scholarly journals A phase I/II study of epertinib plus trastuzumab with or without chemotherapy in patients with HER2-positive metastatic breast cancer

2019 ◽  
Vol 22 (1) ◽  
Author(s):  
Iain R. Macpherson ◽  
Pavlina Spiliopoulou ◽  
Saeed Rafii ◽  
Matilde Saggese ◽  
Richard D. Baird ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastases ◽  
Antitumour Activity ◽  
Objective Response ◽  
Metastatic Breast ◽  
Medical Intervention ◽  
Reversible Inhibitor ◽  
Her2 Positive ◽  
Expansion Cohort

Abstract Background Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC). Methods Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety. Results The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C. Conclusion We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases. Trial registration EudraCT Number: 2013-003894-87; registered 09-September-2013.

scholarly journals Pyrotinib Combined With Vinorelbine in HER2-Positive Metastatic Breast Cancer: A Multicenter Retrospective Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Yi Li ◽  
Yixuan Qiu ◽  
Huihui Li ◽  
Ting Luo ◽  
Wei Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastases ◽  
Objective Response ◽  
Metastatic Breast ◽  
Second Line ◽  
Her2 Positive ◽  
Real World Data ◽  
Clinical Trial Registration ◽  
Line Therapy

IntroductionPyrotinib plus capecitabine has been approved in China for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Meanwhile, vinorelbine is another important chemotherapy option for MBC available in oral and intravenous forms. Thus, pyrotinib plus vinorelbine may represent a new treatment option, particularly for patients with failed capecitabine treatment. This study reported the first real-world data for pyrotinib plus vinorelbine therapy in HER2+ MBC.MethodsHER2+ MBC patients (n = 97) treated with pyrotinib plus vinorelbine in six institutions across China from May 2018 to June 2020 were enrolled. Progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and toxicity profiles were determined.ResultsSixty-seven percent of patients received more than two lines of systematic therapy. Nearly all patients (97.9%) had received trastuzumab and 50.5% were administered lapatinib. When combined with pyrotinib, 74.2% received oral and 25.8% received intravenous vinorelbine. Median PFS (mPFS) was 7.8 (range, 4.7–10.8) months for all patients. The mPFS in patients administered pyrotinib as second-line therapy and third-or-higher-line therapy were 12.0 and 6.4 months, respectively. Patients who received pyrotinib plus oral or intravenous vinorelbine had similar mPFS (7.8 vs. 6.4 months, p = 0.871). The 23 patients with brain metastases had mPFS of 6.3 (range, 3.4–9.2) months. Lapatinib-naïve patients had significantly longer PFS than lapatinib-treated patients (10.8 months vs. 5.6 months, p = 0.020). Median OS was not achieved. The ORR for 96 patients was 34.3%. Common grade 3 and 4 adverse events were diarrhea (22.7%), neutropenia (7.2%), and leukopenia (4.1%).ConclusionsPyrotinib plus vinorelbine therapy demonstrated promising effects in HER2+ MBC with tolerable toxicity, particularly in patients with second-line treatment and without prior lapatinib treatment, as well as in patients with brain metastases. Oral vinorelbine is a useful alternative to the intravenous form when combined with pyrotinib.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT04517305].

Pyrotinib plus capecitabine for HER2-positive metastatic breast cancer patients with brain metastases (PERMEATE): A multicenter, single-arm phase II study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1037-1037
Author(s):  
Min Yan ◽  
Quchang Ouyang ◽  
Tao Sun ◽  
Limin Niu ◽  
Jin Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastases ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Breast Cancer Patients ◽  
Her2 Positive

1037 Background: HER2-positive metastatic breast cancer (BC) has a high risk of brain metastases (BM), leading to poor survival. Small molecule tyrosine kinase inhibitor (TKI) with enhanced penetrability to the blood brain barrier combined with capecitabine have demonstrated promising clinical outcomes in HER2-positive metastatic BC patients with untreated (such as lapatinib) or previously treated (such as neratinib) BM. The randomized phase III PHOEBE trial has proved better efficacy of pyrotinib, an irreversible pan-HER receptor TKI, versus lapatinib when in combination with capecitabine in HER2-positive local relapsed or metastatic BC. This study was conducted to investigate the efficacy and safety of pyrotinib plus capecitabine in HER2-positive metastatic BC patients with BM. Methods: In this multicenter phase II trial (NCT03691051), eligible patients received pyrotinib 400 mg orally once daily without breaks and capecitabine 1000 mg/m2 orally twice daily for 14 days followed by 7 days off. Treatment was continued until disease progression or intolerable toxicity. Prior HER2 TKIs were not allowed. Cohort A included patients with radiotherapy-naive BM, and cohort B included those with progressive BM after whole brain radiotherapy or stereotactic conformal radiotherapy. The primary endpoint was confirmed central nervous system (CNS) objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. Results: Between January 2018 and July 2020, a total of 78 female patients were included (Table). For cohort A (n = 59), the CNS ORR was 74.6% (95%CI: 61.6%-85.0%). For cohort B (n = 19), the CNS ORR was 42.1% (95%CI: 20.3%-66.5%). By the cutoff date on 25 January 2021, the median progression-free survival was 12.1 months (95%CI: 9.0-14.7) in cohort A and 5.6 months (95%CI: 3.4-10.7) in cohort B. The most common grade ≥3 adverse events were diarrhea (23.1% [18/78]), neutrophil count decreased (12.8% [10/78]), white blood cell count decreased (12.8% [10/78]), anemia (9.0% [7/78]), hand-foot syndrome (7.7% [6/78]), hypertriglyceridemia (6.4% [5/78]), and hypokalemia (5.1% [4/78]). Conclusions: Pyrotinib plus capecitabine resulted as an effective and safe treatment for HER2-positive BC patients with radiotherapy-naive BM, but the efficacy was modest in those with radiotherapy-treated BM. Clinical trial information: NCT03691051 .[Table: see text]

