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.

Trastuzumab Emtansine (T-DM1): Hitching a Ride on a Therapeutic Antibody

2012 ◽  
pp. 159-161 ◽  
Author(s):  
Howard A. Burris
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Side Effects ◽  
Phase Ii ◽  
Objective Response ◽  
Metastatic Breast ◽  
Response Rates ◽  
Phase Iii ◽  
Trastuzumab Emtansine ◽  
Her2 Positive

Overview: The treatment of cancers with chemotherapy is frequently limited by side effects. The effectiveness may be improved by the use of monoclonal antibodies to deliver cytotoxic agents to cancer cells while limiting exposure to normal tissues. The use of antibody-drug conjugates (ADCs) is one such strategy: a drug connected by a linker to an antibody specific for a tumor antigen is the basic makeup of an ADC. Overexpression and amplification of HER2 is associated with clinically aggressive breast cancers, and the use of trastuzumab to target HER2 has been highly effective. That said, most patients with HER2-positive metastatic breast cancer will eventually have disease progression during targeted therapy. Trastuzumab emtansine (T–DM1) is a novel ADC that combines the humanized antibody trastuzumab and the potent antimicrotubule agent T-DM1 (derivative of maytansine) using a unique and highly stable linker. The potential of maytansine was found in the 1970s with clinical responses noted against breast cancer; however, substantial toxicity prohibited further development. DM1 possesses in vitro cytotoxicity 10 to 200 times greater than that of taxanes and vinca alkaloids. A phase I trial of T-DM1 for patients with heavily pretreated HER2-positive breast cancer determined a recommended dose of 3.6 mg per kilogram delivered every 3 weeks. Responses were seen in multiple patients. T-DM1 was then studied in phase II trials of patients with HER2-positive metastatic breast cancer. In a studies of 112 and 110 patients in whom disease had progressed during HER2-directed therapy, T-DM1 was associated with objective response rates of 26% and 34%, respectively. The agent was well tolerated in both trials, with most toxicities being grade 1 and 2, and no bleeding episodes or cardiac events occurring. Additional phase II and III trials are now evaluating T-DM1 in the first-line setting. In one such trial, T-DM1 was compared with standard dosing of trastuzumab every 3 weeks plus docetaxel every 3 weeks. Objective response rates were comparable and grade 3 or4 adverse events were substantially reduced in the T-DM1 arm. The anticipated selective activity and reduction in side effects were thus noted. Randomized multicenter phase III trials are ongoing, including the EMILIA trial, an open-label trial of T-DM1 compared with the U.S. Food & Drug Administration-approved regimen of capecitabine plus lapatinib. The results of studies completed to date suggest T-DM1 is active in patients who have cancer resistant to trastuzumab-based combinations.

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.

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].

scholarly journals A lower apatinib dose provides equivalent efficacy and reduced toxicity: A phase II, single-arm study of apatinib and oral etoposide in metastatic breast cancer

2020 ◽  
Author(s):  
Nanlin Hu ◽  
Anjie Zhu ◽  
Yiran Si ◽  
Jian Yue ◽  
Xue Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Metastatic Breast ◽  
Oral Etoposide ◽  
Breast Cancer Patients ◽  
Equivalent Efficacy

