Efficacy Of T-DM1 Research Articles

Breast cancer: T-DM1 - an important agent in the history of breast cancer management.

Updated results from the EMILIA and TH3RESA trials in patients with advanced-stage HER2-positive breast cancer confirm the overall survival benefit and favourable safety profile of T-DM1 after prolonged follow-up durations. The efficacy of T-DM1 as a second or later line of treatment indicates that HER2 is a relevant therapeutic target throughout the course of the disease.

A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience.

We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order.

Efficacy of trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (MBC) previously treated with pertuzumab (P).

1023 Background: T-DM1 was approved for pts with HER2+ MBC previously treated with trastuzumab (H) and a taxane based on the phase III EMILIA study. P in combination with H + docetaxel (T) later became the first-line standard of care for HER2+ MBC, but there are limited data on T-DM1 efficacy in pts who previously received P. We present exploratory efficacy results from pts treated with T-DM1 any time after P from 2 phase III studies: CLEOPATRA and PHEREXA. Methods: CLEOPATRA (NCT00567190) and PHEREXA (NCT01026142) are randomized, 2-arm trials evaluating P-based regimens for HER2+ MBC. CLEOPATRA studies H + T + P vs HT + placebo in pts with no prior anti-HER2 treatment (tx) or chemotherapy for MBC, while PHEREXA studies H + capecitabine (C) +/− P in pts who progressed during/after previous H tx for MBC. We assessed overall survival (OS) in an exploratory analysis of pts who either received or did not receive T-DM1 at any time after discontinuing study-assigned tx in CLEOPATRA or PHEREXA. Results: Of 408 pts who received HTP in CLEOPATRA and 228 pts who received HCP in PHEREXA, 32 and 43 pts received subsequent T-DM1, respectively (Table). Median duration of T-DM1 tx was 7.1 mo (range 0−44) and 4.2 mo (range 0−22), respectively, and median time from discontinuation of P to start of T-DM1 was 3.5 mo (range 1−47) and 10.6 mo (range 1−28). Conclusions: Although data are limited in these exploratory analyses, our results provide additional evidence of T-DM1 clinical activity in pts with HER2+ MBC who progressed on prior P + H, a finding with real-world implications. Clinical trial information: NCT00567190, NCT01026142. [Table: see text]

Application of a PK-PD Modeling and Simulation-Based Strategy for Clinical Translation of Antibody-Drug Conjugates: a Case Study with Trastuzumab Emtansine (T-DM1).

Successful clinical translation of antibody-drug conjugates (ADCs) can be challenging due to complex pharmacokinetics and differences between preclinical and clinical tumors. To facilitate this translation, we have developed a general pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation (M&S)-based strategy for ADCs. Here we present the validation of this strategy using T-DM1 as a case study. A previously developed preclinical tumor disposition model for T-DM1 (Singh and Shah, AAPSJ. 2015; 18(4):861-875) was used to develop a PK-PD model that can characterize in vivo efficacy of T-DM1 in preclinical tumor models. The preclinical data was used to estimate the efficacy parameters for T-DM1. Human PK of T-DM1 was a priori predicted using allometric scaling of monkey PK parameters. The predicted human PK, preclinically estimated efficacy parameters, and clinically observed volume and growth parameters for breast cancer were combined to develop a translated clinical PK-PD model for T-DM1. Clinical trial simulations were performed using the translated PK-PD model to predict progression-free survival (PFS) and objective response rates (ORRs) for T-DM1. The model simulated PFS rates for HER2 1+ and 3+ populations were comparable to the rates observed in three different clinical trials. The model predicted only a modest improvement in ORR with an increase in clinically approved dose of T-DM1. However, the model suggested that a fractionated dosing regimen (e.g., front loading) may provide an improvement in the efficacy. In general, the PK-PD M&S-based strategy presented here is capable of a priori predicting the clinical efficacy of ADCs, and this strategy has been now retrospectively validated for all clinically approved ADCs.

Highlights of This Issue

Because of poor lysosomal degradation, HER2-directed antibody-drug conjugate (ADC), T-DM1 is efficient only in patients with high HER2 overexpression. Thus, there is a need for HER2-directed ADCs effective in patients expressing low/moderate levels of HER2. Prolactin receptor (PRLR) is rapidly and constitutively degraded in lysosomes. Cross-linking HER2 to PRLR, using a HER2 x PRLR bispecific ADC, dramatically enhances lysosomal degradation of HER2. Accordingly, anti-HER2 x PRLR bispecific ADC significantly improves upon T-DM1 efficacy in cells expressing intermediate levels of HER2. These results demonstrate that coupling a tumor-specific ADC target to a rapidly internalizing protein may be a useful approach to enhance efficacy of ADCs.Delta-24-RGD is an oncolytic virus whose replication depends upon a defective p16/RB/E2F pathway, an alternation found in ∼85% of pancreatic adenocarcinomas (PDAC). Dai and colleagues report that exposure of human PDAC cells to Delta-24-RGD induced dramatic cytotoxicity accompanied by robust exposure of phosphatidylserine (PS) on PDAC cell membranes. Sequential combination of Delta-24-RGD followed by a PS-targeting antibody, 1N11, enhanced anticancer activity and favorably altered the innate immune tumor microenvironment. These results suggest that combining these agents sequentially could achieve positive clinical results when used in a molecularly-defined subset of pancreatic cancer.The presence of mature mast cells within tumor tissue, expression of stem cell factor by many tumor cells and previous reports of interactions between mast cells and other innate immune cells suggest that KIT signaling within mast cells may influence tumor growth. Using a KIT-specific inhibitory antibody in syngeneic mouse tumor models, Garton and colleagues demonstrated that anti-KIT treatment enhanced the anti-tumor activity of immune checkpoint inhibitors (anti-CTLA-4 or anti-PD-1), and promoted immune responses by selectively reducing the immunosuppressive monocytic myeloid-derived suppressor cell (M-MDSC) population. These data provide a rationale for clinical investigation of a KIT-directed antibody in combination with checkpoint inhibitors.Using high-throughput profiling of cancer cell lines with candidate anti-cancer agents, Lee and colleagues identified determinants of the response to inhibitors of the Chk1 kinase, a mediator of the DNA damage response. While sensitivity to Chk1 inhibition was previously linked to p53 mutation status, these new findings revealed an unexpected requirement for Chk1 in cells experiencing genotoxic stress after Ras-MEK pathway activation. Chk1 inhibition combined with DNA-targeted chemotherapeutics led to enhanced cell killing in some osteosarcoma, ovarian, and breast cancer cells. These findings provide insight on how to improve the efficacy of Chk1 inhibition in a subpopulation of patients.

