Study Of Trastuzumab Emtansine Research Articles

Predicting Thrombocytopenia in Patients With Breast Cancer Treated With Ado-trastuzumab Emtansine

IntroductionThrombocytopenia is a common and potentially serious adverse event of ado-trastuzumab emtansine (T-DM1) use in patients with advanced breast cancer. However, the risk factors have been minimally explored. Our aim was to develop a clinical prediction model from the clinicopathologic data that would allow for quantification of the personalized risks of thrombocytopenia from T-DM1 usage. Materials and MethodsData from 3 clinical trials, EMILIA (a study of trastuzumab emtansine versus capecitabine + lapatinib in participants with HER2 [human epidermal growth factor receptor 2]-positive locally advanced or metastatic breast cancer), TH3RESA (a study of trastuzumab emtansine in comparison with treatment of physician's choice in participants with HER2-positive breast cancer who have received at least two prior regimens of HER2-directed therapy), and MARIANNE [a study of trastuzumab emtansine (T-DM1) plus pertuzumab/pertuzumab placebo versus trastuzumab (Herceptin) plus a taxane in participants with metastatic breast cancer], were pooled. Cox proportional hazard analysis was used to assess the association between the pretreatment clinicopathologic data and grade ≥ 3 thrombocytopenia occurring within the first 365 days of T-DM1 use. A multivariable clinical prediction model was developed using a backward elimination process. ResultsOf the 1620 participants, 141 (9%) had experienced grade ≥ 3 thrombocytopenia. On univariable analysis, the body mass index, race, presence of brain metastasis, platelet count, white blood cell count, and concomitant corticosteroid use were significantly associated with the occurrence of grade ≥ 3 thrombocytopenia (P < .05). The multivariable prediction model was optimally defined by race (Asian vs. non-Asian) and platelet count (100-220 vs. 220-300 vs. >300 × 109/L). A large discrimination between the prognostic subgroups was observed. The highest risk subgroup (Asian and platelet count of 100-220 cells ×109/L) had a 40% probability of grade ≥ 3 thrombocytopenia within the first 365 days of T-DM1 therapy compared with 2% for the lowest risk subgroup (non-Asian and platelet count > 300 × 109/L). ConclusionA clinical prediction model, defined by race and pretreatment platelet count, was able to discriminate subgroups with a significantly different risk of grade ≥ 3 thrombocytopenia after T-DM1 initiation. The model allows for improved interpretation of the personalized risks and risk/benefit ratio of T-DM1.

Abstract P6-17-26: Care 001: multi-center randomized open-label phase II trial of neoadjuvant trastuzumab emtansine (T-DM1) in combination with lapatinib and nab-paclitaxel compared with paclitaxel, trastuzumab and pertuzumab in HER2-neu over-expressed breast cancer patients (TEAL study)

Abstract Background: We conducted a multicenter, randomized open-label phase II neoadjuvant study of trastuzumab-emtansine (T-DM1), Lapatinib (L) and Nab Paclitaxel (Nab-P) compared to standard of care (SOC) Paclitaxel (Pac), Trastuzumab (T), and Pertuzumab (P) in patients with HER2 over-expressed breast cancer. Methods: Patients in the experimental arm received a biologic window of targeted therapies alone for 6 weeks (T-DM1 and L) followed by T-DM1 3.0 mg/kg Q3W, L 750mg oral daily and Nab-P 80 mg/m2 weekly (QW) X 12 weeks. Patients in SOC arm received targeted therapies alone for 6 weeks (T and P) followed by Pac 80mg/m2QW, T 2mg/kg QW, and P 420mg Q3W X 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or 1. Key secondary objectives included correlative assessments of PIK3CA mutations, PTEN expression, and HER2 subtypes which are being reported. Results: Thirty of the 33 enrolled patients were evaluable. Patient demographics were well balanced. HER2 subtypes and altered PIK3CA (low PTEN or PIK3CA mutations) pathway were not statistically different between both arms. We have previously reported that all patients achieved RCB 0 &amp; I in the T-DM1, L and Nab-P arm, compared to SOC (100% vs. 62.5%, p 0.0035). In the SOC arm, the 6 week change in tumor size on breast MRI during targeted biologic window treatment is significantly different between the responders and non-responders based on two-sided Wilcoxon rank-sum test (p =0.0065). Consistent with literature, among ER positive patients treated with SOC, PTEN low expressers were less likely to respond (0%, 0 of 2) than PTEN high expressers (67%, 2 of 3). In the experimental arm, all patients responded regardless of PTEN. There was only 1 PIK3CA mutation on the experimental arm where all responded. Table 1:Breast MRI Tumor Size Standard of Care ArmResponseNMeanStandard Deviation95% CL MeanMinimumMaximumNo6-0.13330.4457-0.60110.3344-1.00.3Yes52.58001.88330.24154.91850.24.9Sixteen patients total were present in standard of care arm but 5 had incomplete imaging data. Conclusions: TDM1 plus L and Nab-P therapy was well tolerated with noteworthy responses in all patients, including in PTEN low expressers. Change in tumor size at 6 weeks of biologic therapies was significant between responders and non-responders and can be evaluated as a surrogate for future studies. Citation Format: Creamer SL, Patel TA, Ensor JE, Rodriguez AA, Niravath PA, Darcourt JG, Kaklamani VG, Meisel JL, Li X, Zhao J, Kuhn JG, Rosato RR, Qian W, Belcheva A, Boone T, Chang J. Care 001: multi-center randomized open-label phase II trial of neoadjuvant trastuzumab emtansine (T-DM1) in combination with lapatinib and nab-paclitaxel compared with paclitaxel, trastuzumab and pertuzumab in HER2-neu over-expressed breast cancer patients (TEAL study) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-26.

