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Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis.

ABSTRACT: PURPOSE:In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC). METHODS:Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (??6 months) following adjuvant therapy or progression after trastuzumab (Tras)?+?taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints. RESULTS:The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators. CONCLUSIONS:The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC.

SUBMITTER: Paracha N

PROVIDER: S-EPMC7103014 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis.

Paracha Noman N Reyes Adriana A Diéras Véronique V Krop Ian I Pivot Xavier X Urruticoechea Ander A

Breast cancer research and treatment 20200225 3

<h4>Purpose</h4>In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC).<h4>Methods</h4>Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab ...[more]

PMID: 32100144

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Project description:BackgroundSeveral human epidermal growth factor receptor 2 (HER2)-targeted regimens (anti-HER2 target agent combined chemotherapy) have been introduced for the treatment of HER2-positive locally advanced or metastatic breast cancer progressed after trastuzumab. We therefore conducted a network meta-analysis to compare and rank HER2-targeted regimens in this population after trastuzumab therapy.MethodsThe electronic databases of PubMed, EmBase, Cochrane Central Register of Controlled Trials, and the websites of http://clinicaltrials.gov/ (US NIH) were systematically searched for published and unpublished randomized controlled trials (RCTs) from their inception to October, 2020. Nine treatment regimens were eligible to be included in this analysis. The primary outcomes were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS), while the secondary outcomes were grade ≥3 adverse events.ResultsA total of 2,104 citations were identified and 12 RCTs comprising 3,769 patients were selected for final analysis. For HER2 positive unresectable, locally advanced or metastatic patients progressed after trastuzumab therapy pyrotinib plus capecitabine ranked the highest surface under the cumulative ranking area (SUCRA) in PFS, ORR and its SUCRA in OS was higher than Trastuzumab emtansine (T-DM1). T-DM1 plus atezolizumab, pyrotinib plus capecitabine, and pertuzumab plus trastuzumab plus capecitabine had comparable SUCRA in OS (76.1% vs. 74.5% vs. 71.2%). Six of included studies reported any grade ≥3 adverse events, the prevalence of any grade ≥3 adverse events in lapatinib plus capecitabine (353/683), T-DM1 (213/558), trastuzumab plus capecitabine (130/218), pertuzumab plus trastuzumab plus capecitabine (118/228), pyrotinib plus capecitabine (220/384), T-DM1 plus atezolizumab (43/132) and capecitabine (24/94) were 51.7%, 38.2%, 59.6%, 51.8%, 57.3%, 32.6% and 25.5%, respectively. Specific adverse event characteristics related to different HER2-targeted regimens need to be well known ahead and managed during the therapy.ConclusionsThe results indicated that for HER2 positive breast cancer with previous trastuzumab therapy pyrotinib plus capecitabine was probably more efficacious in PFS and ORR. T-DM1 plus atezolizumab, pyrotinib plus capecitabine and pertuzumab plus trastuzumab plus capecitabine have comparable effect on OS improvement and all of them were likely better than T-DM1. The risk of grade ≥3 adverse events for specific treatment regimens were also provided.

Project description:AimsWe conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1), to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy] study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physician's choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer.MethodsWe compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure-response analyses using model-predicted cycle 1 maximum concentration (Cmax ), cycle 1 minimum concentration (Cmin ) and area under the concentration-time curve at steady state (AUCss ). Kaplan-Meier analyses [overall survival (OS), progression-free survival (PFS)] and logistic regression [overall response rate (ORR), safety] were stratified by T-DM1 exposure metrics. Survival hazard ratios (HRs) in the lowest exposure quartile (Q1) of cycle 1 Cmin were compared with matched TPC-treated patients.ResultsT-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 Cmin and AUCss exhibited numerically longer median OS and PFS and higher ORR than patients with lower exposure. Exposure-response relationships were less evident for cycle 1 Cmax . No relationship between exposure and safety was identified. HRs for the comparison of T-DM1-treated patients in the Q1 subgroup with matched TPC-treated patients were 0.96 [95% confidence interval (CI) 0.63, 1.47] for OS and 0.92 (95% CI 0.64, 1.32) for PFS.ConclusionsExposure-response relationships for efficacy were inconsistent across exposure metrics. HRs for survival in patients in the lowest T-DM1 exposure quartile vs. matched TPC-treated patients suggest that, compared with TCP, the approved T-DM1 dose is unlikely to be detrimental to patients with low exposure.

Project description:BACKGROUND:Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation. METHODS:In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety. RESULTS:Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). CONCLUSIONS:Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).

Dataset Information

Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis.

Publications

Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis.

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