Efficacy and safety of T-DM1 in the 'common-practice' of HER2+ advanced breast cancer setting: a multicenter study.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (mBC). The aim of this ‘field-practice’ study was to investigate the efficacy and safety of T-DM1, focusing on treatment line, previous lapatinib treatment and patterns of metastasis. Three hundred and three patients with HER2-positive mBC who received T-DM1 were identified by reviewing the medical records of 24 Italian Institutions. One hundred fourty-nine (49%) and 264 (87%) had received prior hormonal treatment and/or anti-HER2 targeted therapy, respectively. Particularly, 149 patients had been previously treated with lapatinib. The objective response rate (ORR) was 36.2%, and 44.5% when T-DM1 was administrated as second-line therapy. Considering only patients with liver metastases, the ORR was 44.4%. The median progression-free survival (PFS) was 7.0 months in the overall population, but it reached 9.0 and 12.0 months when TDM-1 was administered as second- and third-line treatment, respectively.In conclusion, in this ‘real-word’ study evaluating the effects of T-DM1 in patients with HER2-positive mBC who progressed on prior anti-HER2 therapies, we observed a clinically-relevant benefit in those who had received T-DM1 in early metastatic treatment-line and in subjects previously treated with lapatinib.

Abstract P4-22-24: A retrospective study about re-biopsy at disease progression on T-DM1

Abstract Background: T-DM1 is an antibody-drug conjugate, which consists of trastuzumab, DM1, and linker. It has been established as standard of care for human epidermal receptor (HER) 2-positive metastatic breast cancer (MBC). At the first step, trastuzumab has to combine with extracellular domain of HER2. Then T-DM1 is delivered into HER2-positive cancer cells, and DM1 is released. After that, antitumor activity of DM1 can be exerted. In this way, T-DM1 works on HER2-positive cancer cells with high specificity. This retrospective study is aimed to examine whether HER2 status at disease progression on T-DM1 is related to efficacy of T-DM1. Patients: We identified 23 patients who started treatment with T-DM1 between February 2014 and March 2016 at our department. The data cut-off date was April 30, 2016. Methods: We retrospectively reviewed the medical records of these 23 patients and investigated the following items: patient characteristics, time to failure (TTF), objective response, and results of re-biopsy. TTF were analyzed by the Kaplan–Meier method. The definition of HER2-positive was immunohistochemistry 3+, or FISH &amp;gt;2.2. Results: There were 23 patients who started administration of T-DM1 for MBC at our department in this period. All patients had HER2-positive MBC which was diagnosed as HER2 positive by examination of samples from primary tumor. At the time of data cut-off, five patients had continued T-DM1 therapy, and 18 patients had finished it due to disease progression in 15 patients and adverse events in three patients. Re-biopsy was conducted to 13 (87%) of 15 patients who experienced disease progression during TDM-1 therapy. Samples of re-biopsy were acquired from the site that showed progression during T-DM-1 therapy. Re-biopsy revealed that HER2 status had changed to negative in six (46%) patients (Negative group), and had remained positive in seven (54%) patients (Positive group). Patient characteristics are shown in table. Median TTF was 65.5 days (95% CI: 34-NA) in Negative group, 126 days (95%CI: 70-140) in Positive group, and 196 days (95%CI: 93-594) in all patients. Proportion of progressive disease (PD) was 83% (five in six patients) in Negative group, 43% (three in seven patients) in Positive group, and 39% (nine of 23 patients) in all patients. Patient characteristics All patients (23)Negative group (6)Positive group (7)Age at start T-DM1 (year) Median (rang)61 (38-80)63 (48-71)58 (38-78)ECOG PS 0-121 (91%)6 (100%)7 (100%)2-32 (9%)--ER and/or PgR positive13 (57%)5 (83%)4 (57%)ER and PgR negative10 (43%)1 (17%)3 (43%)Number of prior chemotherapy regimens for MBC Median (rang)2 (1-9)2 (1-9)2 (1-5)Prior Lapatinib10 (43%)2 (33%)4 (57%) Conclusions: In 46% of patients who received re-biopsy, HER2 status changed to negative. There was a trend that TTF was shorter and PD rate was higher in Negative group than in Positive group. We demonstrated that some of patients who experienced PD during T-DM1 therapy had HER2-negative MBC, and in these patients efficacy of T-DM1 was likely to be insufficient. In such a case that disease progression occurs in a few months of T-DM1 therapy, we have to consider whether its HER2 status remains positive or changes to negative. Citation Format: Yoshinami T, Hasegawa A, Fujisawa F, Kittaka N, Ishitobi M, Sugimoto N, Nakayama T, Toshinari Y, Tamaki Y, Imamura F. A retrospective study about re-biopsy at disease progression on T-DM1 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-24.