Abstract Introduction : The effectiveness of antiangiogenic drugs in metastatic breast cancer is still unclear. Apatinib is a small tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor 2 (VEGFR-2). We performed this clinical trial to evaluate the efficacy and safety of apatinib and oral etoposide in patients with HER2-negative locally advanced or metastatic breast cancer(MBC).Methods : Patients with HER2-negative MBC previously treated with anthracycline and taxanes and failed ≥1 prior chemotherapy regimens were recruited. The starting dose of apatinib was 500 mg and 425 mg in patients with Eastern Cooperative Oncology Group (ECOG) scores of 0-1 and 2, respectively. The etoposide capsules were given at 50 mg/m 2 on days 1 to 10 for 21 days. The primary end point was progression-free survival (PFS) which is assessed every 6 weeks (RECIST v1.1). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.Results : Thirty-one eligible patients were enrolled. The median follow-up time was 11 months. The median PFS for all patients was 6.93 months (95% confidence interval (CI), 5.97–7.90), and 6.93 months(95% CI 5.27-8.60) and 6.56 months (95% CI 1.41-11.73) for patients with apatinib 425mg and 500mg once daily, respectively. The ORR was 35.5% (11/31). The DCR was 87.1% (27/31). The median OS was 20.37 months (95% CI, 11.39–29.34). The median PFS of patients who had hypertension and proteinuria was longer than that for those without hypertension and proteinuria. The most common grade 3/4 treatment-related adverse events(AE) were hypertension (12/31, 38.71%), fatigue (3/31, 9.68%), thrombocytopenia (3/31, 9.68%).Conclusion : Apatinib combined with etoposide capsules is effective and tolerable in heavily pretreated, metastatic HER2-negative breast cancer patients. A lower apatinib dose provide equivalent efficacy and reduced toxicity.Trial registration : ClinicalTrails, NCT03535961, Registered 24 May 2018, https://clinicaltrials.gov/ct2/show/NCT03535961?cond=apatinib+etoposide+breast+cancer&draw=2&rank=1

scholarly journals Randomized phase-II evaluation of letrozole plus dasatinib in hormone receptor positive metastatic breast cancer patients

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Devchand Paul ◽  
Svetislava J. Vukelja ◽  
Frankie Ann Holmes ◽  
Joanne L. Blum ◽  
Kristi J. McIntyre ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Therapy Resistance ◽  
Breast Cancer Patients ◽  
Er Positive

Abstract The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

WJOG6110B (ELTOP): Randomized phase II trial comparing trastuzumab plus capecitabine (HX) and lapatinib plus capecitabine (LX) in HER2-positive metastatic breast cancer patients previously treated with trastuzumab and taxanes.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS659-TPS659 ◽  
Author(s):  
Toshimi Takano ◽  
Hideharu Kimura ◽  
Kazuto Nishio ◽  
Takeharu Yamanaka ◽  
Yoshinori Ito ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastases ◽  
Randomized Trial ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Metastatic Breast ◽  
Her2 Positive ◽  
Randomized Phase Ii ◽  
Previously Treated

TPS659 Background: In patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab and taxanes, there are now two standard strategies: trastuzumab beyond progression or switch to lapatinib. A randomized trial comparing trastuzumab plus capecitabine (HX) and capecitabine alone (X) after first-line trastuzumab-based chemotherapy (GBG-26) showed that HX was superior to X in terms of time to progression (TTP). Another randomized trial comparing lapatinib plus capecitabine (LX) and X in patients previously treated with anthracyclines, taxanes, and trastuzumab (EGF100151) showed that LX was superior to X in terms of TTP. To evaluate which strategy is better, we are conducting an open-label, randomized phase II trial comparing HX and LX. Methods: Primary endpoint is progression-free survival, and secondary endpoints are overall response rate, overall survival, proportion of patients progressing brain metastases as site of first progression, and safety. Major eligibility criteria include: (1) HER2-positive MBC, (2) previously treated with taxanes, (3) disease progression or distant relapse while receiving trastuzumab, (4) previously untreated with capecitabine, S-1, and anti-HER2 drugs other than trastuzumab, (5) previously treated with no more than two chemotherapy regimens for MBC, (6) no symptomatic brain metastases (asymptomatic brain metastases are allowed), and (7) baseline left ventricular ejection fraction ≥50%. Patients in the HX arm receive capecitabine 2,500 mg/m2/day on days 1 to 14 plus trastuzumab (8 mg/kg loading dose and 6mg/kg thereafter) on day 1 every 3 weeks. Patients in the LX arm receive capecitabine 2,000 mg/m2/day on days 1 to 14 plus lapatinib 1250 mg/day on days 1 to 21 every 3weeks. Large-scale biomarker analyses are also performed to explore predictive factors of trastuzumab or lapatinib efficacy. We are investigating biomarkers related to HER family and other receptors, PI3K/Akt pathways, ligands, FcγR, circulating tumor cells, and so on. This study has just begun and 7 of planned 170 patients have been enrolled.

Sign in / Sign up

Export Citation Format

Share Document