HER2-positive mBC Research Articles

Abstract P4-12-16: Safety profile and costs of related adverse events of trastuzumab emtansine compared to other regimens in the Canadian health care system

Abstract Background Trastuzumab Emtansine (T-DM1) is an antibody–drug conjugate (ADC) comprised of the microtubule inhibitory cytotoxic agent DM1 and trastuzumab which, in addition to its antitumor properties, targets T-DM1 to HER2–overexpressing cells. The phase III EMILIA study compared the safety and efficacy of T-DM1 (n = 496) versus capecitabine plus lapatinib (CAP+LAP, n = 495) in patients with HER2-positive locally advanced or MBC previously treated with trastuzumab and a taxane. The phase II TDM4450g study compared the safety and efficacy of T-DM1 (n = 67) versus trastuzumab plus docetaxel (TRAZ+DOCE, n = 70) in patients with previously untreated MBC. These trials demonstrated statistically and clinically meaningful differences between T-DM1 and its comparators. In the EMILIA trial, the proportion of patients who developed grade ≥3 treatment-related AEs that were deemed related to treatment by the investigators was lower in the T-DM1 arm (30.6%) compared to the CAP+LAP arm (48.8%) and 5.9% of patients on T-DM1 discontinued treatment due to an AE, compared with 10.7% of patients on CAP+LAP. In the TDM4450g study, the proportion of patients who developed grade ≥3 AEs that were deemed related to treatment by the investigators was lower in the T-DM1 arm (33.3%) versus the TRAZ+DOCE arm (81.82%) and 7.2% of patients on T-DM1 discontinued treatment due to an AE, compared with 34.8% of patients on TRAZ+DOCE. The objective of this analysis was to estimate and compare the Canadian costs of managing the treatment-related AEs of T-DM1 as reported in the EMILIA and TDM4450g trials, from the perspective of Canadian public payers. Methods An Excel based spreadsheet model was utilized to estimate the costs of managing the treatment-related AEs. Clinical data (number and severity of AEs) were obtained from the two trials. Resource utilization and costing information were obtained from the literature, clinical experts, and Canadian standard costing sources (minimum and maximum costs were used). Costs were reported as 2012 CAD. The AEs that were considered for costing in this analysis were all treatment-related grade ≥3 AEs as well as grade 2 AEs that occurred in ≥5% of patients in both arms of either study. Results The management of treatment-related AEs by using T-DM1 resulted in cost savings ranging from $1,684 - $8,036 versus CAP+LAP as reported in the EMILIA trial and from $4,326 - $25,402 versus TRAZ+DOCE as per the TDM4450g trial (see Table 1). Table 1: Range of Costs of Managing Treatment-Related AEs as Reported in the EMILIA and TDM4450g trials EMILIATDM4450g T-DM1CAP + LAPT-DM1TRAZ+DOCECost per patient$1,376 - $2,463$3,060 - $10,499$798 - $2,215$5,124 - $27,617Cost savings$1,684 - $8,036$4,326 - $25,402 Conclusions This analysis demonstrated that utilizing T-DM1 for the management of HER2-positive MBC results in significant cost savings of related AEs management due to the improved safety profile compared to CAP+LAP and TRAZ+DOCE. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-16.

Abstract P4-12-08: Final efficacy results from a single-arm multicenter phase II study evaluating first-line trastuzumab, bevacizumab, and capecitabine (HAX) therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC)

Abstract Background: After median follow-up of 8.8 months, the primary efficacy results from the HAX study [Martín et al., Oncologist 2012] demonstrated a 73% overall response rate (ORR) according to RECIST (primary endpoint), median progression-free survival (PFS) of 14.4 months and a safety profile typical of the component agents; overall survival (OS) data were immature at that time. We present final efficacy results. Methods: Patients with measurable HER2-positive LR/mBC who had received no prior chemotherapy for LR/mBC received bevacizumab 15 mg/kg day 1, trastuzumab 6 mg/kg day 1 (8 mg/kg loading dose in cycle 1), and capecitabine 1000 mg/m2 bid days 1–14, repeated every 3 weeks until progression, unacceptable toxicity, or withdrawal of consent. Results: At the time of data cut-off, median follow-up was 31.8 months (range 1.2–44.5 months). Median duration of study therapy was 9.0, 9.4, and 10.3 months for bevacizumab, capecitabine, and trastuzumab, respectively. More than 8 cycles were administered in 67%, 65%, and 70%, respectively. Efficacy results in the intent-to-treat population (n = 88) and clinically important subgroups are shown below. Patient subgroupBest ORR,% (95% CI)PFS events, n (%)Median PFS, months (95% CI)Deaths, n (%)Median OS, months (95% CI)1-year OS rate,% (95% CI)All patients (n = 88)75 (65-84)70 (80)14.2 (10.5-14.9)40 (45)31.8 (26.3-38.2)94 (86-98)ER and/or PgR positive (n = 37)73 (56-86)32 (86)14.1 (8.5-17.0)19 (51)31.8 (24.4-42.6)100 (*-*)ER and PgR negative (n = 51)77 (63-87)38 (75)14.5 (10.5-18.9)21 (41)33.1 (23.6-44.5)90 (77-96)No prior chemotherapy (n = 37)81 (65-92)27 (73)14.9 (10.5-24.8)14 (38)31.8 (26.3-44.4)94 (80-99)Prior chemotherapy (n = 51)71 (56-83)43 (84)13.6 (8.5-14.8)26 (51)30.9 (24.3-42.1)94 (82-98)Taxane pretreated (n = 28)57 (37-76)26 (93)9.5 (5.2-14.0)17 (61)27.4 (21.4-33.2)93 (74-98)Prior anti-HER2 therapy (n = 22)73 (50-89)18 (82)12.1 (5.2-17.0)11 (50)30.9 (24.3-*)95 (72-99)Age >60 years (n = 25)72 (51-88)16 (64)14.2 (10.5-21.7)11 (44)33.2 (22.0-*)100 (*-*)*Not reached The most common grade ≥3 adverse events were hand-foot syndrome (26% of patients), diarrhea (11%), and hypertension (11%). The majority of deaths (38/40) were from progressive/underlying disease. The cause of the two remaining deaths was described as unknown; one was reported at the primary analysis and the other occurred 19 months after last study drug administration, following progression. Detailed long-term safety results will be presented. Conclusion: Long-term follow-up results from the HAX study show that this is an active and tolerable first-line triplet therapy for HER2-positive mBC, demonstrating median OS of 31.8 months. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-08.