scholarly journals Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial

2020 ◽  
Vol 38 (27) ◽  
pp. 3138-3149 ◽  
Author(s):  
Cristina Saura ◽  
Mafalda Oliveira ◽  
Yin-Hsun Feng ◽  
Ming-Shen Dai ◽  
Shang-Wen Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Her2 Positive ◽  
End Points ◽  
Cns Disease

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Preliminary safety, efficacy and pharmacokinetics (PK) results of KN026, a HER2 bispecific antibody in patients (pts) with HER2-positive metastatic breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1041-1041 ◽  
Author(s):  
Dongmei Ji ◽  
Jian Zhang ◽  
Weina Shen ◽  
Yiqun Du ◽  
June Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Bispecific Antibody ◽  
Objective Response ◽  
Metastatic Breast ◽  
Chinese Patients ◽  
Pharmacokinetic Analysis ◽  
Phase 2 ◽  
Phase Ii Trials ◽  
Her2 Positive

1041 Background: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes, the same domains as trastuzumab (ECD4) and pertuzumab (ECD2). It blocks ligand-dependent and independent tumor growth and enhances HER2 receptor internalization. In preclinical studies, KN026 showed activity in trastuzumab plus pertuzumab resistant tumor cell lines. This first-in-human study evaluated the safety/tolerability, pharmacokinetics (PK), and preliminary efficacy of KN026 monotherapy. Methods: This dose-escalation and expansion study enrolled Chinese patients (pts) with metastatic breast cancer who have failed prior anti-HER2 therapy. All pts intravenously received KN026 monotherapy at ascending dose of 5 mg/kg (QW), 10 mg/kg (QW), 20 mg/kg (Q2W) or 30 mg/kg (Q3W). Dose limiting toxicity (DLT) evaluation period was 28 days for QW and Q2W, and 21 days for Q3W. Efficacy evaluation was performed by RECIST 1.1 every 6 weeks and safety assessment according to CTCAE v 4.03. Results: As of the Jan, 22, 2020, 63 pts [median age: 54 years (31~69)] enrolled and 62 pts were included in the efficacy analysis. 41 pts remained on treatment and 22 pts discontinued treatment due to disease progression (n = 21) and adverse events (n = 1). The median treatment duration was 12 weeks (range: 4~62 weeks). Median prior lines of therapies are 3 (range: 1~15), and median prior lines of HER2 target therapies are 2 (range: 1~12). No DLTs were observed. Treatment-related AEs (TRAEs) occurred in 49 pts and 4 pts experienced 4 grade 3 TRAE (hypertension, infusion related reaction, transaminases increased and ventricular arrhythmia). The common (≥ 10%) TRAE were pyrexia (23.8%), diarrhea (19.0%), aspartate aminotransferase increased (15.9%), neutrophil count decreased (11.1%) and white blood cell count decreased (11.1%). The objective response rate at recommended Phase 2 dose levels (n = 56) was 32.1% (95% CI 20.3, 46.0) and disease control rate 76.8% (95% CI 63.6, 87.0). Pharmacokinetic analysis showed exposure (Cmax and AUC0-t) of KN026 increased by dose. The recommended Phase 2 dose (RP2D) were 20 mg/kg Q2W and 30 mg/kg Q3W. Conclusions: KN026 is well tolerated and has demonstrated encouraging anti-tumor activity in HER2-positive breast cancer patients who have failed standard anti-HER2 therapies. The recommended Phase 2 dose (RP2D) of KN026 were 20 mg/kg Q2W and 30 mg/kg Q3W. Phase II trials in various HER2-positive and HER2-low/intermediate solid tumors are currently ongoing. Clinical trial information: NCT03619681 .

Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1036-1036
Author(s):  
Shanu Modi ◽  
Fabrice Andre ◽  
Ian E. Krop ◽  
Cristina Saura ◽  
Toshinari Yamashita ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Topoisomerase I ◽  
Objective Response ◽  
Metastatic Breast ◽  
Continuous Variable ◽  
Cox Proportional Hazards ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Open Label

1036 Background: Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor. In the pivotal DESTINY-Breast01 trial, efficacy of T-DXd in HER2-positive metastatic breast cancer (mBC) was demonstrated, with an objective response rate (ORR) of 60.9% and median progression-free survival (mPFS) of 16.4 months. Methods: DESTINY-Breast01 was a single-group, open-label, multicenter, phase II trial of 184 patients with HER2-positive mBC previously treated with trastuzumab emtansine (T-DM1) who received T-DXd at 5.4 mg/kg. Multivariate analysis using logistic regression models (ORR) and Cox proportional hazards models (duration of response [DOR], mPFS) explored 15 relevant clinical predictor variables. Circulating tumor DNA (ctDNA) was collected prior to the first dose, every 3 cycles of treatment, and at the end of treatment. Sequencing was done via GuardantOMNI (Guardant Health) for single-nucleotide variation/insertion and deletion, amplification, and fusion of ≈ 500 genes. Results: Efficacy in all evaluated clinical subgroups was similar to the overall ORR 60.9% and mPFS 16.4 months with ranges from ORR 46.4%-74.5% and mPFS 12.3-18.1 months. Variables associated with improved ORR, DOR, or mPFS included hormone receptor positive status, fewer prior treatment regimens (continuous variable), pertuzumab given in the first or second line, and normal renal and hepatic function. Variables that did not impact efficacy outcomes compared to the overall population include age, race, region, ECOG PS, HER2 IHC 3+ status, progesterone receptor status, best response to T-DM1, time since diagnosis, and history of brain metastases. In 48 subjects with progression as of data cut date, metastases were most commonly observed in the liver, lung, and lymph nodes. Only 8% (4 of 48) had progression involvement in the brain upon disease progression. Decrease of ERBB2 copy number in ctDNA was seen on treatment and correlated with clinical response. Additional changes in molecular markers on treatment and following progression will be described. Conclusions: T-DXd demonstrated strong efficacy in all clinical subgroups analyzed. Further exploration of both clinical and molecular variables to determine biomarkers of efficacy may be warranted. Clinical trial information: NCT03248492 .

scholarly journals Lapatinib concentration in cerebrospinal fluid in two patients with HER2-positive metastatic breast cancer and brain metastases

2014 ◽  
Vol 25 (4) ◽  
pp. 912-913 ◽  
Author(s):  
S. Gori ◽  
G. Lunardi ◽  
A. Inno ◽  
J. Foglietta ◽  
B. Cardinali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cerebrospinal Fluid ◽  
Metastatic Breast Cancer ◽  
Brain Metastases ◽  
Metastatic Breast ◽  
Her2 Positive

Brain metastases in HER2-positive metastatic breast cancer patients who received chemotherapy with or without trastuzumab

Breast Cancer ◽  
2014 ◽  
Vol 22 (5) ◽  
pp. 503-509 ◽  
Author(s):  
Muhammet Ali Kaplan ◽  
Hamza Ertugrul ◽  
Ugur Firat ◽  
Mehmet Kucukoner ◽  
Ali İnal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastases ◽  
Cancer Patients ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Her2 Positive

scholarly journals Efficacy and Safety of the use of Pertuzumab in Metastatic Breast Cancer Patients in a Real-World Setting: Results from the SUPER-GONO (Gruppo Oncologico del Nord Ovest) Study

2021 ◽  
Author(s):  
Ornella Garrone ◽  
Tommaso Giarratano ◽  
Eva Blondeaux ◽  
Loretta D'Onofrio ◽  
Andrea Michelotti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Practice ◽  
Real World ◽  
Objective Response ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Real World Data ◽  
Adjuvant Trastuzumab

Abstract Background: Real world data have the potential to demonstrate the applicability of the results of randomized studies in the general population. SUPER trial was conducted in order to assess the activity, the efficacy and the safety of the combination of pertuzumab, trastuzumab and chemotherapy in clinical practice.Material and methods: Patients diagnosed with HER2 positive metastatic breast cancer (mBC) and treated with pertuzumab, trastuzumab and chemotherapy were accrued at 18 italian hospitals. Data were retrospectively collected in the time frame between pertuzumab availability in clinical practice and study approval in 2016, and prospectively collected thereafter. Results: Overall 342 HER2 positive mBC were accrued. 172 patients had relapsed disease and 56.4% of them received neo/adjuvant trastuzumab. 205 patients received docetaxel. Objective response rate was 76.3% (95%CI: 71.4–80.7). Median progression free survival (PFS) and overall survival (OS) were 24.3 months (95% CI: 20.0–28.9) and 70.2 months (95% CI: 61.4–79.0) respectively. Triple positive patients treated with endocrine therapy in addition to pertuzumab and trastuzumab maintenance had a significant longer PFS and OS than patients who did not. mPFS was 31.2 months and 13 months respectively (HR=0.47; 95% CI: 0.33–0.66; p<0.001) and mOS was 72.3 months and 56.8 months respectively (HR=0.58; 95% CI: 0.36–0.92; p=0.02). Pretreatment with trastuzumab did not hamper the outcome. In addition, maintaining the dual blockade inhibition at disease progression with the same CT partner or alternative endocrine agent leading to further benefit.Conclusions: SUPER suggests that results of first-line treatment with pertuzumab, trastuzumab and chemotherapy in unselected patients are consistent with findings from CLEOPATRA trial.Moreover, as expected from real world evidence, new insights have emerged.

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