between Jan 2014 and Dec 2020 from an institutional cancer registry. All patients had pre-treatment multiple-gated acquisition (MUGA) scan or echocardiogram, and subsequently at 3-monthly intervals until end of treatment to monitor left ventricular ejection fraction (LVEF). Patients on treatment for ≥36 months were considered long-responders. The Wilcoxon signed-rank test was used to assess any significant difference in LVEF at various landmark time-points in comparison to their pretreatment baseline. Results: 101 women with HER2+ ABC were eligible for analysis. Median age at treatment was 62 (IQR, 56.0-69.0). The median duration of treatment was 17.3 months (IQR, 9.0-31.3). 22.8% of patients were long-responders, who received a median of 67 cycles of treatment (IQR, 58-88). Compared to baseline, median LVEF was significantly decreased at 6m (median, 66% vs 69%, p=0.02), however there were no significant differences for any of the subsequent time-points up to 84 m. All of the larger LVEF drop (≥10% from baseline) occurred by the first 24 months, representing 4.7% of the overall measurements. Risk factors present for patients experienced treatment suspension (n=3) included previous exposures to anthracycline and left sided radiotherapy. Conclusions: In patients with HER2+ ABC who were long-responders to first-line PT-D, prolonged exposure to dual anti-HER2 antibodies was not associated with significant cardiotoxicity. It is safe to de-escalate the cardiac surveillance for this population. [Table: see text]