Efficacy and safety of first-line (1L) pertuzumab (P), trastuzumab (T), and docetaxel (D) in HER2-positive MBC (CLEOPATRA) in patients previously exposed to trastuzumab.

600 Background: CLEOPATRA is a global phase III trial of P + T + D vs placebo + T + D in HER2-positive 1L MBC. Results showed a significant improvement in PFS (Baselga NEJM 2012) and OS (Swain SABCS 2012) favoring P + T + D. CLEOPATRA started recruitment in 2008 soon after the approval of T in the adjuvant setting in 2006 and mandated a disease-free interval (DFI) of ≥12 mos from the end of adjuvant therapy to MBC diagnosis. Due to this, a low proportion of pts with prior T exposure was included. Here we present the efficacy and safety of 1L P + T + D in the subset of pts in CLEOPATRA with prior T exposure. Methods: Pts received P + T + D or placebo + T + D, had a DFI ≥12 mos, baseline left ventricular ejection fraction (LVEF) ≥50% and no LVEF decline to <50% during/after prior T therapy. Exploratory analyses of PFS and OS in pts with (neo)adjuvant therapy with or without T were conducted. Results: Of the study population, 47% had received (neo)adjuvant therapy and 11% had received (neo)adjuvant T; 82% of the prior T group came from Europe or North America. A univariate Cox regression analysis did not identify prior T therapy as a statistically significant risk factor for developing left ventricular systolic dysfunction (LVSD). However, due to the low number of LVSD events overall, this analysis has limited sensitivity. Conclusions: Data from CLEOPATRA show that pts with HER2-positive 1L MBC who have received prior T (DFI ≥12 mos) derive the same magnitude of benefit from the combination of P + T + D when compared with the whole study population or those who are T-naïve. This is in agreement with prior evidence of the activity of P + T in pts pretreated with T (Baselga JCO 2010). Efficacy and safety of P-T-based therapy is being explored in the PERUSE and PHEREXA trials, in a pt population with wider exposure to prior T and a shorter DFI, which may better represent current clinical practice. Clinical trial information: NCT00567190. [Table: see text]

Lapatinib with trastuzumab for heavily treated HER2-positive metastatic breast cancer (mBC).

e11561 Background: Trastuzumab and lapatinib show complementary and non-cross resistant mechanisms of anti-HER2 action. Dual HER2 blockade has been preclinically and clinically assessed with encouraging results. Trastuzumab and lapatinib combination is effective in terms of survival in patients with heavily pretreated HER2-positive mBC. We aim to report our experience with lapatinib plus trastuzumab in this setting. Methods: Descriptive retrospective study of trastuzumab plus lapatinib activity in patients with HER2-overexpressing metastatic breast cancer treated in two institutions from 01/2007 to 12/2012. The objective of this analysis is to report the response rate (RR), progression-free survival (PFS) and toxicity. Results: 23 HER2-positive mBC patients previously treated with trastuzumab received trastuzumab plus lapatinib based therapy. 15 patients (65%) received 2 or more previous lines. 17 patients (74%) had visceral disease. Chemotherapy (CT) was added to the dual HER2 blockade treatment in 13 patients (56%) whereas hormonotherapy (HT) was added in 8 patients (35%) and 2 patients (9%) received lapatinib plus trastuzumab without any other agent. Chemotherapeutic drugs most used were: capecitabine (54%) and vinorelbine (15%). RR: partial response 22% (5/23), stable disease 39% (9/23). Median of follow-up was 11 months. PFS in the overall population was 4 months. PFS in patients with CT was 5 months, while PFS in patients with HT was only 2. PFS in hormone receptor positive and negative was 3 and 5 months respectively. The most common toxicities were: diarrhea (48%), anemia (39%), asthenia (39%) and hand-and-foot syndrome (17%). Grade ≥ 3 toxicity was diarrhea (26%) and hand-and-foot syndrome (9%). The incidence of cardiotoxicity was 9% (grade 2). Conclusions: These findings suggest that dual HER2 blockade in combination with CT is feasible and active in heavily pretreated HER2-positive mBC patients. However, further investigation is warranted to demonstrate superiority over sequential blockade with trastuzumab and lapatinib in this setting.

Abstract P5-18-06: Trastuzumab emtansine in HER2-positive metastatic breast cancer: pooled safety analysis from seven studies