Care 001: Multicenter randomized open label phase II trial of neoadjuvant trastuzumabemtansine (T-DM1) in combination with lapatinib and nab-paclitaxel compared with paclitaxel, trastuzumab and pertuzumab in HER 2 neu over-expressed breast cancer patients (TEAL study).

581Background: Based on data from our phase I study of trastuzumab-emtansine (T-DM1), Lapatinib (L) and Nab Paclitaxel (Nab-P), a multicenter randomized open label phase II neoadjuvant study was co...

Phase ib study of trastuzumab emtansine (TDM1) in combination with lapatinib and nab-paclitaxel in metastatic HER2-neu overexpressed breast cancer patients: Stela results.

1035Background: Based on our preclinical data, we conducted a phase I study oftrastuzumab-emtansine (T-DM1) in combination with Lapatinib and Nab-paclitaxel in patients with HER2 over-expressed sta...

Abstract OT3-01-10: A prospective, open-label, single-arm, multi-center, phase II exploratory study to evaluate the efficacy and safety of poziotinib (NOV120101) in patients with HER2-positive metastatic breast cancer who have received at least two prior HER2-directed regimens

Abstract Background: Poziotinib is a novel, oral, irreversible pan-HER inhibitor that has shown promising clinical activity in Phase 1 studies of patients (pts) with advance HER2 positive breast cancer who have failed at least 2 prior lines of HER2-directed therapy. A Phase 2 study of poziotinib was initiated in Korea in March 2015 in pts with HER2+ metastatic breast cancer. This phase 2 study is designed to seek accelerated approval for poziotinib for the treatment of metastatic breast cancer in Korea. Trial Design: Prospective Phase 2, open-label, single-arm, multi-center study in pts with recurrent, Stage IV breast cancer with HER2-overexpression who had received at least 2 prior HER2-directed regimens Eligibility Criteria: Histologically confirmed breast cancer patients, at least 19 years of age, with confirmed HER2 positive evaluable tumors (per RECIST, 1.1) who have adequate hematologic, renal, and hepatic function and have failed at least two HER2-directed regimens that included a taxane-containing anticancer chemotherapy, with a life expectancy of at least 12 weeks. Specific Aims: The Primary Efficacy Endpoint of the study was Progression-Free Survival (PFS). The Secondary Efficacy Endpoints included: PFS rate at 12 weeks post-dose; Objective Response Rate (ORR) including Complete Response (CR) and Partial Response (PR) rates; Disease Control Rate (DCR) including CR, PR, and Stable Disease (SD); Duration of Disease Control; Overall Survival (OS); Time to Progression (TTP); Time to Objective Response and Duration of Objective Response. The Exploratory Endpoints included: Population Pharmacokinetic (PK) Profile and Exploratory Genomic and Biomarker Analyses. Statistical Methods: In the randomized, multicenter, 2-arm, open-label study of trastuzumab emtansine (TH3RESA18), the median PFS was shown to be 3.3 months in subjects with optimal treatment per Investigator's Choice. This ongoing study with poziotinib expects a median PFS of 4.5 months based on data from a previous Phase 1 study of poziotinib (NOV120101). Based on the following assumptions, a 5% one-sided significance level, and 80% power, and 2 months of accrual and 12 months of follow-up, 66 subjects will be required. Accounting for a 10% drop-out rate, a total of 74 subjects will be recruited into this ongoing Phase 2 study. Present Accrual and Target Accrual: 17 patients enrolled as of May 20, 2015 with a total target enrollment of 74 patients Contact information: ClinicalTrials.gov Identifier: NCT02418689. Citation Format: Park Y-H, Jung KH, Sohn JH, Lee KS, Lee KH, Kim J-H, Kim J-Y, Jung J, Han H, Park W-Y, Im S-A. A prospective, open-label, single-arm, multi-center, phase II exploratory study to evaluate the efficacy and safety of poziotinib (NOV120101) in patients with HER2-positive metastatic breast cancer who have received at least two prior HER2-directed regimens. [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 OT3-01-10.

