HER2-overexpressing Metastatic Breast Cancer Research Articles

Abstract 5468: GEP01: A phase I pharmacokinetic study of lapatinib and iv vinorelbine in the treatment of HER2-positive locally advanced or metastatic breast cancer

Abstract Background: A novel combination of oral lapatinib (LPT), a selective dual ErbB1/ErbB2 targeted drug, + iv vinorelbine (VNR), a cell-cycle inhibiting agent, could provide a high-potential treatment for locally-advanced or metastatic HER2-overexpressing breast cancer refractory to first or second-line chemotherapy associated to trastuzumab. LPT has been shown to be a strong inhibitor of CYP3A4 which is also mainly involved in VNR metabolism. In this study we investigated the potential pharmacokinetic (PK) interactions related to the association of VNR and LPT. Methods: Women with HER2+ locally advanced or metastatic breast cancer progressing after ≤ 2 lines of trastuzumab-based treatment, were treated with LPT starting 7 days (D) (D-7 to D0) before adding VNR on a D1 & D8 q3w IV schedule. LPT was given orally continuously. Dose levels [DL, LPT (mg)/VNR (mg/m2)] ranged from 750/20 to 1,250/30. A total of 29 patients, 36 to 75 years old, were treated by the association of LPT + VNR. For PK analysis, 7 time point samples were collected on D1 of cycle 1 for LPT and VNR assays. For VNR and LPT respectively, whole blood and plasma concentrations were measured using UPLC coupled with tandem mass spectrometry validated methods. Population PK was modelled using a non linear mixed effect model program (Monolix version 3.1s) by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization). Results: A three-compartment open model adequately described VNR time versus concentration courses. The inter-individual variabilities (ISV) could be well estimated for all stuctural parameters (clearance : CL, volume of distribution : V, inter-compartmental clearances : Q) except for Q3 and V3. The population PK parameters obtained for the structural model were: CL=40.2 L/h, V1=8.49 L, Q2=46.9 L/h, V2=1290 L, Q3=61.9 L/h and V3=60.9 L. Influence of platelet counts and LPT dose values on blood VNR CL were significant according to the Bayesian Information Criteria (BIC). A one-compartment model adequately fitted the LPT plasma concentration-time data. The population PK parameters were CL=27.9 L/h, V=61.5 L and the absorption constant, ka=0.071 h−1. The ISV were 55.7% and 81.7% for CL and V respectively. No covariate effect, including body surface area and VNR dose values on any PK parameters for LPT could be identified. Conclusions: A PK interaction occured between VNR and LPT. When the LPT dose level increased, the VNR CL decreased significantly, probably due to CYP450-3A4 interaction. The LPT dose which should decrease VNR CL by 50% was defined as 1790 mg. No covariate effects on any LPT PK parameters had been identified. A PK/PD modelling using tumour evaluation and absolute neutrophil count (ANC) is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5468. doi:10.1158/1538-7445.AM2011-5468

How Long Is Long Enough?

How Long Is Long Enough?

A prospective multicenter phase II study of oral and i.v. vinorelbine plus trastuzumab as first-line therapy in HER2-overexpressing metastatic breast cancer

BackgroundTo evaluate the efficacy and safety of oral and i.v. vinorelbine plus trastuzumab as first-line regimen in a patient-convenient application for human epidermal growth factor receptor 2 (HER2)-overexpressing patients with metastatic breast cancer. Patients and methodsForty-two women were enrolled in a multicenter study. The patients received i.v. vinorelbine at a dose of 25 mg/m2 on day 1 followed by oral vinorelbine at a dose of 60 mg/m2 on days 8 and 15 in a 3-week cycle. Standard dose trastuzumab was given at 3-week intervals. ResultsComplete response was observed in 7 patients (18.9%) and partial response in 19 patients (51.4%), for an overall response rate of 70.3% [95% confidence interval (CI) 53.0–84.1]. The disease control rate reached 91.9% (95% CI 78.1–98.3). The median time to progression was 9.3 months, while median overall survival reached 35.6 months. Hematological and non-hematological toxic effects were acceptable with grade 3–4 leukopenia of 14% and neutropenia of 38%; cardiac toxicity did not reach the level of clinical relevance. ConclusionThe combination of i.v. and oral vinorelbine plus trastuzumab demonstrates high activity and good tolerability in first-line treatment of HER2-overexpressing metastatic breast cancer. In addition, it offers convenience for the patients with only one i.v. treatment every 3 weeks.