Abstract Background: The antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1) combines the antitumor activities of trastuzumab with intracellular delivery of the cytotoxic agent DM1 and represents a new approach to therapy for HER2-positive MBC. Recently, the first phase 3 data have been reported with significant improvements in PFS (9.6 vs 6.4 months; HR=0.650; P<0.0001) and lower incidence of grade ≥3 adverse events (AEs) (57% vs 41%) vs capecitabine + lapatinib (Blackwell 2012). This pooled analysis reports the overall safety profile of T-DM1 3.6 mg/kg q3w in 882 patients treated with T-DM1. Methods: Data were included from treated patients in 7 studies of single-agent T-DM1 3.6 mg/kg q3w: 1 phase 1 study in previously treated MBC (TDM3569g, Krop 2010, n=15 treated at 3.6 mg/kg q3w); 3 phase 2 single-arm studies in previously treated MBC (TDM4258g, Burris 2011, N=112; TDM4374g, Krop 2012, N=110; TDM4688g, Gupta 2011, n=51); 1 randomized phase 2 study in previously untreated MBC (Hurvitz 2011, TDM4450g/BO21976, n=69); 1 extension study (TDM4529/BO25430, n=43 from parent studies); and 1 phase 3 study in MBC previously treated with trastuzumab and a taxane (EMILIA, Blackwell 2012, n=490). Data were analyzed in 4 groups: (1) all T-DM1-treated pts (7 studies, N=882), (2) pts originally enrolled in single-arm studies (n = 288), (3) T-DM1 pts from TDM4450g (n = 69), and (4) T-DM1 pts from EMILIA (n = 490). Results: Among all pts (N = 882), median age was 53 years (range 25–85 years); 52.7% had ≥3 metastatic sites; 81.7% had received prior treatment for MBC; and the median number of prior non-endocrine agents for MBC was 3.0 (range 0–19). All-grade AEs occurring in ≥25% of patients were fatigue (45.4%), nausea (42.3%), headache (28.7%), thrombocytopenia (28.7%), and constipation (25.5%). Grade ≥3 AEs occurring in ≥2% were thrombocytopenia, increased AST, increased ALT, fatigue, hypokalemia, and anemia. Table 1 describes the grade ≥3 incidence of these AEs, as well as selected AEs with known association to T-DM1 or potential risk based on the components of T-DM1 or on preclinical data. Conclusions: The safety profile of T-DM1 3.6 mg/kg q3w was consistent across the studies and the different patient populations with HER2-positive MBC. Additional analyses on hepatic transaminase increases and those exploring potential associations between thrombocytopenia and hemorrhage will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-06.

Abstract P5-18-01: Pertuzumab (P) in combination with trastuzumab (T) and docetaxel (D) in elderly patients with HER2-positive metastatic breast cancer in the CLEOPATRA study

Abstract Background: The incidence of cancer increases with age as does the risk of treatment-related adverse events (AEs) due to underlying comorbidities. A better understanding of cancer therapy-related AEs in elderly pts may help identify the optimal therapy by balancing treatment benefit and risk. CLEOPATRA, a double-blind Phase III trial, compared placebo (Pla)+T+D with P+T+D in pts with HER2-positive 1L MBC (Baselga 2012). Here we report safety and efficacy by age group. Methods: P/Pla: 840 mg initial dose, 420 mg q3w iv; T: 8 mg/kg initial dose, 6 mg/kg q3w iv; D: 75 mg/m2 q3w iv, escalating to 100 mg/m2 if tolerated. P/Pla+T were given until progressive disease (PD) or unacceptable toxicity. At least 6 cycles of D were recommended; <6 cycles were allowed for PD or unacceptable toxicity, >6 cycles were allowed at investigators' discretion. At baseline, pts were required to have ECOG PS of 0 or 1, LVEF ≥50% and no decline to <50% during or following prior T therapy. The cumulative exposure to prior doxorubicin must not have exceeded 360 mg/m2 or its equivalent. The primary endpoint was independently assessed PFS; secondary endpoints included overall survival, objective response, safety. Results: In the safety population, 678 pts (332 Pla arm, 346 P arm) were <65 yrs and 126 pts (65 Pla arm, 61 P arm) were ≥65 yrs. In pts <65 yrs, the median number of D cycles was 8 (1–41) in the Pla arm (median D dose intensity: 24.8 mg/m2/week) and 8 (1–35) in the P arm (24.5 mg/m2/week). The median number of D cycles was lower in pts ≥65 yrs, with 6.5 (1–26) in the Pla arm (24.8 mg/m2/week) and 6 (1–16) in the P arm (24.8 mg/m2/week). In elderly pts, the incidence of diarrhea, fatigue, and dysgeusia appeared to be higher in both arms, whereas neutropenia and febrile neutropenia were reported less frequently. Grade ≥3 diarrhea was reported in 4.8% (Pla arm) and 6.6% (P arm) of pts <65 yrs and in 6.2% (Pla arm) and 14.8% (P arm) of pts ≥65 yrs. In a univariate Cox regression analysis, age had no statistically significant association with the development of asymptomatic or symptomatic left ventricular systolic dysfunction (LVSD); however, due to the low number of LVSD events overall this analysis has limited sensitivity to detect differences in time to event by age group. An exploratory post hoc analysis of independently assessed PFS in the ITT population showed a median PFS of 12.5 months in the Pla arm and 17.2 months in the P arm (HR = 0.65, 95% CI 0.53–0.80) in pts <65 yrs. In pts ≥65 yrs, the median PFS was 10.4 months in the Pla arm and 21.6 months in the P arm (HR = 0.52, 95% CI 0.31–0.86). Conclusions: Overall, the AE profile reported in CLEOPATRA suggests that, in pts with good performance status, the use of P should not be limited by age. Therapy with P+T+D resulted in improved efficacy in pts aged < and ≥65 yrs. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-01.

226P - Exploratory Analysis of the Relationship Between Her2 Expression (BY QRT-PCR) and Efficacy with First-Line Trastuzumab Emtansine (T-DM1) Vs Trastuzumab Plus Docetaxel (HT) in a Randomized Phase 2 Study of Patients (PTS) with HER2-Positive MBC