A randomized, open-label, multicenter, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1) versus a taxane (TAX) in patients (pts) with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (LA/MGC/GEJC).

5 Background: Trastuzumab (H) + capecitabine/fluorouracil + cisplatin is standard of care for 1st-line HER2-positive MGC/GEJC but there is no established HER2-targeted 2nd-line regimen. T-DM1 (H linked to DM1) is approved for HER2-positive metastatic breast cancer previously treated with H + TAX (separately or in combination). This and preclinical HER2-positive GC models provided the rationale for GATSBY (NCT01641939). Methods: GATSBY is a 3-arm randomized, adaptive, seamless phase 2/3 global study of T-DM1 vs TAX in pts with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization-positive), unresectable LA/MGC/GEJC who progressed during or after 1st-line fluoropyrimidine + platinum ± HER2-targeted therapy. Pts were initially randomized 2:2:1 to T-DM1 3.6 mg/kg every 3 weeks (q3w), T-DM1 2.4 mg/kg weekly (qw), or physician’s choice of paclitaxel 80 mg/m2 qw or docetaxel 75 mg/m2q3w. An independent data monitoring committee selected T-DM1 qw for further study and subsequent patients were randomized 2:1 to this or TAX. The primary endpoint is overall survival (OS); all T-DM1 qw data are analyzed, including dose selection. Results: At clinical cutoff, 06/30/15, 415 pts had been randomized overall: 228 to T-DM1 qw, 117 to TAX (70 T-DM1 q3w pts reported separately); 77.4% had prior HER2-targeted therapy; 29.9% prior gastrectomy; 46.1% were Asian. Efficacy/safety are tabulated. Conclusions: T-DM1 2.4 mg/kg qw did not show an efficacy benefit over TAX. Grade ≥3 AE rates were numerically lower with T-DM1 vs TAX and rates of SAEs, fatal AEs, and treatment discontinuations due to AEs were comparable between arms. Clinical trial information: NCT01641939. [Table: see text]

Abstract P4-15-09: Phase 1 study of trastuzumab emtansine in HER2-positive metastatic breast cancer patients with normal or reduced hepatic function

Abstract Introduction Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab, a stable linker, and the microtubule inhibitor DM1. In phase 3 studies of HER2-positive metastatic breast cancer (MBC), T-DM1 significantly increased progression-free survival (EMILIA and TH3RESA) and overall survival (EMILIA) vs. control regimens. Few patients (2–4%) treated with T-DM1 experience grade ≥3 increases in transaminases. Currently, there are no data on the pharmacokinetics (PK) of T-DM1 in patients with hepatic impairment. This international, multicenter, open-label, parallel group, phase 1 PK study (BO25499/NCT01513083) is designed to assess the PK of T-DM1 and relevant analytes in MBC patients with normal hepatic function and mild or moderate hepatic impairment; safety and efficacy will also be evaluated. Methods To obtain 8 evaluable patients, up to 10 patients each with HER2-positive MBC and ECOG performance status of 0–2 were enrolled in 1 of 3 independent cohorts based on hepatic function per Child-Pugh criteria: normal hepatic function, mild hepatic impairment (Child-Pugh A), and moderate hepatic impairment (Child-Pugh B). Patients with severe hepatic impairment (Child Pugh C) were ineligible. Patients received 3 cycles of T-DM1 3.6 mg/kg every 3 weeks. After 3 cycles, patients could continue to receive T-DM1 until disease progression, unmanageable toxicity, or study termination in the present study, or enroll in an extension study (BO25430/TDM4529g). PK samples were collected during cycle 1 (days 1 [predose, 30 m and 4 h postinfusion], 2, 3, 4, 8, 11, 15, and 18); cycle 2 (day 1 [predose, 30 m postinfusion]); and cycle 3 (days 1 [predose, 30 m postinfusion], 8, 15, and 22). T-DM1, total trastuzumab, DM1, MCC-DM1, and Lys-MCC-DM1 were measured using validated assays. Adverse events were graded per NCI CTCAE, v4.03. All analyses are descriptive. The clinical cutoff date for this interim analysis was January 30, 2014. Results PK data were fully evaluable for 10 out of 10 patients each in the normal and mild cohorts and for 6 out of 7 patients in the moderate cohort. Compared with the normal cohort, T-DM1 clearance at cycle 1 was ∼1.9- and 3.3-fold faster in the mild and moderate cohorts, respectively. The trend of faster clearance was less apparent for cycle 3 after repeated dosing, with similar T-DM1 exposures across the 3 cohorts. Plasma concentrations of DM1 and DM1-containing catabolites were largely comparable across the 3 cohorts. No new safety signals were seen relative to the known safety profile of T-DM1. Updated safety data will be presented. Conclusions There is a trend for faster clearance of T-DM1 at cycle 1 in patients with mild and moderate hepatic impairment vs. those with normal hepatic function, which can be partly explained by demographic and pathophysiological covariates such as tumor burden, albumin, and body weight. The study’s small sample size could also partly explain the variability. Work to better understand the mechanisms for the observed differences in clearance is ongoing. No increase in the systemic concentration of DM1 was observed in patients with mild or moderate hepatic impairment vs. those with normal hepatic function. No additional safety concerns were observed. Citation Format: Chunze Li, Priya Agarwal, Susan Dent, Anthony Goncalves, Joo-Hee Yi, Alexander Strasak, Marjorie Green, Sandhya Girish, Pat LoRusso. Phase 1 study of trastuzumab emtansine in HER2-positive metastatic breast cancer patients with normal or reduced hepatic function [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-09.