Abstract OT1-02-03: Phase I multicenter clinical trial evaluating the combination of trastuzumab emtansine (T-DM1) and non-pegylated liposomal doxorubicin (NPLD) in HER2-positive metastatic breast cancer (MBC) (MEDOPP038 study)

Abstract BACKGROUND: Clinical efficacy and safety of T-DM1 for the treatment of HER2-positive MBC has been assessed in several phase II and III trials and is now considered the standard of care in taxane-and trastuzumab-progressing patients. However, although T-DM1 has shown encouraging antitumor activity in the advanced setting, several strategies to improve T-DM1 efficacy are currently evaluated, including the combination with non-pegylated liposomal doxorubicin (NPLD), considering that: i) doxorubicin is one of the most active chemotherapeutic agents against HER2-positive breast cancer; ii) the combination of doxorubicin and trastuzumab induces synergistic antitumor activity in HER2-overexpressing preclinical models; and iii) liposomal formulations of doxorubicin have a reduced risk of developing cardiac toxicity. OBJECTIVES: The primary objective of this trial is to determine the maximum tolerated dose (MTD) of the combination of T-DM1 and NPLD in patients with HER2-positive MBC naïve of anthracyclines and previously treated with trastuzumab and a taxane. The secondary objectives include 1) safety, with special emphasis on cardiac safety evaluated by left ventricular ejection fraction, high-sensitivity troponin I and B-type natriuretic peptide (BNP) levels, 2) pharmacokinetics, 3) antitumor activity, and the 4) role of single nucleotide polymorphisms of HER2 gene for developing cardiotoxicity. TRIAL DESIGN: This is a dose-finding, open-label, non-randomized and multicenter phase I clinical trial of T-DM1 at a fixed dose of 3.6 mg/kg IV in combination with three different dose levels (DL) of NPLD (45, 50, and 60 mg/m2) IV administered on Day 1 every three weeks. The trial follows a modified dose escalation scheme with a 3+3 design.A total of three patients will be included in the first cohort and observed for dose-limiting toxicities (DLTs) during the first two cycles of treatment. If none of these patients experiences a DLT, three other patients will be treated at the next DL. However, in case of at least one patient experiences a DLT, three more patients will be treated at the same DL. The MTD will be defined as the highest DL at which ≤1 of six patients experiences a DLT during the first two cycles of treatment. An expansion cohort of six additional patients at the MTD will be included. ELIGIBILITY: Anthracycline-naïve patients with HER2-positive MBC and up to two prior chemotherapy regimens in the advanced setting who previously were treated with trastuzumab and a taxane. ECOG performance status of 0-1. Adequate organ and cardiovascular function with LVEF ≥ 55%. RECIST v1.1 evaluable disease. ACCRUAL: A total of 12-24 patients will be enrolled at four sites in Spain and France. Recruitment was opened on September 2015. To date, four patients (three at DL1 and one at DL2) have been recruited. Citation Format: López-Miranda E, Brain E, Saura C, Gligorov J, Dubot C, Dieras V, Suter TM, Aguirre E, Perez-García JM, Llombart A, Cortés J. Phase I multicenter clinical trial evaluating the combination of trastuzumab emtansine (T-DM1) and non-pegylated liposomal doxorubicin (NPLD) in HER2-positive metastatic breast cancer (MBC) (MEDOPP038 study) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-02-03.

Abstract P4-21-11: T-DM1 in HER2 positive advanced breast cancer patients: Real world practice from a multicenter observational study