New Strategies in HER2-Overexpressing Breast Cancer: Many Combinations of Targeted Drugs Available

The anti-HER2 drugs trastuzumab and lapatinib are increasingly changing the natural history of early and metastatic HER2-overexpressing breast cancer. Many other agents targeted against the HER2 signaling network are in clinical development, and these are or will soon be combined with the currently approved anti-HER2 therapies. We review herein recent data in support of the early use of combinations of agents targeted to the HER2 network as the most rational approach against this subtype of breast cancer. We propose that the optimal combination or combinations of anti-HER2 agents delivered early in the natural history of HER2+ breast cancer should close to eliminate acquired drug resistance, shorten the duration of therapy, and potentially dispense with the need of concurrent chemotherapy.

Phase II Study of Vinorelbine Plus Trastuzumab in HER2 Overexpressing Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes

PurposeThe role of first-line trastuzumab-based therapy has been firmly established in patients with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer. In this trial, we evaluated the efficacy and safety of a vinorelbine and trastuzumab combination chemotherapy in patients who were pretreated with anthracyclines and taxanes.MethodsThirty-three patients with HER2 overexpressing metastatic breast cancer, all of whom had previously been treated with anthracyclines and taxanes, were included in this study. The patients were treated with 25 mg/m2 of vinorelbine (over a 15-minute infusion) on days 1 and 8 every 3 weeks. Additionally, trastuzumab was administered at an initial dose of 4 mg/kg over 90 minutes, and was subsequently administered at weekly doses of 2 mg/kg (over 30 minutes).ResultsThe median age of the patients was 53 years (range, 39-72 years). The overall response rate was 30.3% (10 patients; 95% confidence interval [CI], 23-57%). The median time to progression was 6.8 months (95% CI, 5.3-8.2 months). The median overall survival was 12.4 months (95% CI, 10.3-14.6 months). In the 194 cycles of treatment, the incidence rates of grade ≥3 neutropenia and anemia were 7.2% and 1.0%, respectively. Neutropenic fever was detected in three cycles (1.5%). The non-hematological toxicities were not severe: grade 1 or 2 nausea or vomiting was detected in 15.2%, and grade 2 neuropathy was noted in 6.1% of patients. None of the patients experienced any serious cardiac toxicity, and no treatment-related deaths occurred.ConclusionThese results show that a combination chemotherapy consisting of vinorelbine and trastuzumab is useful in patients with HER2-overexpressing metastatic breast cancer who were pretreated with anthracyclines and taxanes, with a favorable toxicity profile.

Abstract P3-14-24: Overall Survival Benefit Observed with Lapatinib (L) Plus Paclitaxel (P) as First-Line Therapy in Patients with HER2-Overexpressing Metastatic Breast Cancer (MBC)