HER2異常等の低頻度の分子異常を有する非小細胞肺癌の臨床病理学的特徴を明らかにするための前向き観察研究（HER2-CS Study）と標準化学療法後再発・増悪または標準化学療法不応性のHER2陽性非小細胞肺癌患者を対象としたトラスツズマブエムタンシン（遺伝子組換え）の第2相試験

HER2異常等の低頻度の分子異常を有する非小細胞肺癌の臨床病理学的特徴を明らかにするための前向き観察研究（HER2-CS Study）と標準化学療法後再発・増悪または標準化学療法不応性のHER2陽性非小細胞肺癌患者を対象としたトラスツズマブエムタンシン（遺伝子組換え）の第2相試験

Patient-reported outcomes (PROs) from TH3RESA, a phase 3 study of trastuzumab emtansine (T-DM1) versus treatment of physician’s choice (TPC) in patients with pretreated HER2-positive advanced breast cancer.

153 Background: Progression-free survival and objective response rate were significantly improved with T-DM1 vs TPC in TH3RESA. The impact of treatment on quality of life is a key aspect in determining treatment value. Here we present the PRO results from the TH3RESA study. Methods: Patients were randomized 2:1 to T-DM1 (3.6 mg/kg every 21 days) or TPC. Patients were asked to complete the EORTC QLQ-C30 (a 30-item questionnaire assessing symptom bother, functioning and health status) and the EORTC QLQ-BM22 (a 22-item survey evaluating pain from bone metastases) at the start of each cycle. Data from patients with a baseline and ≥1 post-baseline assessment were included; a clinically meaningful difference was defined as ≥10 points. Time to pain progression (TPP) was assessed using the Kaplan-Meier method and Cox proportional-hazards models. Results: A greater proportion of patients in the T-DM1 arm (n=297) vs. the TPC arm (n=117) experienced a clinically meaningful improvement in global health status (57.8% [95% CI; 52.0–63.3] vs. 47.1% [95% CI; 38.4–56.4]). The most bothersome symptoms in the T-DM1 arm as measured by the EORTC QLQ-C30 were fatigue and pain. Over the first 10 T-DM1 treatment cycles, 19–30% of patients reported being impacted “quite a bit” or “very much” by fatigue, and 16–25% by pain. Nausea/vomiting and diarrhea were perceived as more tolerable, with 1–5% and 1–4% of patients reporting “quite a bit” or “very much” impact, respectively. TTP was 2.9 months in the T-DM1 arm vs 3.6 months in the TPC arm, but was not significantly different (HR 1.12 [95% CI; 0.82–1.52], p = 0.495). Mean baseline EORTC QLQ-BM22 pain scores were similar in the T-DM1 (n = 306) and TPC arms (n = 130); (25.4 ± 23.8 [SD]) and (27.3 ± 24.4), respectively. There were no clinically meaningful changes in pain levels from baseline over time in either arm. Conclusions: For patients on T-DM1, the most impactful symptoms were fatigue and pain, while the least bothersome were diarrhea and nausea/vomiting; distribution of severity of impact was relatively stable over the first 10 cycles of treatment. TPP was similar between the T-DM1 and TPC arms. Clinical trial information: NCT01419197.

Relationship between tumor biomarkers (BM) and efficacy in TH3RESA, a phase 3 study of trastuzumab emtansine (T-DM1) versus treatment of physician’s choice (TPC) in HER2-positive advanced breast cancer (BC) previously treated with trastuzumab and lapatinib.