ABSTRACT Background In TDM4450g (NCT00679341), 137 pts with HER2-positive MBC and no prior treatment for metastatic disease were randomized to T-DM1 or HT. Median progression-free survival (PFS) was 14.2 vs 9.2 mo, respectively (HR = 0.594); objective response rates (ORR) were 64.2% and 58.0%, respectively (Hurvitz 2011). In exploratory analyses of single-arm phase 2 MBC studies of T-DM1, greater expression of HER2 mRNA (assessed by qRT-PCR) was associated with greater ORR and longer PFS (Burris 2011; Krop 2012, in press). We now report a retrospective exploratory analysis of the relationship between qRT-PCR HER2 expression and efficacy outcomes in pts receiving T-DM1 or HT in TDM4450g. Table: 226P Median pre-treatment HER2 levels, concentration ratio units (range) HT T-DM1 (n = 61) 8.7 (0.5-105.0) (n = 55) 10.3 (0.4-103.0) Median PFS, months HER2 expression HT T-DM1 Hazard ratio relative to HT (95% CI) Low (n = 32) 9.8 (n = 26) 10.6 0.85 (0.44-1.67) High (n = 29) 8.8 (n = 29) Not reached 0.39 (0.18-0.85) ORR, % HER2 expression HT T-DM1 Odds ratio relative to HT (95% CI) Low (n = 31) 58.1 (n = 26) 53.8 0.84 (0.30-2.41) High (n = 29) 65.5 (n = 29) 72.4 1.58 (0.50-4.98) Methods Pts were randomized 1:1 to T-DM1 3.6 mg/kg q3w or H 6 mg/kg q3w (8 kg/mg in cycle 1) + T 75 or 100 mg/m2 q3w and treated until disease progression. HER2 expression was measured by qRT-PCR in archival tissue samples from all randomized pts. Efficacy outcomes included investigator-assessed PFS and ORR. The analysis results presented here are based on the clinical data with a median follow-up of ∼14 mo in each arm. Results In total, 122 tumor samples from 137 randomized pts were available for analysis of pre-treatment HER2 by qRT-PCR, resulting in a valid result for 116 pts (6 samples were below the limit of quantification). Efficacy outcomes by low ( Conclusions These results from an exploratory analysis suggest that the magnitude of efficacy from T-DM1 vs HT may correlate with HER2 expression levels (by qRT-PCR); this effect appears to be most pronounced for PFS. Analyses exploring the relationship between these findings and baseline characteristics are planned. Similar analyses are planned for ongoing phase 3 studies of T-DM1. Disclosure S. Hurvitz: SA Hurvitz has received support for study-related travel from Roche and research funding for her institution from Roche. L.C. Amler: Dr. Amler is employed by Genentech and has stock ownership in F. Hoffmann-La Roche. V. Ng: Dr. Ng is employed by Genentech and has stock ownership in F. Hoffmann-La Roche. E. Guardino: Dr. Guardino is employed by Genentech and has stock ownership in F. Hoffmann-La Roche. L. Gianni: L Gianni has had compensated consultant/advisory relationships with Genentech/Roche, GlaxoSmithKline and Pfizer. All other authors have declared no conflicts of interest.

346P - Characteristics of Patients With HER2-Positive Metastatic (MBC) or Locally Advanced Breast Cancer (ABC), Treated With Trastuzumab (T) as 1st Line-Therapy and Progression-Free for at Least 3 Years: Interim Analysis of the Lorha Study

ABSTRACT Background For more than ten years, treatment of HER2-positive mBC patients (Pts) is based on T plus taxane in 1st line therapy. So far, in numerous studies, we have observed few subsets of Pts (long-term responders) who have not experienced disease progression for several years after T-based regimen in 1st line treatment. This study aims to characterise these Pts in the daily practice from a clinical and biological perspective. Material and methods This is an ambispective French multicentre non-interventional study. Eligible Pts were women aged ≥18 years with HER2-positive mBC or aBC treated with T as 1st line and who were progression-free for at least 3 years after starting T. The primary objective was to describe the clinical and tumor characteristics of these Pts. Progression Free Survival (PFS), Overall Survival (OS), data on treatment administration and safety were also collected. An exploratory biomarkers analysis is planned on tumor tissue samples. Here we present some preliminary results based on the interim analysis performed at the end of inclusions. Results 159 Pts were enrolled in 2011 and 110 Pts were eligible for data analysis. Median age was 59 years [34-95]. Tumor characteristics were: invasive ductal carcinoma for 96 Pts (88%), positive hormonal receptors in 63 Pts (58%). At initial diagnosis, presenting stages were I-II for 52 Pts (50%). 36 Pts (33%) had a mBC de novo or an aBC. The main metastatic localisations were bone, liver and lung in 51 (47%), 35 (32%) and 22 (20%) Pts respectively. Median T treatment duration was 4.1 years [0.8 - 11.0] in 1st line. T was associated with a taxane-based chemotherapy in 86 Pts (78%). Median PFS was 6.4 years [4.9; - ]. Median OS was not reached. 13 retrospective adverse events related to T (cardiac or leading to discontinuation) were reported. None of these was serious. Conclusions In this long PFS population treated with a T-based treatment in first line for aBC or mBC Pts, no specific profile in terms of clinical or histological characteristics have been observed. Thus, the exploratory biomarkers analysis will be useful to identify such a profile. Disclosure O. Tredan: Roche consultant. P. Beuzeboc: Roche consultant. D. Coeffic: Roche consultant. M. Fellous: Roche employee. L. Arnould: Roche Consultant. All other authors have declared no conflicts of interest.

409TiP - Pertuzumab in Combination with Trastuzumab and a Taxane for the First-Line Treatment of Patients with HER2-Positive Advanced Breast Cancer: A Single Arm Phase IIIB Study (Peruse)