Abstract Background: T-DM1 showed remarkable activity in metastatic HER-2 positive breast cancer (mBC) and it was recently approved for clinical use in patients (pts) who previously failed Trastuzumab- and Taxanes-based therapies. Currently, little is known on the performance of T-DM1 in a “real life” scenario. Therefore, we investigated effectiveness and safety of T-DM1 in Italian daily practice. Methods: Pts baseline characteristics and clinical outcome of pts with HER-2 positive mBC treated with T-DM1 between 2013 and 2015 at 20 Italian Institutions were retrospectively collected and analyzed. Results: 300 pts were included in our analysis. Median age was 51 years (27-78); visceral metastases were present in 204 (68%) pts and brain metastases in 86 (29%). It is noteworthy that 111 (37%) pts received T-DM1 as pure second line, 83 (28%) as third line and 96 (32%) as further lines. Moreover 10 (3%) pts had T-DM1 as first line because disease recurrence occurred during or adjuvant trastuzumab of within 6 months of its completion. The overall response rate (ORR) was 40%, global disease control rate (gDCR) 64%, median progression-free survival (PFS) 7.0 months (C.I.95%: 5.6-8.4) and overall survival (OS) at 2 years 63%. Pts with 1, 2 and 3 or more metastatic site had OS at 2 years of 87%, 67% and 46%, respectively (p&amp;lt;0.0001). When T-DM1 was given as second line the PFS was 8.0 months and beyond second-line was 6.8 months. Interestingly, for 38 (13%) pts who progressed after Pertuzumab-plus trastuzumab and taxanes as first line treatment, ORR and gDCR were similar to pertuzumab-naïve patients (38% and 62%, respectively) However PFS was 5.0 months (C.I.95%: 4.3-5.7) compared to 9.0 (95% C.I. 5.5-12.4) achieved in pts not receiving a previous pertuzumab-based treatment. Most frequent grade ≥3 toxicities were thrombocytopenia (2.6%), alopecia (2.1%), hypertransaminasemia (2.2%), neutropenia (1.3%), asthenia (1.3%) and diarrhea (0.4%). Conclusions: To our knowledge, this is the first real life, multicenter retrospective analysis evaluating efficacy and safety of T-DM1 in pretreated HER-2 positive mBC pts. We observed remarkable results in terms of PFS and OS, especially when T-DM1 was given early in the course of metastatic disease. Shortened PFS in patients progressing after pertuzumab suggest further analyses to better define possible molecular mechanisms of cross-resistences between two molecules. As a whole there was no evidence of significant or unexpected toxicities. Although these findings should be taken with caution due to the retrospective analysis and the different lines of previous treatment considered, we confirmed the potential therapeutic role of T-DM1 across a heterogeneous population of HER-2 positive mBC patients. The final analysis will be presented to the meeting. Citation Format: Fabi A, De Laurentiis M, Caruso M, Valle E, Moscetti L, Santini D, Cannita K, Carbognin L, Ciccarese M, Rossello R, Arpino G, Leonardi V, Montemurro F, La Verde N, Generali DG, Zambelli A, Scandurra G, Russillo M, Paris I, D'Ottavio AM, Filippelli G, Giampaglia M, Stani S, Fabbri A, Alesini D, Giannarelli D, Cognetti F. T-DM1 in HER2 positive advanced breast cancer patients: Real world practice from a multicenter observational study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-11.

T-DM1 Activity in Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancers That Received Prior Therapy With Trastuzumab and Pertuzumab.

Purpose Ado-trastuzumab emtansine (T-DM1) is currently approved for treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (MBC) who previously received trastuzumab and a taxane. However, there are no data on the activity of T-DM1 in patients who received prior pertuzumab, which is now included as standard first-line therapy. The goal of this study was to assess the efficacy of T-DM1 in routine clinical practice in a contemporary patient population that received both prior trastuzumab and pertuzumab. Patients and Methods We identified all patients with HER2-positive MBC who received T-DM1 after trastuzumab and pertuzumab between March 1, 2013, and July 15, 2015, via electronic pharmacy records and departmental databases at three institutions: MD Anderson Cancer Center, Smilow Cancer Hospital at Yale, and The James Cancer Hospital at the Ohio State University. We reviewed medical records of each case to confirm treatment sequencing and outcome. Results Of patients, 82 were identified and 78 were available for outcome analysis; 32% received T-DM1 as first- and second-line line therapy, and 48% received it as fourth-line treatment or later. Rate of prolonged duration on therapy, defined as duration on therapy ≥ 6 months, was 30.8% (95% CI, 20.6% to 41.1%), and tumor response rate was 17.9% (95% CI, 9.4% to 26.4%). Median duration on therapy was 4.0 months (95% CI, 2.7 to 5.1; range, 0 to 22.5 months). T-DM1 was discontinued for disease progression in 84% of patients and for toxicity in 10%. Conclusion Tumor response rates were lower than in prior reports of trastuzumab-resistant, HER2-positive MBC, but one third of patients received therapy with T-DM1 for ≥ 6 months, which suggests a clinically relevant benefit in patients who received prior pertuzumab.

F55 - Safety and efficacy of T-DM1 in HER2 positive metastatic breast cancer patients: a real word experience

F55 - Safety and efficacy of T-DM1 in HER2 positive metastatic breast cancer patients: a real word experience

F21 - Trastuzumab Emtansine (T-DM1) in Patients (pts) With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer (MBC): results From a Multicenter Retrospective Analysis

Background: T-DM1 improved outcomes in pts with HER2+ MBC, but few data concerning its use in routine clinical practice are available. Patients and methods: We retrospectively enrolled 194 HER2+ (IHC 3+ or 2+ amplified) MBC pts treated with T-DM1 in real-world practice in 20 Italian oncologic centers. Results: Baseline pts and tumors characteristics are listed in Table 1. Median (m) follow up was 9.8 months (mo) (range,2-37), m T-DM1 treatment duration was 5 mo (range, 1-30). Among 183 evaluable pts, 5.4% had a complete response and 35% a partial response, for an Overall Response Rate of 40% (95%CI, 33-47). A stable disease (SD) was recorded in 26.8% pts, with a clinical benefit (CB: response or SD lasting ≥ 6 mo) of 55% (95%CI, 47-62). No significant differences in responses have emerged according to disease sites. M Progression Free Survival (PFS) was 6 mo (95%CI, 5-7), m Overall Survival (OS) was 35 mo (95%CI, 11-59). Pts who have previously carried out ≤3 lines for MBC had improved PFS (p = 0.006). At multivariate analysis, factors related to PFS benefit were lower ECOG performance status (PS) (p < 0.0001) and HER2+ status at first diagnosis (p = 0.03), while OS benefit was related with lower ECOG PS (p = 0.01), absence of brain metastases (p = 0.08), other than ductal histology (p = 0.04) and CB (p < 0.0001). Central nervous system (CNS) progression occurred in 10.4% of the pts without CNS metastases, and in 29.1% of the pts with CNS metastases at baseline. Pts with CNS metastases at baseline have a m PFS similar to that observed in the general population, whereas m OS was shorter (16 mo, C.I. 95%, 12-21). Toxicity was manageable, with grade ≥3 adverse events reported in 5.6% of pts, most commonly thrombocytopenia and fatigue. Cardiac dysfunction was reported in 2 pts (1%). Conclusion: In this real-world setting of heterogeneous HER2+ MBC pts, efficacy of T-DM1 was comparable with that reported in phase II-III studies. No new safety issues were observed.Table: F21Main baseline characteristics of the study participants (N = 194)CharacteristicsN (%)AgeMedian (range)56 (34-82)HystologyDuctal173 (89.2)Lobular11 (5.7)Other10 (5.1)GradingG255 (28.4)G3124 (63.9)Unknown (Uk)15 (7.7)Metastatic at diagnosisYes47 (24.2)No147 (75.8)HER2+ at diagnosisYes157 (80.9)No25 (12.9)Uk12 (6.2)ECOG PS097 (50)163 (32.5)29 (4.6)31 (0.5)Uk24 (12.4)Previous regimen for MBC010 (5.2)140 (20.6)247 (24.2)≥397 (50) Open table in a new tab