605 Background: T-DM1, an antibody–drug conjugate comprising trastuzumab, DM1 (microtubule inhibitor), and a stable linker, is approved for patients (pts) with HER2-positive metastatic BC previousl...

Abstract P4-12-09: Results from a phase 2a study of trastuzumab emtansine, paclitaxel, and pertuzumab in patients with HER2-positive metastatic breast cancer

Abstract Introduction The antibody-drug conjugate trastuzumab emtansine (T-DM1) combines the antitumor properties of trastuzumab (H) with the cytotoxic agent DM1 via a stable linker. T-DM1 prolonged PFS and OS vs standard therapy in a phase 3 study of patients (pts) with HER2-positive metastatic breast cancer (MBC) previously treated with H and a taxane. Preclinical data suggest synergy when T-DM1 is combined with paclitaxel (T) or pertuzumab (P). In the phase 1b study TDM4652g, the maximum tolerated doses of T-DM1 + T ± P were defined. Here we present results from the phase 2a expansion, which further explored feasibility and safety. Methods TDM4652g is a phase 1b/2a open-label study of pts with HER2-positive locally advanced or MBC. Pts had no prior T-DM1 or P, no baseline peripheral neuropathy (PN; phase 2a only), and had LVEF ≥50%. Pts in phase 2a were randomized to T-DM1 3.6 mg/kg q3w + T 80 mg/m2 qw ± P 840 mg loading dose [LD], then 420 mg q3w. The primary objective, feasibility, was assessed by the percent of evaluable pts receiving ≥12 doses of T within 15 weeks of cycle 1, day 1, and those receiving 12 consecutive weeks of T. Results Forty-four pts were enrolled (T-DM1 + T, n = 22; T-DM1 + T + P, n = 22); the data snapshot date was May 23, 2013. Median age was 52.5 years (range, 35–81); median number of prior agents for MBC was 6 (range, 0–12). 43 (98%) pts had previously received H, and 36 (82%) pts had received taxane therapy. Median dose intensities were T-DM1, 94% (range 54–105); T, 50% (range 9–100) and P, 100% (range 67–100). 2 pts were not evaluable for feasibility (progressive disease [PD] before receiving 12 doses of T). 21/42 (50%) pts received ≥12 doses of T within 15 weeks; 6/42 (14%) pts received 12 consecutive doses by week 12, and 33/42 (79%) pts received ≥8 doses within 12 weeks. Grade 3/4 adverse events (AEs) were reported for 18 (82%) and 17 (77%) pts in the T-DM1 + T and T-DM1 + T + P groups, respectively (see Table for AEs and best responses). Ten pts discontinued early due to PD (n = 6), PD-related death (n = 2), AEs (n = 1), or withdrawal from the study (n = 1). 21 pts discontinued T due to AEs, most commonly PN (n = 12). Grade 3/4 AEs occurring in &amp;gt;1 patientAE, n (%)All patients (N = 44)TDM1 3.6 mg/kg q3w + T 80 mg/m2 qw (n = 22)TDM1 3.6 mg/kg q3w + T 80 mg/m2 qw + P 840 mg LD, 420 mg q3w (n = 22)Neutropenia10 (23)6 (27)4 (18)Peripheral neuropathy9 (20)3 (14)6 (27)Fatigue6 (14)3 (14)3 (14)Thrombocytopenia6 (14)5 (23)1 (5)Anemia3 (7)2 (9)1 (5)Abdominal pain2 (5)2 (9)0Decreased hemoglobin2 (5)1 (5)1 (5)Muscosal inflammation2 (5)1 (5)1 (5)Muscular weakness2 (5)02 (9)Nausea2 (5)1 (5)1 (5)Best response,* n (%)CR2 (5)1 (5)1 (5)CR confirmed1 (2)1 (5)0PR27 (61)13 (59)14 (64)PR confirmed8 (18)3 (14)5 (23)SD10 (23)6 (27)4 (18)PD3 (7)1 (5)2 (9)*At any time point with responses ordered CR&amp;gt;PR&amp;gt;SD&amp;gt;PD. Conclusions Overall, 50% of pts received ≥12 doses of T within 15 weeks. Adding P to the combination of T-DM1 + T did not appear to increase the incidence of grade 3/4 AEs. Data support further investigation of T-DM1 + T ± P in larger studies in early breast cancer. Final data from all phase 2a patients will be available for the full report. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-09.