ABSTRACT Background Pertuzumab (P) inhibits downstream signaling of HER2 by preventing its heterodimerization with other HER family members. The epitope recognized by P is distinct from that bound by trastuzumab (H) and their complementary mechanisms of action lead to a more comprehensive HER2 blockade when combined. Data from the phase III trial CLEOPATRA showed significantly improved PFS in pts with HER2-positive 1L MBC given P + H + docetaxel (D). As H was not widely available in the (neo)adjuvant setting prior to CLEOPATRA recruitment, a relatively low proportion of pts in CLEOPATRA had previously received H. PERUSE will assess the safety and tolerability of P + H + one of a choice of taxanes (T) as 1L therapy for pts with HER2-positive metastatic or locally advanced BC. Efficacy endpoints will also be recorded in PERUSE, in a pt population likely to have experienced wider exposure to prior H therapy. Methods PERUSE is a phase IIIb, multicenter, open-label, single-arm study in pts with HER2-positive BC who have not been treated with systemic non-hormonal anticancer therapy for MBC. The planned sample size is 1500. Pts will receive, P: 840mg initial dose, 420mg q3w IV; H: 8mg/kg initial dose, 6mg/kg q3w IV, T: D, paclitaxel or nab-paclitaxel according to local guidelines. A planned protocol amendment will allow HR-positive pts to receive endocrine therapy in conjunction with P + H following completion of T in line with clinical practice. Treatment will be administered until disease progression or unacceptable toxicity. At baseline, pts must have an LVEF of ≥50%, ECOG PS of 0, 1 or 2 and must not have received prior anti-HER2 agents for MBC. Prior H and/or lapatinib in the (neo)adjuvant setting is allowed, provided there was no disease progression on-treatment. A disease-free interval of ≥6 months is required. The primary endpoint is safety and tolerability. Secondary endpoints include PFS, OS, ORR, CBR, duration of response, time to response and QoL. The final analysis will be carried out when pts have been followed up for ≥12 months. Interim analyses are planned after enrollment of ∼350, 700 and 1000 pts. Regular interim safety assessments by a DSMB will take place. Disclosure D. Miles: I have an interest in relation with one organisation that could be perceived as a possible conflict of interest in the context of the subject of this abstract. I have served on Advisory Board Meetings for Roche/Genentech. F. Puglisi: I have an interest in relation with one organisation that could be perceived as a possible conflict of interest in the context of the subject of this abstract. I participate in Advisory Board Meetings for Roche. A. Schneeweiss: I have an interest in relation with one organisation that could be perceived as a possible conflict of interest in the context of the subject of this abstract. I serve on Roche Advisory Boards and am in volved with corporate-sponsored research with Roche. L. Mitchell: I am currently an employee of F. Hoffmann-La Roche. A. Dunne: I have an interest in relation with one organisation that could be perceived as a possible conflict of interest in the context of the subject of this abstract. I am an employee of hoffmann-La Roche. T. Bachelot: I have an interest in relation with one organisation that could be perceived as a possible conflict of interest in the context of the subject of this abstract. I am involved with Roche sponsoredresearch and Roche advisory Board Meetings. All other authors have declared no conflicts of interest.

408TiP - Pertuzumab and Trastuzumab in Combination with Vinorelbine for First-Line Treatment of Patients with HER2-Positive Locally Advanced or Metastatic Breast Cancer (LABC/MBC): A Single-Arm, Two-Cohort, Phase II Study (Velvet)

ABSTRACT Background The humanised monoclonal antibody pertuzumab binds to the dimerisation domain of HER2, preventing heterodimerisation and downstream signalling. As pertuzumab is directed against a different epitope to trastuzumab, a more comprehensive HER2 blockade is achieved by combining the agents. The CLEOPATRA study showed significantly improved efficacy for pertuzumab and trastuzumab plus docetaxel, but pertuzumab with trastuzumab has not been tested with other chemotherapies in MBC. Trastuzumab plus vinorelbine (V) has comparable efficacy to trastuzumab plus docetaxel but with fewer adverse events. VELVET will assess the overall response rate (ORR) of pertuzumab with trastuzumab + V in first-line treatment of HER2-positive MBC. Administration of pertuzumab and trastuzumab in the same infusion bag will also be assessed. Methods VELVET is a multicentre, open-label, two-cohort, Phase II trial in patients (pts) with HER2-positive LABC/MBC not previously treated in the metastatic setting with non-hormonal anticancer therapy. Pts must have LVEF ≥55% and ECOG PS of 0/1. Enrolment began in April 2012 and 210 pts will be recruited. Cohort 1 (first 105 pts enrolled) will receive pertuzumab and trastuzumab sequentially, and Cohort 2 (next 105 pts) will receive pertuzumab and trastuzumab in the same infusion bag at Cycle 2 onwards assuming Cycle 1 was tolerated. V will be given in both cohorts. Treatment will continue until disease progression/unacceptable toxicity. Study doses (all iv): pertuzumab: 840 mg initial dose, 420 mg q3w; trastuzumab: 8 mg/kg initial dose, 6 mg/kg q3w, and V: 25 mg/m2 Day 1 and 8 (first cycle) then 30 - 35 mg/m2 Days 1 and 8 q3w (dose escalation at investigator discretion). Assuming best overall response of 70–80% and aiming at a distance from the estimated proportion to the CI limits of 8–11%, a total of 95 pts need to be evaluable per cohort (assuming withdrawal rate ∼10%). Primary endpoint is ORR by independent assessment. Secondary endpoints include investigator ORR assessment, time to response, duration of response, PFS, TTP, OS, safety/ tolerability and QoL. Disclosure T. Petit: I declare that have served on a advisory board for F. Hoffmann-La Roche. L. Mitchell: I am currently an employee of F. Hoffmann-La Roche. C. Pelizon: I am currently an employee of F. Hoffmann-La Roche. E.A. Perez: I declare that my institute has received research finding from Genentech, Sanofi Onc. and GSK. All other authors have declared no conflicts of interest.

329P - Patient-Reported Outcomes (PROS) From EMILIA, a Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine and Lapatinib (XL) In HER2-Positive Locally Advanced or MBC

ABSTRACT Background The antibody-drug conjugate T-DM1 combines the antitumor activities of trastuzumab (T) with intracellular delivery of the cytotoxic agent DM1. In the EMILIA study, the efficacy and safety of T-DM1 was compared to XL. Here we report the PRO results. Methods Pts with centrally confirmed HER2-positive MBC and prior therapy with T and a taxane were randomized to T-DM1 or XL administered in 21-day cycles. Pts completed the FACT-B, a 37-item questionnaire composed of 5 subscales at baseline and on day 1 every 2 cycles until disease progression (PD), 6 wks after PD and every 3 mos thereafter. A 24-item subset of FACT-B, the Trial Outcome Index (TOI) provides a summary of physical and functional well-being and breast cancer-specific symptoms. Time to FACT-B TOI worsening (ie, ≥5 point decrease in TOI), the main PRO analysis, was assessed by Kaplan-Meier methods and a Cox model in female pts with baseline and ≥1 post-baseline TOI score. An exploratory PRO end point was the incidence of symptoms measured by the Diarrhea Assessment Scale (DAS), in which pts rated diarrhea symptoms in 4 domains (frequency, urgency, discomfort, stool consistency) on a 4-point scale at baseline and on day 1 of each cycle until PD.Results: Pts treated with T-DM1 had longer PFS (9.6 vs 6.4 months; HR=0.650; P 1 stool per day (57% vs 30%); loose or watery stools (70% vs 37%); somewhat to very urgent stools (54% vs 26%) and mild-moderate to very severe abdominal discomfort with bowel movements (45% vs 25%). Conclusions Improvements in efficacy and safety were accompanied by, clinically significant benefits in health-related quality of life in pts treated with T-DM1 vs XL. Keywords diarrhea, T-DM1, patient-reported outcomes, HER2-positive. Disclosure V. Dieras: *Compensated consultant/advisory relationship with Genentech/Roche, Novartis, Sanofi, Amgen, Clovis, Pfizer, GSK *Honoraria from Genentech/Roche, Novartis, Sanofi, Amgen, Clovis, Pfizer, GSK J. Sohn: Research funding from Roche, Amgen and GSKS. Hurvitz: *Support for study-related travel from Roche *Research funding for institution from Roche D. Lalla: Genentech employee, owns Roche stockL. Fang: Genentech employee, owns Roche stockE. Guardino: Genentech employee, owns Roche stock All other authors have declared no conflicts of interest.