Abstract CT042: Efficacy of T-DM1+pertuzumab over standard therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL

Abstract Background: Pathologic complete response (pCR) is an established prognostic biomarker for aggressive HER2+ breast cancer (BC). Improving pCR rates may identify new therapies that improve survival. T-DM1 and pertuzumab have established benefits in metastatic HER2+ BC. We tested their ability when combined, without paclitaxel, to improve pCR rates (ypT0ypN0) over standard therapy in the randomized, phase 2, I-SPY 2 neoadjuvant trial. Methods: Enrolled patients (pts) had invasive breast cancer ?2.5 cm in HER2-positive subsets. Pts were adaptively randomized to 12 wkly cycles of paclitaxel+trastuzumab (TH, control) or T-DM1+pertuzumab (T-DM1+P) without T, followed by doxorubicin/cyclophosphamide (AC) x 4 and surgery. We utilized all TH control pts accrued over the course of the trial, adjusting for potential differences due to time period treated, which were informed by the several other treatment arms that have been in the trial. Adaptive assignment to the various experimental arms in the trial was based on current Bayesian probabilities of superiority vs. control. “Graduation” by signature and futility stopping were based upon Bayesian predictive probability of success in a future 2-arm, N = 300 neoadjuvant Phase 3 randomized 1:1 trial of T-DM1+P vs. control with pCR endpoint. Results: T-DM1+P met the predictive probability criterion and graduated from I-SPY 2 in 3 signatures: all HER2+, HER2+/HR+, HER2+/HR- (Table 1). Final accrual: 52 T-DM1+P and 31 TH. Safety data will be shown. Conclusions: I-SPY 2's standing platform trial mechanism efficiently evaluates agents in biomarker-defined pt subsets. T-DM1+P (w/o T) -&amp;gt; AC substantially improves pCR rates over standard TH -&amp;gt; AC in all 3 HER2+ signatures, including HR+ and HR- subsets. These findings warrant further investigation of these agents without paclitaxel in a neoadjuvant trial powered for survival endpoints. Table 1Signature*Estimated pCR Rate (95% probability interval)Probability T-DM1+P Is Superior to Control**Predictive Probability of Success in Phase 3T-DM1+PControl (TH)HER2+52% (36%-68%)22% (5%-39%)99.5%94%HER2+/HR+46% (26%-66%)17% (0% - 34%)99.1%93%HER2+/HR-64% (39%-88%)33% (6%-59%)98%90%*HR = Hormone Receptor Citation Format: Angela M. DeMichele, Stacy Moulder, Meredith Buxton, Douglas Yee, Anne Wallace, Jo Chien, Claudine Isaacs, Kathy Albain, Judy Boughey, Kathleen Kemmer, Barbara Haley, Julie Lang, Henry Kaplan, Susan Minton, Andres Forero, Anthony Elias, Rita Nanda, Larissa Korde, Richard Schwab, Michelle Melisko, Ashish Sanil, Michael Hogarth, Nola Hylton, Melissa Paoloni, Fraser Symmans, Jane Perlmutter, Julia Lyandres, Christina Yau, Don Berry, Laura Esserman, I-SPY 2 TRIAL Investigators. Efficacy of T-DM1+pertuzumab over standard therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT042.

Abstract 4358: Neutralization of BCL2/XL enhances the cytotoxicity of T-DM1 in vivo