Abstract Background: Lapatinib (L) is a potent, oral selective, reversible, inhibitor of EGFR (ErbB1) and HER2 (ErbB2) receptor tyrosine kinases. EGF104535 is a phase III, international, randomized, double-blind study comparing lapatinib plus paclitaxel (L+P) versus P alone as 1st linetreatment for pts with HER2-positive+ (MBC). The study was focused in the Asia Pacific region. Methods: Pts with centrally confirmed HER2-positive (by FISH) MBC and measurable disease were randomized to L 1500 mg daily + P 80mg/m2/wk 3 out of 4 wk or to P 80mg/m2/wk 3 out of 4 wk alone. Pts were administered P for 6 cycles with additional cycles at investigator discretion, and continued on blinded randomized therapy until disease progression (PD). At time of PD, there was an optional monotherapy extension to allow pts on P alone arm to receive L monotherapy. The primary endpoint of the study was overall survival (OS); secondary endpoints included progressionfree survival (PFS), overall response rate (ORR), clinical benefit rate (CBR) and safety. Analyses were conducted on the intent-to-treat population. Results: 444 pts (N=222/arm) across 43 centers were randomized: 67% of P pts received L monotherapy. Baseline demographics were well-balanced between treatment groups. OS was significantly longer in the combination therapy (L+P) as compared with P alone. [Cox Regression Analysis: Treatment Hazard Ratio (HR) (95% CI)=0.64(0.49,0.82), p=0.0005, Kaplan-Meier estimates: median OS 27.8 mos (95% CI=23.2,32.2) vs 20.5 mos (95% CI=17.9,24.3), respectively]. Median PFS increased to 9.7 mos (95% CI=9.2, 11.1) compared with 6.5 mos (95% CI=5.5, 7.3), in the L+P vs P, respectively [HR (95%CI)=0.52(0.42,0.64), stratified log rank P<0.0001]. ORR for L+P was 69% (95% CI=63%,75%) compared with 50% (95% CI=43%,56%) for P alone [Odds Ratio=2.3 (1.54, 3.47), P<0.0001]. CBR improved with L+P (75%, 95% CI=69%,80%) compared with P alone (56%, 95% CI=49%,63%) [Odds Ratio=2.34 (1.54, 3.58), P<0.0001]. The most frequent adverse events (AEs) were diarrhea (L+P, 77%, Grade 3/4 20/0; P, 29% Grade 3/4, <1/<1) and neutropenia (L+P, 77% Grade 3/4, 35/16; P, 47%, Grade 3/4, 15/5). The incidence of withdrawal from treatment due to AEs (13% vs 10%) was a similar. Conclusion: The combination of L+P showed a statistically and clinically meaningful survival advantage. Secondary endpoints support the observed clinical benefit. The combination of L+P was well tolerated. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-24.

Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer

To determine the feasible dose and schedule for everolimus, an oral mTOR inhibitor, combined with vinorelbine and trastuzumab for patients with HER2-overexpressing metastatic breast cancer pretreated with trastuzumab. In this phase Ib multicenter, Bayesian dose-escalation study, 50 patients received everolimus 5 mg/day, 20 mg/week, or 30 mg/week plus vinorelbine (25 mg/m² on day 1 and 8 every 3 weeks) and trastuzumab (2 mg/kg weekly). Endpoints included end-of-cycle-1 dose-limiting toxicity (DLT) rate (primary endpoint), safety, relative dose intensity, overall response rate (ORR), and pharmacokinetics. Grade 3/4 neutropenia was the most common end-of-cycle-1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg/day and 30 mg/week cohorts, respectively. Other end-of-cycle-1 DLTs included single cases of febrile neutropenia, grade 3 stomatitis with concomitant fatigue, grade 2 stomatitis, grade 3 anorexia, and grade 2 acneiform dermatitis, all in the 5-mg/day cohort. Based on the recorded DLTs and global safety, everolimus 5 mg/day and 30 mg/week were chosen as the optimal dose levels for the daily and weekly arms. Forty-seven patients were evaluable for efficacy. ORR was 19.1%, with a disease control rate of 83.0% and median progression-free survival of 30.7 weeks. No drug interaction was observed between everolimus and vinorelbine. Everolimus combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with HER2-overexpressing metastatic breast cancer that progressed on trastuzumab (NCT00426530).

