Tdm1 breast cancer trial

The median DOR was 6. Frequent adverse events considered to be related to tucatinib included nausea, diarrhea, fatigue, increased AST levels, vomiting, decreased appetite, increased ALT levels, and hypokalemia. Dose interruptions for tucatinib were needed in 32 patients and 5 patients discontinued tucatinib due to an adverse event. Featured Clinical Focus. October 11, Lisa Astor. Accessed October 10, Definitive surgical resection with lumpectomy or mastectomy, including management of the axilla was performed according to National Comprehensive Cancer Network guidelines Post-operative treatment was not mandated on the trial, but investigators were encouraged to give standard of care adjuvant treatment consisting of 9 additional months of trastuzumab with or without pertuzumab, once approved , radiation per NCCN guidelines and endocrine therapy for those with hormone-receptor positive tumors.

Core tumor biopsies, blood draws, and bilateral breast MRI were performed at baseline and at specified intervals during treatment Supplementary Fig. The primary endpoint was assessed using resected tumors by local pathologists trained in the residual cancer burden RCB method in which pCR is RCB 0 As I-SPY2 is modified intent-to-treat, patients receiving any dose of study therapy are considered evaluable; those who switch to non-protocol therapy, progress, forgo surgery, or withdraw are deemed non-pCR.

Drug manufacturers supplied investigational agents and funding but played no role in study design, data accrual, data analysis, or manuscript preparation. The study complies with all local and national regulations regarding the use of human study participants and was conducted in accordance to the criteria set by the Declaration of Helsinki. An independent data and safety monitoring board DSMB convened monthly.

Probability distributions of pCR rates are calculated using a Bayesian time and covariate-adjusted logistic model with HR, HER2, and MammaPrint statuses as covariates used to calculate the probability that the pCR rate of the investigational arm is greater than control for each signature 20 , 21 , 22 , similarly for the predictive probabilities of success in a future trial.

Experimental arms are not statistically compared to each other. In response, a revised statistical plan was adopted and approved by the DSMB which adjusts for time trends to allow comparison against a control population consisting of subjects enrolled since the beginning of I-SPY2. The initial statistical analyses in I-SPY2 compared investigational arms with concurrently randomized controls.

We wanted to be able to use the results for the original control arm but were concerned about the possibility of a drift in the prognosis of patient population over time and within patient subtype. Having multiple arms in the trial with different time periods during which they are accruing patients enabled bridging across the different eras of trial accrual.

The time machine discounts results from the past, with more discounting if they are further in the past.

The mathematical basis and motivation was a statistical model for bridging eras in sports The model description follows. The control rate for an investigational arm is adjusted to the time period when the arm was being randomized to patients. Each investigational arm is compared directly against its concurrently randomized controls. The time machine strengthens this comparison by bridging to earlier controls via a series of direct comparisons.

These direct comparisons are the various comparisons of arms that have been randomized in the trial, including comparisons of investigational arms against each other as well as against controls.

The strength of this borrowing depends on the time-period overlaps among the various arms, both control and investigational arms. The greater uncertainty associated with results during periods of relatively low accrual and when fewer arms are being randomized is incorporated into the final analyses of the various arms. We explicitly incorporate terms in the model to account for potential time trends in the pCR rate; we account for molecular subtype and treatment as well.

This is accomplished using time-dependent offset terms in a logistic model. Time is set to 0 at each analysis. We partition time in the past into bins of 90 days each. The index of the most recent bin, that for the previous 0—90 days, is 1. The index of the bin 91— days in the past is 2. And so on. Let t i be the index of the bin for the randomization time of patient i. These are additive parameters in the model for the log-odds ratio of pCR rate for each investigational arm compared with control.

The NDLM uses the data within bins to estimate the respective log-odds ratios, but it also serves to smooth the effect across bins. An exploratory analysis of EFS was performed using patients with follow-up data as of February 26, EFS was assessed as time from treatment consent to any locoregional or distant recurrence or death from any cause; and patients without events were censored at last follow-up.

Statistics from this exploratory analysis are descriptive and not inferential—sample sizes are small within signatures and I-SPY2 is not powered for EFS or other survival endpoints. In addition, LCM was performed to isolate tumor epithelium for signaling protein activation profiling by reverse phase protein arrays RPPA.