Abstract One of the most recent advances in the treatment of HER2+ breast cancer is the development of the antibody-drug conjugate, T-DM1, composed of trastuzumab (T) linked to the cytotoxic maytansinoid (DM1). T-DM1 has proven clinical benefits for patients with advanced and/or metastatic breast cancer who have progressed on prior HER2-targeted therapies. However, T-DM1 resistance ultimately occurs and represents a major obstacle in the effective treatment of this disease. We previously identified BCL2 upregulation as a critical component and biomarker of the adaptive response to inhibition of PI3K/mTOR or HER2, and thus examined whether BCL2/XL combinatorial strategies could improve the initial efficacy of T-DM1. Here, we demonstrate that combined inhibition of BCL2/XL plus T-DM1 significantly enhances the cytotoxicity of T-DM1 in vivo. The effectiveness of T-DM1 plus BCL2/XL inhibition was evaluated in two patient-derived xenograft (PDX) models of advanced HER2+ER- resistant disease (PDX8;PDX12). Animals were randomized into one of four groups: T-DM1, ABT-737, T-DM1 + ABT-737 or vehicles. Our initial results after a 14d treatment period indicate that combined treatment with T-DM1 and ABT-737, the dual BCL2/XL inhibitor, confers an exceptional tumor cell cytotoxic advantage characterized by widespread elimination of the tumor cells. To evaluate whether ABT-263, the clinically relevant BCL2/XL inhibitor, mimics ABT-737, we randomized animals into one of four groups: T-DM1, ABT-263, T-DM1 + ABT-263 or vehicles. To minimize thrombocytopenia that is induced by ABT-263, we included a fifth group that received pulsed treatment of ABT-263 + T-DM1. Notably, unlike continuous treatment, pulsed administration of ABT-263 reduced weight loss to vehicle levels and allowed recovery of platelets. Evaluation of pathological responses by H&amp;E staining indicated that T-DM1 + ABT-263 mimics T-DM1 + ABT-737. To better distinguish tumor cells from stromal elements, we used epithelial membrane antigen IHC to specifically visualize tumor cells and Trichrome stain to visualize stromal content and scored the tissue sections blindly. ABT-263 had no observable effect. T-DM1 induced a 38.75% and 20% average reduction in tumor cell content in the two PDX models, whereas the combined treatment caused a 74% and 54% average reduction after the 14d treatment period. The loss of tumor cell content was associated with an increased stromal reaction at the tumor bed. T-DM1 treated tumors contained 27.5% and 47.5% average stromal content, whereas combination treated tumors contained 86% and 85.6% average stromal content. Importantly, T-DM1 + pulsed ABT-263 elicited a similar response as continuous treatment in the PDX8 model, but was not as effective in PDX12. The dramatic improvement in tumor regression observed in these preclinical studies, together with the safety benefits of modified dosing of ABT-263, provides substantial rationale for the clinical investigation of this drug combination. Citation Format: Jason J. Zoeller, Roderick T. Bronson, Deepak Sampath, Joel Leverson, Joan S. Brugge. Neutralization of BCL2/XL enhances the cytotoxicity of T-DM1 in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4358.

Abstract 5187: PET imaging of trastuzumab emtansine (T-DM1) drug delivery to intracranial patient derived xenograft (PDX) models of breast cancer metastasis

Abstract Background: It is estimated that 10-30% of all breast cancer patients at some point develop brain metastases. Overexpression of the human epidermal growth factor receptor 2 (HER2) is a independent risk factor for development of brain metastases. Up to 37% of patients with HER2-positive metastatic breast cancer develop brain metastases and half of these patients die as a result of failure to control the intracranial disease. A reason for this is the challenge to obtain efficient drug delivery across the blood brain barrier (BBB). Subcutaneous patient derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, when targeting brain tumors or metastases, the major impact of the BBB on drug bioavailability must be taken into consideration. Clinical PET imaging with 64Cu or 89Zr labeled trastuzumab has previously been able to visualize breast cancer brain metastases. The aim of our study was to investigate if PET imaging with 64Cu-labeled trastuzumab was predictive of the efficacy of trastuzumab emtansine (T-DM1) in a HER2 positive breast cancer PDX model established as an intracranial brain metastases model. Methods: The intracranial PDX model was established by stereotactic intracranial injection of enzymatically digested ST1339 tumor tissue. At confirmed tumor take, mice were randomized into two arms: control and T-DM1 (10 mg/kg/week x4). Treatment response was monitored by contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) and positron emission tomography (PET) with the amino acid radiotracer O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). PET/CT imaging with 64Cu-trastuzumab was performed in animals with confirmed intracranial ST1339 tumors prior to treatment with T-DM1 (10 mg/kg/week x4). Results: T-DM1 treatment with 10 mg/kg/week x4 of mice with intracranial tumors inhibited tumor growth and prolonged survival compared to non-treated animals. A variable response within the treatment group was observed. Forty percent had tumor shrinkage while 60% exhibited tumor growth within the duration of the therapy. The intracranial tumors were clearly visible on the 64Cu-trastuzumab PET images co-registered with T2-weighted MR images for anatomical localization. Interestingly, the intracranial tumor uptake between the animals was rather heterogeneous. Conclusion: A treatment response to T-DM1 was observed in an intracranial ST1339 HER2 positive breast cancer PDX model. PET imaging with 64Cu-trastuzumab confirmed delivery of trastuzumab to the tumors. Further quantitative image analysis of the intracranial 64Cu-trastuzumab tumor uptake will reveal if the drug delivery measured by 64Cu-trastuzumab PET imaging is predictive of the efficacy of T-DM1 in a HER2 positive PDX breast cancer brain metastases model. Citation Format: Carsten Haagen Nielsen, Mette K. Nedergaard, Lotte K. Kristensen, Camilla S. Knudsen, Michael J. Wick, Kyri Papadopoulos, Anthony Tolcher, Andreas Kjaer. PET imaging of trastuzumab emtansine (T-DM1) drug delivery to intracranial patient derived xenograft (PDX) models of breast cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5187.

Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases.