Patient‐reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T‐DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2–positive locally advanced or metastatic breast cancer

This report describes the results of an analysis of patient-reported outcomes from EMILIA (TDM4370g/BO21977), a randomized phase 3 study of the antibody-drug conjugate trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer. A secondary endpoint of the EMILIA study was time to symptom worsening (time from randomization to the first documentation of a ≥ 5-point decrease from baseline) as measured by the Trial Outcome Index Physical/Functional/Breast (TOI-PFB) subset of the Functional Assessment of Cancer Therapy-Breast questionnaire. Predefined exploratory patient-reported outcome endpoints included proportion of patients with a clinically significant improvement in symptoms (per TOI-PFB) and proportion of patients with diarrhea symptoms (per Diarrhea Assessment Scale). In the T-DM1 arm, 450 of 495 patients had a baseline and ≥ 1 postbaseline TOI-PFB score versus 445 of 496 patients in the capecitabine-plus-lapatinib arm. Time to symptom worsening was delayed in the T-DM1 arm versus the capecitabine-plus-lapatinib arm (7.1 months versus 4.6 months, respectively; hazard ratio = 0.796; P = .0121). In the T-DM1 arm, 55.3% of patients developed clinically significant improvement in symptoms from baseline versus 49.4% in the capecitabine-plus-lapatinib arm (P = .0842). Although similar at baseline, the number of patients reporting diarrhea symptoms increased 1.5- to 2-fold during treatment with capecitabine and lapatinib but remained near baseline levels in the T-DM1 arm. Together with the EMILIA primary data, these results support the concept that T-DM1 has greater efficacy and tolerability than capecitabine plus lapatinib, which may translate into improvements in health-related quality of life.

SY3–5 - A Phase 2 Study of Trastuzumab Emtansine in Japanese Patients with HER2 Positive Metastatic Breast Cancer

SY3–5 - A Phase 2 Study of Trastuzumab Emtansine in Japanese Patients with HER2 Positive Metastatic Breast Cancer

Abstract P5-18-05: Interim Results from a Phase 1b/2a Study of Trastuzumab Emtansine and Docetaxel, With and Without Pertuzumab, in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer

Abstract Introduction: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab, a stable linker, and DM1 (a microtubule inhibitor). In 2 randomized trials in patients (pts) with HER2-positive metastatic breast cancer (MBC), T-DM1 significantly prolonged progression-free survival (PFS) compared with standard therapy (Hurvitz, ESMO 2011; Blackwell, ASCO 2012). The combination of T-DM1 and docetaxel (D) or pertuzumab (P) has shown enhanced antitumor activity in preclinical models of HER2-positive BC (Lewis Phillips, AACR 2008; Fields, AACR 2010). Methods: This phase 1b/2a dose-escalation study examines the safety, tolerability, efficacy, and pharmacokinetics (PK) of T-DM1 (starting dose 2.4 mg/kg every 3 weeks [q3w]) combined with D (starting dose 75 mg/m2 q3w) in pts with MBC, and T-DM1 with D±P (840 mg loading dose, then 420 mg q3w) in pts with newly diagnosed locally advanced BC (LABC; clinical stage IIa-IIIc). The maximum tolerated dose (MTD) for T-DM1+D is established in pts with MBC and used as the starting dose for feasibility of T-DM1+D±P (up to 6 cycles) in pts with LABC. Eligibility criteria include HER2-positive MBC (locally assessed) or LABC (centrally confirmed). This interim report includes data from pts who completed at least 1 treatment cycle in phase 1b. Results: During MBC feasibility, 21 pts were enrolled; median age was 47.0 years (yr; range, 33–70); median number of prior lines of MBC therapy was 2 (range, 0–10). Four pts experienced 6 DLTs (Table 1). The MTD was T-DM1 3.6 mg/kg q3w + D 60 mg/m2 q3w. Common grade (G) 3/4 adverse events (AEs): neutropenia (81%), leukopenia (52%), and thrombocytopenia (29%). ORR was 76.2% (16/21); median PFS was 11.8 months (range, 1.6–26.9). In LABC feasibility, 18 pts were enrolled; median age was 49.5 yr (range, 34–74). Four pts experienced 4 DLTs (Table 2). The MTD for T-DM1+D was 3.6 mg/kg q3w + 75 mg/m2 q3w; MTD for T-DM1+D+P was 3.6 mg/kg q3w + 75 mg/m2 q3w + 840 mg (with G-CSF primary prophylaxis). Common G3/4 AEs: T-DM1+D, neutropenia (2/9; 22%), increased alanine aminotransferase (ALT; 2/9; 22%), thrombocytopenia (TCP; 1/9; 11%); T-DM1+D+P, neutropenia (5/9; 56%), TCP (2/9; 22%), increased ALT (2/9; 22%), and cytolytic hepatitis (1/9; 11%). With 9 pts enrolled in the T-DM1+D LABC cohorts and 8 pts currently evaluable, pCR rate (ypT0N0) is 87.5%. Conclusions: Full-dose T-DM1 can be safely combined with D in pts with MBC, and with D±P in pts with LABC. G-CSF is needed with higher doses of D. Pathological assessment for all LABC patients and PK analyses will be available for the full presentation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-05.