The consort diagram with the number of evaluable patients for each molecular profiling analysis is shown in Figure Y. Details of the sample preparation and data processing are as previously described These analyses were also performed adjusting for HR status as a covariate, and within receptor subsets, sample size permitting.

Associations between categorical variables e. Biomarkers were assessed individually without adjustment for multiple hypothesis testing. All computation was performed in the R programming environment version 3. Further information on research design is available in the Nature Research Reporting Summary linked to this article. Source data are provided with this paper for all outcomes except adverse events in Supplementary Data 1. A summary of all adverse events observed are provided in Supplementary Data 2.

Biomarker data analysis was performed using R version 3. The randomization engine and Bayesian analytic software used in efficacy analysis are used under license from Berry Consultants, LLC; requests for code should be directed to don berryconsultants. Cortazar, P. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet , — Article Google Scholar. Carey, L. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB , a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib.

Corrigan, P. Ado-trastuzumab emtansine: a HER2-positive targeted antibody-drug conjugate. Gagliato, D. Oncotarget 7 , — Gwin, W. Cancer Res. Hurvitz, S. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer KRISTINE : a randomised, open-label, multicentre, phase 3 trial.

Lancet Oncol. Schneeweiss, A. Minckwitz, Gvon et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. Gianni, L. 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.

Swain, S. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. Pathologic complete response and outcomes by intrinsic subtypes in NSABP B, a randomized neoadjuvant trial of chemotherapy with trastuzumab, lapatinib, or the combination. Breast Cancer Res. Wulfkuhle, J. Jco Precis. Google Scholar. Denkert, C. Murthy, R. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. Cardoso, F. Park, J. Adaptive randomization of neratinib in early breast cancer.

Rugo, H. Adaptive randomization of veliparib—carboplatin treatment in breast cancer. In more detail, concerning stratification, data were analyzed within strata defined upon a given pre-specified variable. In doing so, we managed the confounding effects of a given variable possibly acting as a confounding at the price of a reduction of the study power in detecting the association of interest in the case of small strata. These latter approach allowed to simultaneously control for more than one confounder at the time, and help interpret the effect of each confounder in light of the others.

In addition, data retrieving was performed by ad hoc trained research assistants who worked in strict collaboration with the oncologists involved at the single centre level.

This may have minimized the chances of residual confounding. Indeed, when comparing the pre- and post-treatment HER2 scores for each of the 4 patients examined, the IHC assessment uniformly showed a score reduction.

In addition, it may reflect the selective pressure applied by the prior administration of anti-HER2 agents. Although hypothesis-generating, data from the study herein presented, as well as from prior similar studies within this same research pipeline, are limited in nature.

Still, they provided an appropriate ground in terms of preliminary evidence, on which we designed a randomized clinical trial investigating the optimal treatment sequence in HER2-positive ABC patients. Immunohistochemistry: VL. In vivo mice experiments: MP and CL.

All authors contributed equally to the analysis and interpretation of data. The study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent. The protocol was approved by institutional review boards at each study site.

Houston, TX and at Exiris Inc. Rome, IT. ADL received consulting fees from Novartis and Roche. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Giulia Bon, Email: ti. Eriseld Krasniqi, Email: moc. National Center for Biotechnology Information , U. J Exp Clin Cancer Res. Published online Dec Author information Article notes Copyright and License information Disclaimer.

Chiara Hospital, Pisa, Italy. Gemelli, Rome, Italy. Corresponding author. Received Sep 4; Accepted Dec 2.

The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.

If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. This article has been cited by other articles in PMC. Associated Data Supplementary Materials Additional file 1. Additional file 2. Conclusions Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells.

Supplementary Information The online version contains supplementary material available at Statistical analysis Within the overall cohort of the patients, the associations of interest were also evaluated in light of: a. Open in a separate window. Table 4 Median OS, median PFS in first-line of treatment and median PFS in second-line of treatment by treatment sequences in the overall population and by subgroups defined upon immunohistochemical characterization of molecules features N Supplementary Information Additional file 1.

Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki. Contributor Information Giulia Bon, Email: ti. References 1. Iqbal N, Iqbal N. Human epidermal growth factor receptor 2 HER2 in cancers: overexpression and therapeutic implications.

Mol Biol Int. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. N Engl J Med. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M study group.

Brufsky A. Trastuzumab-based therapy for patients with HER2-positive breast cancer: from early scientific development to foundation of care.

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