Few data are currently available regarding the efficacy and safety of T-DM1 in breast cancer (BC) patients with unselected brain metastases (BM), since most clinical trials have excluded BM patients or have only included highly selected patients. HER2+BC patients with BM treated with T-DM1 in 5 French centers were included in this retrospective study. Clinical management was performed according to the product guidelines. Efficacy was evaluated recording tumor response rates, progression-free (PFS) and overall survival, treatment compliance, and safety. Thirty nine patients received T-DM1, among whom 82% presented with concomitant extra-cerebral disease. Median number of previous metastatic chemotherapy and HER2-directed targeted therapy regimens was 2 (range 0-8) and 1 (0-7), respectively. Thirty six patients had received BM loco-regional treatment (72% whole-brain radiation therapy). After a median follow-up of 8.1months (1.4-39.6), 24 patients had progressed (first site of progression: brain 14; meningeal 2; outside of the central nervous system 5; both intra- and extra-cerebral 3), 12 patients had died (disease progression), and 27 patients were still alive. Median number of T-DM1 cycles was 8 (1-43). There were 17 partial responses (44%) and 6 patients achieved disease stabilization (59% clinical benefit rate). Median PFS was 6.1months (95%CI 5.2-18.3), with one- and two-year PFS rates of 33 and 17%, respectively. Treatment was well tolerated, without unexpected toxicities, treatment delay, or dose reduction. In this retrospective study, T-DM1 appeared to be an effective and well-tolerated therapeutic option in unselected HER2+BC patients with BM. These findings require a prospective validation.

Hormone Receptor/Human Epidermal Growth Factor Receptor 2-positive breast cancer: Where we are now and where we are going.

Near 75% of all breast cancers (BC) express estrogen receptors (ER) and/or progesterone receptors (PgR), while up to 20% of BC show an overexpression/amplification of Human Epidermal Growth Factor Receptor 2 (HER2). Around 50% of all HER2-overexpressing BC show the coexistence of both HER2 overexpression/amplification and ER and/or PgR overexpression. Numerous in vitro and in vivo studies suggest the existence of a cross-talk between their downstream pathways, which seem to affect the natural history, response to therapy and outcome of patients affected by this subset of BC. Meta-analyses or subgroup analysis of numerous neo-/adjuvant trials demonstrated significant clinical implications deriving from ER/HER2 co-existence, consisting in a different pattern of relapse and dissimilar outcome in response to anti-HER2 therapy. However, only two randomized trials in early disease and three in advanced disease specifically addressed the issue whether a combined approach with both hormonal and anti-HER2 therapy would have a better therapeutic impact in this subset of BC compared to the lone anti-HER2 or hormonal therapies (HT). None of these trials demonstrated improvements in overall survival, even though several efficacy end-points such as progression free survival, in advanced setting, or pCR rates in neoadjuvant setting, often favored the combined hormonal and anti-HER2 therapeutic approach. In the next few years, a certain number of ongoing randomized trials, both in neoadjuvant and advanced setting, will evaluate the efficacy of new anti-HER2 drugs, T-DM1 and pertuzumab, in combination with HT, helping to improve the therapeutic strategy for this specific subtype of breast tumors.

Safety and Efficacy of Trastuzumab Emtansine in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: a Meta-analysis.

Advanced or metastatic breast cancer is an incurable disease with high mortality rate worldwide and about 20% of breast cancers overexpress and amplify the human epidermal growth factor receptor 2 (HER2). Achievements in targeted therapy have benefited people during the past decades. Trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate playing a powerful role in anti-tumor activity, not only blocks the HER2 signaling pathways, but also disturbs the microtubule dynamics. To access the efficacy and safety of T-DM1, we analyzed 9 clinical trials on T-DM1. Results showed that fatigue (0.604, 95% CI 0.551, 0.654), nausea (0.450, 95% CI 0.365, 0.537), increased transaminases (0.425, 95% CI 0.353, 0.500) and thrombocytopenia (0.383, 95% CI 0.322, 0.448) occurred more frequently in participants with single T-DM1. In controlled trials, increased transaminases (OR = 4.040, 95% CI 1.429, 11.427), thrombocytopenia (OR = 8.500, 95% CI 3.964, 18.226) and fatigue (OR = 1.288, 95% CI 1.041, 1.593) were statistically significant. Only thrombocytopenia appeared as severe adverse event (grade ≥ 3) in single-arm and control-arm studies. Meanwhile, T-DM1 stabilized cancer and prolonged life with notable improved progression-free survival (PFS) and overall survival (OS). In conclusion, it is a safe and effective agent in advanced or metastatic breast cancer, but should be carefully applied on patients with severe hepatic and neurological disease.

Abstract P6-17-03: Trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer and brain metastases