Abstract P5-18-11: Pharmacokinetics and exposure-efficacy relationship of trastuzumab emtansine in EMILIA, a phase 3 study of trastuzumab emtansine vs capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer

Abstract Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab (T), the cytotoxic agent DM1, and a stable thioether linker; it is being evaluated for the treatment (tx) of HER2-positive cancer. EMILIA is a randomized, multicenter, open-label phase 3 study assessing the efficacy and safety of T-DM1 vs capecitabine (X) and lapatinib (L) in pts with HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with T and a taxane. We report the pharmacokinetics (PK) of T-DM1 in EMILIA and compare these data with historical data of single-agent T-DM1. The effects of T-DM1 exposure on efficacy outcomes in EMILIA are also reported. Methods: In EMILIA, pts were randomized 1:1 to receive T-DM1 3.6 mg/kg q3w (n = 495) or X + L (n = 496) in 21-day cycles. At least 1 PK sample was collected from 350 pts in the T-DM1 arm; 307 of these had adequate PK profiles for the estimation of ≥1 PK parameter in cycle 1. PK parameters were estimated by noncompartmental analysis for serum T-DM1, serum total T (conjugated and unconjugated T), and plasma DM1. A logistic regression model was used to evaluate the relationship between T-DM1 exposure (ie, T-DM1 AUC and DM1 Cmax) and objective response rates (ORR). Analyses of progression-free survival (PFS) and overall survival (OS), stratified by T-DM1 exposure, were conducted. Cox regression was used to evaluate the effect of T-DM1 exposure and other potential covariates on PFS and OS. Results: The PK parameters for T-DM1, total T, and DM1 in EMILIA and other studies of single-agent T-DM1 are summarized in Table 1. The PK parameters appear similar regardless of prior tx for MBC. No significant differences in mean serum T-DM1 AUC (P = 0.091) or plasma DM1 Cmax (P = 0.812) were observed between responders and non-responders following T-DM1 tx. Furthermore, variability in T-DM1 AUC and DM1 Cmax does not appear to affect the probability of response to therapy (P = 0.23 for T-DM1 AUC and P = 0.74 for DM1 Cmax). Based on Cox proportional hazards analysis, no significant exposure-efficacy relationship was observed between T-DM1 AUC (P = 0.23 for PFS and p = 0.53 for OS) or DM1 Cmax (P = 0.96 for PFS and P = 0.34 for OS) and PFS or OS, respectively. Conclusions: T-DM1 PK data in EMILIA pts were similar to those observed in previous phase 2 studies, which include pts who have and have not received prior therapy for MBC. Variation in T-DM1 exposure among pts who received T-DM1 3.6 mg/kg q3w had no significant impact on ORR, PFS, or OS. Detailed analyses will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-11.

Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane.

98 Background: T-DM1 is an antibody-drug conjugate comprising T, a stable linker, and the potent cytotoxic agent DM1; it incorporates the antitumor activities of T and the HER2-targeted delivery of DM1. Methods: EMILIA is a randomized study of T-DM1 vs XL, the only approved combination for T-refractory HER2+ MBC. Patients (pts) received T-DM1 (3.6 mg/kg IV q3w) or X (1,000 mg/m2PO bid, days 1–14 q3w) + L (1,250 mg PO daily) until progressive disease (PD) or unmanageable toxicity. Pts had confirmed HER2+ MBC (IHC3+ and/or FISH+), and prior therapy with T and a taxane. Primary end points were PFS by independent review, OS and safety. An interim OS analysis was planned at the time of the final PFS analysis. Results: 991 pts were enrolled; 978 received treatment. Median (med) durations of follow-up were 12.9 (T-DM1) and 12.4 (XL) months (mo). Baseline demographics, prior therapy and disease characteristics were balanced. There was a significant improvement in PFS favoring T-DM1 (med 9.6 vs 6.4 mo; HR=0.650 [95% CI, 0.549–0.771]; p &lt; .0001). The med T-DM1 OS was not reached vs 23.3 mo (HR=0.621 [95% CI, 0.475–0.813]; p =.0005); the interim efficacy boundary was not crossed (HR= 0.617; p =.0003). T-DM1 was well tolerated with no unexpected safety signals. The most common Grade ≥3 adverse events (AEs) per treatment were for T-DM1: thrombocytopenia (12.9% vs 0.2%), increased AST (4.3% vs 0.8%), and increased ALT (2.9% vs 1.4%); for XL: diarrhea (20.7% vs 1.6%), palmar plantar erythrodysesthesia (16.4% vs 0) and vomiting (4.5% vs 0.8%). The table lists other end points. Conclusions: T-DM1 conferred a significant and clinically meaningful improvement in PFS compared with XL. Other end points support T-DM1 as an active and well-tolerated novel therapy for HER2+ advanced BC. [Table: see text]