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer

Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination. DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate. There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92). Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

A combination of pertuzumab, trastuzumab, and vinorelbine for first-line treatment of patients with HER2-positive metastatic breast cancer: An open-label, two-cohort, phase II study (VELVET).

TPS653 Background: Pertuzumab (P) is a humanized monoclonal antibody directed against the dimerization domain of HER2: it prevents HER2 heterodimerization and thus activation of downstream signaling. Since P targets a different epitope than trastuzumab (H), a more comprehensive HER2 blockade is achieved by combining the two agents. Data from CLEOPATRA showed improved efficacy for P and H plus docetaxel. The combination of P and H has not yet been assessed with other chemotherapy partners in the metastatic setting. H plus vinorelbine (V) has shown comparable efficacy to H plus docetaxel but with a superior safety profile. VELVET will assess the overall response rate (ORR) of P with H+V in first-line patients (pts) with HER2-positive MBC. Co-administration of P and H within the same infusion bag will also be investigated as this could increase pt convenience by reducing administration and observation time. Methods: VELVET is a multicenter, open-label, two-cohort, Phase II trial. Pts with HER2-positive LABC or MBC not previously treated in the metastatic setting with non-hormonal anticancer therapy are eligible. Pts must have an LVEF &gt;55% at baseline and an ECOG PS of 0 or 1. Study enrollment started in January 2012. A total of 210 pts will be included. Based on statistical assumptions, 95 pts must be evaluable per cohort, which assumes a withdrawal rate around 10%. Pts in Cohort 1 (the first 105 pts enrolled) will receive P and H sequentially and pts in Cohort 2 (the next 105 pts) will receive P and H in the same infusion bag at Cycle 2 onwards if drug administration in Cycle 1 was well tolerated. V will be given in both cohorts. Treatment duration is until disease progression or unacceptable toxicity. Study dose: P: 840 mg loading dose, 420 mg q3w (iv); H: 8 mg/kg loading dose, 6 mg/kg q3w (iv), and V: 25 mg/m2 Day 1 and 8 (first cycle) then 30−35 mg/m2 Day 1 and 8 q3w (iv) (dose escalation at investigator’s discretion). The primary endpoint is ORR by independent assessment. Secondary endpoints include investigator assessment of ORR, time to response, duration of response, PFS, time to progression, overall survival, safety and tolerability, and QoL.

Adverse events with pertuzumab and trastuzumab: Evolution during treatment with and without docetaxel in CLEOPATRA.

597^ Background: In CLEOPATRA, the HER2-dimerization inhibitor pertuzumab (P) was combined with trastuzumab (T) and docetaxel (D) in HER2-positive 1st-line MBC. P+T+D significantly improved efficacy compared with placebo (Pla)+T+D while having little effect on safety. Pts were recommended to receive ≥6 cycles of D but could discontinue D prior to Cycle 6 due to poor tolerability or progressive disease (PD) or continue D beyond Cycle 6 at investigators’ discretion. Once D was discontinued, pts received Pla+T or P+T until PD. To understand the full safety profile of the regimen, adverse events (AEs) occurring before and after D discontinuation were analyzed. Methods: Treatment was given q3w (Pla/P: 840 mg loading, then 420 mg; T: 8 mg/kg loading, then 6 mg/kg; D: 75 mg/m2, escalating to 100 mg/m2 if tolerated; de-escalation by 25% allowed). AEs were graded according to NCI-CTCAE v3.0, monitored continuously during the treatment period, and their relationship to study drugs was assessed by investigators. Results: From 808 pts enrolled, 804 were analyzed in the safety population (pts who received ≥1 dose of study treatment). AEs that led to discontinuation of all study treatment were experienced by 5.3% (Pla+T+D) and 6.1% (P+T+D) of pts, whereas discontinuation of D alone due to AEs occurred in 23.2% (Pla+T+D) and 23.6% (P+T+D) of pts. Conclusions: Treatment in both arms was well tolerated. After discontinuation of D, there was a clear reduction in grade ≥3 AEs; however, the incidence of grade ≥3 diarrhea remained slightly elevated with P+T+D. The AE profile of P+T is consistent with that seen in previous Phase II studies (Gianni Lancet Oncol 2012; Baselga JCO 2010). These data suggest that the combination of P+T may also be well tolerated in other breast cancer settings, such as in adjuvant therapy, which is currently under phase III study (APHINITY; NCT01358877). [Table: see text]

Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in the CLEOPATRA study.

