Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

Generalized predictive control tuning by controller matching

The tuning of state-space model predictive control (MPC) based on reverse engineering has been investigated in literature using the inverse optimality problem ( [1] and [2]). The aim of the inverse optimality is to find the tuning parameters of MPC to obtain the same behavior as an arbitrary linear-time-invariant (LTI) controller (favorite controller). This requires equal control horizon and prediction horizon, and loop-shifting is often used to handle non-strictly-proper favorite controllers. This paper presents a reverse-engineering tuning method for MPC based on transfer function formulation, also known as generalized predictive control (GPC). The feasibility conditions of the matching of a GPC with a favorite controller are investigated. This approach uses a control horizon equal to one and does not require any loop-shifting techniques to deal with non-strictly-proper favorite controllers. The method is applied to a binary distillation column exampl

Generalized predictive control tuning by controller matching

The tuning of state-space model predictive control (MPC) based on reverse engineering has been investigated in literature using the inverse optimality problem ( [1] and [2]). The aim of the inverse optimality is to find the tuning parameters of MPC to obtain the same behavior as an arbitrary linear-time-invariant (LTI) controller (favorite controller). This requires equal control horizon and prediction horizon, and loop-shifting is often used to handle non-strictly-proper favorite controllers. This paper presents a reverse-engineering tuning method for MPC based on transfer function formulation, also known as generalized predictive control (GPC). The feasibility conditions of the matching of a GPC with a favorite controller are investigated. This approach uses a control horizon equal to one and does not require any loop-shifting techniques to deal with non-strictly-proper favorite controllers. The method is applied to a binary distillation column exampl

Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: Cohort B of the phase II KEYNOTE-086 study

Background Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Patients and methods Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival. Results All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9-31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9-34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0-2.2), and median overall survival was 18.0 months (95% CI 12.9-23.0). Conclusions Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC. Clinical trial registration ClinicalTrials.gov, NCT02447003