Abstract Purpose: Few data are currently available regarding the efficacy and safety of T-DM1 in breast cancer (BC) patients with brain metastases (BM), since clinical trials excluded these patients or included highly selected ones. We report here the experience of our institutions with the T-DM1 use in daily care practice BM BC patients. Patients and methods: HER2+ BC patients presenting with BM treated by T-DM1 in one of our institutions, using a standard dose of 3.6 mg per kilogram intravenously every 21 days, were considered in this retrospective study. Dose delays, reductions, and discontinuations due to toxic effects were performed according to the product guidelines. Treatment was continued until progression or unacceptable toxicity. We analyzed efficacy data by recording tumor response rates, progression-free survival (PFS) and overall survival (OS), treatment compliance (Relative Dose Intensity [RDI]) and safety by analyzing clinical and biological toxicities using NCI CTCAE v4.03. Results: 17 patients were treated between 2012 and 2015, with a median age of 52.8 years (range 35.2-68.8 years). 81.3% of the tumors were of the invasive ductal carcinoma subtype. No tumor was recorded to be Scarf, Bloom and Richardson grade I, 47.1% were estrogen receptor negative. 94% of the patients presented with concomitant extra-cerebral disease, mainly bone (71%), liver (47%), lymph node (47%) and lung (12%) metastases. The number of previous chemotherapy and trastuzumab regimens in the metastatic setting were 3 (1-7) and 2 (1-7) respectively. 15 out of the 17 patients previously received the capecitabine – lapatinib association. All patients previously received a locoregional treatment for their BM (whole brain radiation therapy in 88.2% of the cases). After a median follow-up of 4.3 months (95%IC 3.5 – 13.6), 9 patients presented a disease progression (first site of progression: brain 5; meningeal 2; outside of the CNS 2), 4 patients died due to progressive disease and 13 patients are still alive. The median number of T-DM1 cycles was 6 (range 1-27). There were 5 partial responses (29.4%), with an additional 35.3% disease stabilization, for a total 64.7% of patients with clinical benefit. Median PFS was 5.5 months (95%CI: 2 – Not Reached). Median OS was not reached at the moment of the present statistical analysis. There were no presumed treatment-related deaths. No dose reduction was required, the median RDI was 1. Treatment was well tolerated, without unexpected toxicities, treatment delay or dose reduction. Only one patient discontinued T-DM1 after 27 cycles due to bilirubin increase, while experiencing sustained disease stability. There were only one grade 3 toxicity (fatigue), and no reported grade 4 toxicities. Conclusion: In this limited population of unselected, heavily pretreated, patients affected by BM from HER2+ BC, T-DM1 appears to be a safe option, with clinical activity, even if it appears inferior to the ones reported in the pivotal trials. These results could be linked to the more advanced status of the population. A larger population, altogether with a longer follow-up appears mandatory to more accurately evaluate this agent in the BC BM. Thus this study will be updated for the meeting in term of number of patients and follow-up. Citation Format: Jacot W, Pons E, Guiu S, Levy C, Frenel J-S, Bachelot T, D'Hondt V, Firmin N, Romieu G, Thezenas S, Dalenc F. Trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer and brain metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-17-03.

Abstract P4-14-02: Neutralization of BCL2/BCL-XL enhances the cytotoxicity of T-DM1 in vivo

Abstract One of the most recent advances in the treatment of HER2+ breast cancer is the development of the antibody-drug conjugate, T-DM1, composed of trastuzumab (T) linked to the cytotoxic maytansinoid (DM1). T-DM1 has proven clinical benefits for patients with advanced and/or metastatic breast cancer who have progressed on prior HER2-targeted therapies. However, T-DM1 resistance ultimately occurs and represents a major obstacle in the effective treatment of this disease. We previously identified BCL2 upregulation as a critical component and biomarker of the adaptive response to inhibition of PI3K/mTOR or HER2, and thus examined whether BCL2/BCL-XL combinatorial strategies could improve the initial efficacy of T-DM1. Here, we demonstrate that combined inhibition of BCL2/BCL-XL proteins plus T-DM1 significantly enhances the cytotoxicity of T-DM1 in vivo. The effectiveness of T-DM1 plus BCL2/BCL-XL inhibition was evaluated in two patient-derived xenograft (PDX) models of advanced HER2+ER- resistant disease (PDX8 and PDX12). Animals were randomized into one of four treatment arms: T-DM1, ABT-737, T-DM1 + ABT-737 or vehicle controls. Our initial results after a 14d treatment period indicate that combined treatment with T-DM1 and ABT-737, the dual BCL2/BCL-XL inhibitor, confers an exceptional tumor cell cytotoxic advantage characterized by widespread elimination of the tumor cells. To evaluate whether ABT-263, the clinically relevant BCL2/BCL-XL inhibitor, mimics ABT-737, we randomized animals into one of four treatment arms: T-DM1 (administered weekly), ABT-263 (administered daily), T-DM1 + ABT-263 or vehicle controls. To minimize thrombocytopenia that is induced by ABT-263, we included a fifth treatment arm that received pulsed treatment of ABT-263 + T-DM1. Notably, unlike continuous treatment, pulsed administration of ABT-263 reduced weight loss to vehicle levels and allowed recovery of platelet counts. Evaluation of pathological responses by H&amp;E staining indicated that T-DM1 + ABT-263 mimics T-DM1 + ABT-737. To better distinguish tumor cells from stromal elements, we used epithelial membrane antigen immunostaining to specifically visualize tumor cells and Trichrome stain to visualize stromal content and scored the tissue sections blindly. ABT-263 had no observable effect. T-DM1 induced a 38.75% and 20% average reduction in tumor cell content in the two PDX models, whereas the combined treatment caused a 74% and 54% average reduction after the 14d treatment period. The loss of tumor cell content was associated with an increased stromal reaction at the tumor bed. T-DM1 treated tumors contained 27.5% and 47.5% average stromal content, whereas combination treated tumors contained 86% and 85.6% average stromal content. Importantly, T-DM1 + pulsed ABT-263 treatment elicited a similar response as continuous treatment in the PDX8 model, but was not as effective in PDX12. The dramatic improvement in tumor regression observed in these preclinical studies, together with the safety benefits of modified dosing of ABT-263, provides substantial rationale for the clinical investigation of this combination therapy. Furthermore, thorough investigation of treatments that combine anti-apoptotic drugs with tumor-targeted chemotherapeutics could have broad implications in other cancer types. Citation Format: Zoeller JJ, Bronson RT, Sampath D, Leverson J, Brugge JS. Neutralization of BCL2/BCL-XL enhances the cytotoxicity of T-DM1 in vivo. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-02.