533^ Background: Addition of trastuzumab (T) to chemotherapy has transformed outcomes in pts with HER2-positive breast cancer. In pts who had received anthracyclines (A), T has been associated with cardiac dysfunction. Monitoring cardiac tolerability of anticancer drugs is important, including that of a new regimen combining T with a second anti-HER2 antibody that inhibits HER2 dimerization, pertuzumab (P). In CLEOPATRA, efficacy and safety of P+T+docetaxel (D) were studied in HER2-positive 1st-line MBC (Baselga 2012). Methods: CLEOPATRA, a randomized, double-blind, placebo-controlled, ph III trial, enrolled 808 pts; 804 were included in the safety population. A baseline (BL) LVEF ≥50%, no history of congestive heart failure, and no LVEF decline to &lt;50% during/after prior T were required. Treatment was administered q3w until disease progression or unmanageable toxicity (P/placebo [Pla]: 840 mg, followed by 420 mg; T: 8 mg/kg, followed by 6 mg/kg; D [≥6 cycles recommended]: 75 mg/m2, escalating to 100 mg/m2 if tolerated). LVEF was assessed by ECHO or MUGA at BL, every 9 wks during treatment, at discontinuation, and up to 3 yrs thereafter. Adverse events (AE) were monitored continuously and graded according to NCI-CTCAE v3.0. Results: The incidence of any cardiac disorder (grade ≥1) as assessed by the investigators was similar with Pla+T+D (16.4%) and P+T+D (14.5%). LVSD (grade ≥1) was the most frequent cardiac AE and more common with Pla+T+D. At the time of data cutoff for this analysis, 8/11 symptomatic LVSD events had resolved; none fatal. All pts who developed symptomatic LVSD had ≥1 potential cardiac risk factor (prior A, prior T, radiation, smoking, diabetes, hypertension, other). Compared to the overall pt population, only prior A and radiation were higher in pts who developed symptomatic LVSD. Conclusions: CLEOPATRA provides evidence that P+T+D does not increase overall cardiac disorders, specifically symptomatic LVSD, compared to Pla+T+D. [Table: see text]

Quality of life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer.

598^ Background: CLEOPATRA compared the efficacy and safety of the HER2 dimerization inhibitor pertuzumab (P) plus trastuzumab (T) and docetaxel (D) with placebo (Pla)+T+D in HER2-positive 1st-line MBC. Pts in both arms received a median of 8 cycles of D; Pla/P+T was continued until progressive disease (PD). The safety profile in both arms was similar with a substantial decrease in adverse events (AEs) once chemotherapy finished. The independently assessed progression-free survival was significantly improved with P+T+D compared with Pla+T+D; objective response and duration of response were also improved with P+T+D (Baselga NEJM 2012). Here we report health-related quality of life (HRQoL) data from CLEOPATRA. Methods: Time to deterioration of HRQoL was evaluated using the FACT-B questionnaire and defined as decrease from baseline (BL) of ≥5 points in the TOI-PFB subscale score. Female pts completed questionnaires every 3rd cycle of therapy within 3 days before each tumor assessment until independently determined PD. An exploratory analysis investigated time to deterioration in breast cancer symptoms and functions. Results: 56.7% (Pla+T+D) and 59.5% (P+T+D) of pts experienced deterioration of HRQoL during the study based on TOI-PFB. The median time to deterioration was 18.3 vs 18.4 wks (~6 cycles) (HR 0.97; P = .7161). At Cycle 6, the mean reduction in TOI-PFB score from BL was –3.5 (Pla+T+D) vs –3.0 (P+T+D). At subsequent cycles, when most pts had discontinued D, mean reductions were smaller, suggesting that after an early decline patients’ scores improved slightly. Overall, mean changes were small in both arms. Compliance with completion of the FACT-B questionnaire was ≥75% beyond the 1st year in both arms. An exploratory analysis suggested that time to deterioration in BCS score, which measures symptoms and issues relevant in breast cancer, was delayed with P+T+D (18.3 vs 26.7 wks; HR 0.77; P = .0061). Conclusions: Combining P with T+D appears to have no detrimental effect on HRQoL. Results suggest that P+T+D is associated with a substantial delay in the time to deterioration in BCS score as would be expected given the improved efficacy and the low incidence of AEs once D is discontinued.

Concordance between independently and investigator-assessed progression-free survival in CLEOPATRA.

e11055^ Background: In CLEOPATRA, pertuzumab (P) + trastuzumab (T) + docetaxel (D) was compared to placebo (Pla)+T+D in HER2-positive 1st-line MBC. In MBC trials, PFS rather than overall survival is often defined as the primary endpoint as PFS data are available earlier and later-line therapy does not impact results. The primary endpoint in CLEOPATRA, PFS, was assessed by an Independent Review Facility (IRF), with investigator (inv)-assessed PFS as a secondary endpoint. As a measure of consistency and robustness, concordance between IRF- and inv-assessed PFS was analyzed. Methods: PFS was defined as time from randomization to first documented radiographic evidence of progressive disease (PD) or death from any cause within 18 wk of the last IRF tumor assessment. Tumor assessments took place every 9 wk and continued until IRF-confirmed PD. Treatment decisions were solely based on the inv’s assessment of PD. Indicators of concordance between IRF- and inv-assessed PFS included: PFS event by IRF only; PFS event by inv only; PFS event by IRF and inv; no PFS event by IRF and inv. These indicators were assessed at any time on study, within 30 d or within 9 wk. Several pre-specified sensitivity analyses for PFS were also performed. Results: 808 pt were enrolled and central tumor assessments performed for 781 pt. Compliance with the schedule of tumor assessments was generally high and comparable between arms, with &gt;78% of pt undergoing assessments within 7 d of the scheduled visit over the 1st yr. At any time on study, concordance between IRF- and inv-assessed PFS was 85%. Of the 15% discordant cases, an equal proportion was assessed by the IRF as a PFS event but not by the inv and vice versa. Estimates of the median time to PFS event based on IRF and inv assessments were identical, Pla+T+D: 12.4 mo, P+T+D: 18.5 mo (IRF: HR 0.62, P &lt; .0001; inv: HR 0.65, P &lt; .0001). Conclusions: Concordance between IRF- and inv-assessed PFS was high, supporting consistency and robustness of the PFS analyses. The subjective nature of PD and potential for bias were reduced by the double-blind, placebo-controlled study design; RECIST 1.0 criteria; identical schedule of assessments in both arms; IRF review and continuation of tumor assessments until IRF confirmation of PD.

