Jayantha Ratnayake

Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial

BACKGROUND Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. METHODS In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2), escalating, if tolerated, to 100 mg/m(2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. FINDINGS Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients). INTERPRETATION Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. FUNDING F Hoffmann-La Roche.

Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA)

BACKGROUND Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. PATIENTS AND METHODS In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. RESULTS Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients. CONCLUSION The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.

Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study

IntroductionMolecular markers that predict responses to particular therapies are invaluable for optimization of patient treatment. The TRYPHAENA study showed that pertuzumab and trastuzumab with chemotherapy was an efficacious and tolerable combination for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the neoadjuvant setting. We analyzed whether particular biomarkers correlated with the responses observed and therefore may predict outcomes in patients given pertuzumab plus trastuzumab.MethodsWe describe the analysis of a panel of biomarkers including HER2, human epidermal growth factor receptor 3 (HER3), epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) by qRT-PCR, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), enzyme-linked immunosorbent assay (ELISA), and PCR-based mutational analyses as appropriate. For each marker analyzed, patients were categorized into ‘low’ (generally below median) or ‘high’ (generally above median) subgroups at baseline and post-treatment.ResultsCorrelation of marker subgroups with the achievement of a pathological complete response (pCR) (ypT0/is) was analyzed. HER2 protein and mRNA expression levels were associated with pCR rate in two of the three study arms and the pooled analyses. Correlations of biomarker status with pCR occurred in one individual arm only and the pooled analyses with EGFR and PTEN; however, interpretation of these results is limited by a strong imbalance in patient numbers between the high and low subgroups and inconsistency between arms. We also found no association between expression levels of TOP2A and pCR rate in either the anthracycline-containing or free arms of TRYPHAENA.ConclusionsAccording to these analyses, and in line with other analyses of pertuzumab and trastuzumab in the neoadjuvant setting, we conclude that HER2 expression remains the only marker suitable for patient selection for this regimen at present.Trial registrationThe TRYPHAENA study was registered with ClinicalTrials.gov, NCT00976989, on September 14 2009.

A statistician's perspective on biomarkers in drug development

Biomarkers play an increasingly important role in many aspects of pharmaceutical discovery and development, including personalized medicine and the assessment of safety data, with heavy reliance being placed on their delivery. Statisticians have a fundamental role to play in ensuring that biomarkers and the data they generate are used appropriately and to address relevant objectives such as the estimation of biological effects or the forecast of outcomes so that claims of predictivity or surrogacy are only made based upon sound scientific arguments. This includes ensuring that studies are designed to answer specific and pertinent questions, that the analyses performed account for all levels and sources of variability and that the conclusions drawn are robust in the presence of multiplicity and confounding factors, especially as many biomarkers are multidimensional or may be an indirect measure of the clinical outcome. In all of these areas, as in any area of drug development, statistical best practice incorporating both scientific rigor and a practical understanding of the situation should be followed. This article is intended as an introduction for statisticians embarking upon biomarker-based work and discusses these issues from a practising statisticians perspective with reference to examples.

Abstract 2940: Comprehensive biomarker program demonstrates proof of mechanism and modulation of the tumor microenvironment due to RG7155, a novel therapeutic antibody targeting tumor associated macrophages

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The tumor microenvironment (TME) is a dynamic, highly complex network consisting of a variety of stromal cell types which support tumorigenesis. Myeloid derived cells probably represent the most abundant cell lineage in the TME, including tumor associated macrophages (TAMs). TAMs have been identified as an independent poor prognostic factor in several cancer types. RG7155 is a novel humanized monoclonal antibody targeting colony stimulating factor-1 receptor (CSF-1R). In vitro, RG7155 treatment results in cell death of CSF1-differentiated CD163+ M2-like macrophages. The associated mode of action and clinical proof of principle was evaluated in a first-in-man phase 1 study in patients with pigmented villonodular synovitis (PVNS), a neoplastic disorder characterized by CSF1 overexpression, as well as in patients with other advanced solid tumor entities. The associated biomarker program involves mandatory paired pre- and on-treatment biopsies of tumor and surrogate skin tissue as well as pharmacodynamic marker assessment in circulating blood. Biomarker analysis in tumor and skin includes multiplex IHC assays to assess tumor associated macrophages (CD163/CD68/CSF1R), T cells (CD4/CD8), tumor proliferation (Ki67) and vascularization (CD31). Tissue analysis is complemented by systematic peripheral blood sampling allowing flow cytometric analysis of circulating white blood cells (CD45/CD3/CD4/CD8/CD19/CD56/CD14/CD16/MHCII) and profiling of cytokines and growth factors. Here, we report the initial biomarker data from representative patients from the ongoing Phase 1 study. RG7155 induced a profound reduction of TAMs both in PVNS and various solid malignancies of up to 95% vs. baseline. We also observed depletion of macrophages in the skin which therefore may qualify as a surrogate tissue for mechanistic response. In peripheral blood RG7155 induced sustained modulation of CSF-1 (increase) and alternatively activated monocytes (decrease) was detected. Furthermore, preliminary data indicates a trend for overall increase of CD8/CD4 T cell ratio in the TME following RG7155 treatment, thus a secondary effect of TAM depletion causing intratumoral T cell modulation and tumor microenvironment re-education. Taken together, the individual biomarker program accompanying the first-in-man phase 1 study of RG7155 is demonstrating proof of mechanism and identified surrogate tissue as well as circulating markers to support optimal biological dose and regimen selection for future studies. Citation Format: Ann-Marie Broske, Irina Klaman, Jayantha Ratnayake, Georgina Meneses-Lorente, Kevin Smart, Phiippe Cassier, Carlos Gomez-Roca, Christophe Le Tourneau, Antoine Italiano, Jean-Pierre Delord, Jean-Yves Blay, Carola Ries, Dominik Ruettinger, Michael Cannarile. Comprehensive biomarker program demonstrates proof of mechanism and modulation of the tumor microenvironment due to RG7155, a novel therapeutic antibody targeting tumor associated macrophages. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2940. doi:10.1158/1538-7445.AM2014-2940