LBA12 - Results from Emilia, A Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine (X) and Lapatinib (L) in Her2-Positive Locally Advanced or Metastatic Breast Cancer (MBC)

LBA12 - Results from Emilia, A Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine (X) and Lapatinib (L) in Her2-Positive Locally Advanced or Metastatic Breast Cancer (MBC)

Cardiac safety in a phase II study of trastuzumab emtansine (T-DM1) following anthracycline-based chemotherapy as adjuvant or neoadjuvant therapy for early-stage HER2-positive breast cancer.

532 Background: T-DM1 has demonstrated clinical activity as a single agent in patients (pts) with previously untreated MBC. In a previous phase II randomized trial of T-DM1 vs trastuzumab + docetaxel, T-DM1 had no clinically significant cardiac events, no cases of post-baseline left ventricular ejection fraction (LVEF) ≤40%, and fewer grade ≥3 adverse events (AEs; Hurvitz, ESMO 2011). This phase II study assessed the clinical safety and feasibility of T-DM1 following anthracycline-based chemotherapy in the adjuvant or neoadjuvant setting for early-stage HER2-positive breast cancer. Methods: TDM4874g (NCT01196052) is a phase II single-arm, open-label study of T-DM1 (3.6 mg/kg q3w IV; up to 17 cycles) following completion of doxorubicin/cyclophosphamide (AC; q2w or q3w for 4 cycles), or 5-fluorouracil/epirubicin (100 mg/m2)/cyclophosphamide (FEC; q3w for 3-4 cycles) chemotherapy in pts with early-stage HER2-positive breast cancer. Pre-chemotherapy LVEF by MUGA/ECHO ≥55% was required for enrollment. Co-primary endpoints are safety and rate of pre-specified cardiac events following initiation of T-DM1 treatment. An interim analysis was planned for the first 60 pts evaluable for cardiac safety (received ≥1 T-DM1 dose). Results: For pts in the interim analysis (20 received AC, 40 FEC), the most common all-grade T-DM1-related AEs were nausea (n=20), asthenia (n=17), and headache (n=17); 8 pts had grade 3/4 T-DM1-related AEs (including 3 with grade 3 increased aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT]). No deaths occurred. Two pts had AEs leading to T-DM1 discontinuation (grade 3 AST and grade 2 ALT increase; grade 3 thrombocytopenia). No pre-specified cardiac events occurred; no pts delayed or discontinued T-DM1 due to cardiac AEs; there were no reports of grade ≥2 left ventricular systolic dysfunction, heart failure, or LVEF &lt;50%. Results will be updated with data from all 153 enrolled pts. Conclusions: T-DM1 following anthracycline-based chemotherapy was not associated with cardiac toxicity in pts with early-stage HER2-positive breast cancer; this study continues without modification.

Results from a phase Ib study of trastuzumab emtansine (T-DM1), paclitaxel (T), and pertuzumab (P) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab.

528 Background: The antibody–drug conjugate T-DM1 has shown single-agent activity in phase II studies in patients (pts) with HER2–positive MBC. Preclinical data suggest synergy for T-DM1 combined with taxanes and with P. Methods: TDM4652g is a phase Ib, open-label, dose-escalation study evaluating the safety and tolerability of T-DM1 (qw and q3w) + T (qw) ± P (q3w) in pts with HER2-positive MBC previously treated with trastuzumab. A 3+3 dose-escalation scheme is used for T-DM1 + T to determine the maximum tolerated dose (MTD); P is added at this MTD. Initial restrictive dose-limiting toxicity (DLT) criteria were modified to establish a more clinically relevant MTD. Results: We report interim results with T-DM1 (qw and q3w) + T (+ P) using modified DLT criteria. 24 pts have been enrolled in these cohorts; median age was 53 yrs (range, 23–69)*; median number of prior systemic therapies in MBC was 7 (range, 2–15)*. See table below. Conclusions: Data support combining T-DM1 + T ± P at the MTD for future clinical trials. The MTD for weekly T-DM1 + T is 2.4 mg/kg + 80 mg/m2 qw; MTD for weekly T-DM1 + T + P is 2.4 mg/kg + 80 mg/m2 qw + 840 mg LD, 420 mg q3w. Updated results will be presented, including the MTD for T-DM1 q3w + T qw ± P q3w, outcomes from pts with prolonged follow-up, and duration of response from an extension trial. [Table: see text]