Pertuzumab in combination with trastuzumab plus an aromatase inhibitor in patients with hormone receptor-positive, HER2-positive metastatic breast cancer: A randomized phase II study (PERTAIN).

TPS654^ Background: Resistance to endocrine therapy in patients (pts) with breast cancer remains a major clinical concern. Preclinical studies suggest that complete blockade of the hormone receptor (HR) combined with the inhibition of HER family members may be necessary to overcome resistance and improve clinical outcome in HR-positive and HER2-positive breast cancer (BC). The combination of pertuzumab (P) and trastuzumab (H) with docetaxel significantly improves patient outcome by blocking, more efficiently and completely, the HER signalling pathway. This benefit, however, may be smaller in HR-positive patients. PERTAIN is the first clinical trial to study whether a more potent blockade of the HER pathway with P and H in combination with endocrine therapy may restore or enhance endocrine sensitivity of HER2-positive BC and provide an effective treatment option in pts with HER2-positive and HR-positive MBC. Methods: PERTAIN is a multicenter, open-label, Phase II trial for post-menopausal women with HER2- and HR-positive BC, studying the efficacy of the combination of P plus H with an aromatase inhibitor (AI) as first-line therapy for MBC. Pts will be randomized 1:1 to Arm 1 (P: 840 mg loading dose, 420 mg q3w IV; H: 8 mg/kg loading dose, 6 mg/kg q3w IV; AI [anastrozole 1 mg or letrozole 2.5 mg qd po]) or Arm 2 (H + AI at same dose as Arm 1). Pts in either arm may also receive induction chemotherapy (docetaxel or paclitaxel) for up to 18 weeks at the investigator’s discretion. Study medication will be administered until disease progression or unacceptable toxicity. Pts must not have previously been treated with anti-HER2 agents except H and/or lapatinib in the (neo)adjuvant setting, and must have no CNS involvement or clinically significant cardiovascular disease. The primary endpoint is PFS, and secondary endpoints include overall survival, overall response rate, clinical benefit rate, duration of response, time to response, safety and tolerability, and quality of life. The study opened in January 2012 and will recruit 250 pts. Analysis of the primary endpoint will be performed after 165 PFS events using the Kaplan-Meier approach.

Abstract 1395: Docetaxel pretreatment is associated with increased incidence of CNS-metastases in a murine model of HER2-positive breast cancer

Abstract Breast cancer is the most frequent neoplasm in females as it affects 1:10 women. In populations of early breast cancer subsequent brain metastases develop in 5%, while in metastatic breast cancer (mBC), the incidence of CNS-metastases reaches 10-16% [Ann Oncol 2006; 17:935]. The incidence is particularly high (30%-50%) in patients (pts) with HER2-positive mBC [Ann Oncol 2008; 19:1837]. Similarly, the incidence of CNS-metastases is high in pts treated with taxanes for mBC [Ann Oncol 2001; 12:353]. Therefore, we aimed to investigate the role of taxanes on CNS metastases in a murine breast cancer model using the MDA-MB-231BR cell line which has a tropism to metastasize into the CNS upon intracardiac injection [J Natl Ca Inst 2008;100:1092]. Groups of Balb/c nude mice were injected intravenously with docetaxel at a dose of 10mg/kg every 2 weeks for 5 injections (long tax, N=17) or with only 2 similar injections (short tax, N=16) or no injection (control, N=14). Two weeks later MDA-MB-231 BR tumor cells (500′000 cells in 0.1mL PBS) were injected into the left ventricle. Four weeks after that, animals were sacrificed for collection of organs and analysis by histology. The main finding was that metastatic foci were significantly increased in long-tax mice (median number of foci 52, range 0-76) compared to control mice (median number of foci 20, range 0-52; p=0.015). In short-tax animals an intermediate incidence of foci was found (median 30, range 0-79), with a trend, but not a significant difference compared to untreated animals (p=0.7) Histologically we observed a mainly perivascular intraparenchymal infiltration pattern while superficial metastases or a spread to the cerebrospinal fluid was only rarely seen. We therefore assessed changes of the blood-brain barrier (BBB) by ultrastructural approaches. However, we have not found obvious differences in the BBB configuration after taxane treatment. In summary, our results provide evidence that taxane treatment might facilitate spread of breast cancer cells into the CNS, however underlying mechanisms remain to be determined. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1395. doi:1538-7445.AM2012-1395

Correlation of efficacy between rash and lapatinib/capecitabine therapy in Japanese HER2-positive metastatic breast cancer patients.

62 Background: Lapatinib (L) is an oral dual-tyrosine kinase inhibitor with specificity for both EGFR and HER2. A phase III randomized trial (EGF100151) demonstrated that L+ capecitabine (C) is superior to C alone in patients with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Although, Japanese phase I/II trial (EGF109749) demonstrated better response rate and higher rate of rash over a previous phase III trial. Recent reports demonstrated the correlation of efficacy between EGFR targeted therapy and rash in colon cancer. In lung cancer EGFR mutation, which are predominantly found in patients of East Asia origin are highly sensitive to EGFR-TKI. Analyzing correlation of efficacy between rash and EGFR targeted therapy is important in breast cancer. Methods: From June 2009 to February 2010, we treated 28 HER2-positive MBC patients who developed progression after anthracyclines, taxanes and trastuzumab based regimens with L 1,250 mg p.o. daily plus C 2,000 mg/m2 p.o. days 1-14 q 21 in Saitama Cancer Center. EGFR status was evaluated by immunohistochemistry. We analyzed the correlation among rash, clinical outcome and EGFR status. Results: Fourteen (50%) patients experienced rash, which were two grade 3, four grade 2 and eight grade 1. Rash experienced group showed superior response rate (77% : 24%, p&lt;0.05) and median survival time (N/A: 259 days, p&lt;0.05) over non-rash group. EGFR status has no correlation between rash and clinical outcome. Conclusions: According to our single institute experience, rash might be predictive factor in Japanese HER2 positive breast cancer patients treated with L+C therapy.