A Single-Arm Phase II Trial of First-Line Paclitaxel in Combination with Lapatinib in HER2-Overexpressing Metastatic Breast Cancer

Introduction: Lapatinib, an orally active tyrosine kinase inhibitor of epidermal growth factor receptor ErbB1 (EGFR) and ErbB2 (HER2), has activity as monotherapy and in combination with chemotherapy in HER2-overexpressing metastatic breast cancer (MBC). Methods: This phase II single-arm trial assessed the safety and efficacy of first-line lapatinib in combination with paclitaxel in previously untreated patients with HER2-overexpressing MBC. The primary endpoint was the overall response rate (ORR). Secondary endpoints were the duration of response (DoR), time to response, time to progression, progression-free survival (PFS), overall survival, and the incidence and severity of adverse events. All endpoints were investigator- and independent review committee (IRC)-assessed. Results: The IRC-assessed ORR was 51% (29/57 patients with complete or partial response) while the investigator-assessed ORR was 77% (44/57). As per the IRC, the median DoR was 39.7 weeks, and the median PFS was 47.9 weeks. The most common toxicities were diarrhea (56%), neutropenia (44%), rash (40%), fatigue (25%), and peripheral sensory neuropathy (25%). Conclusions: First-line lapatinib plus paclitaxel for HER2-overexpressing MBC produced an encouraging ORR with manageable toxicities. This combination may be useful in first-line treatment for patients with HER2-overexpressing MBC and supports the ongoing evaluation of this combination as first-line therapy in HER2-overexpressing MBC.

Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab in Patients With Metastatic Breast Cancer Pretreated With Trastuzumab

To determine the recommended dose of everolimus, a mammalian target of rapamycin inhibitor, combined with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer pretreated with trastuzumab. In this phase Ib, multicenter, dose-escalation study, patients were treated with everolimus 5 mg/d, 10 mg/d, or 30 mg/wk in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (2 mg/kg weekly). End points included end-of-cycle 1 dose-limiting toxicity (DLT) rate (primary end point), safety, relative dose intensity of study drugs, overall response rate (ORR), and pharmacokinetics. Of 33 patients enrolled, 31 were pretreated with taxanes, and 32 were resistant to trastuzumab. Patients received a median of two lines of chemotherapy in the metastatic setting (range, 0 to 17 lines). Three patients experienced cycle 1 DLTs: febrile neutropenia (5 mg/d), stomatitis (10 mg/d), and confusion (30 mg/wk). Grade 3 to 4 neutropenia was the most common toxicity observed (n = 17 patients [52%]). On the basis of observed DLTs and overall safety, 10 mg/d was recommended for additional development. Twenty-seven patients had measurable disease and were evaluable for efficacy. Among these patients, ORR was 44%. Overall disease was controlled for 6 months or more in 74%. Median progression-free survival was 34 weeks (95% CI, 29.1 to 40.7 weeks). Among 11 patients who were resistant to both trastuzumab and taxane, a similar level of antitumor activity was observed (ORR, 55%). Everolimus combined with weekly paclitaxel and trastuzumab was generally well tolerated and had encouraging antitumor activity in patients with trastuzumab-pretreated and -resistant metastatic HER2-overexpressing breast cancer.

PTEN, PIK3CA, p-AKT, and p-p70S6K Status: Association with Trastuzumab Response and Survival in Patients with HER2-Positive Metastatic Breast Cancer

Phosphatase and tensin homolog (PTEN) is a key modulator of trastuzumab sensitivity in HER2-overexpressing breast cancer. Because PTEN opposes the downstream signaling of phosphoinositide 3-kinase (PI3K), we investigated the role of PTEN and other components of the PI3K pathway in trastuzumab resistance. We analyzed the status of PTEN, p-AKT-Ser473, and p-p70S6K-Thr389 using immunohistochemistry. PIK3CA mutation status was analyzed by direct sequencing. Primary tumor tissue was available from 137 patients with HER2-overexpressing metastatic breast cancer who had received trastuzumab-based chemotherapy. We observed that each of the four biomarkers alone did not significantly correlate with trastuzumab response, whereas PTEN loss alone significantly correlated with shorter survival times (P = 0.023). PI3K pathway activation, defined as PTEN loss and/or PIK3CA mutation, was associated with a poor response to trastuzumab (P = 0.047) and a shorter survival time (P = 0.015). PTEN loss was significantly associated with a poor response to trastuzumab (P = 0.028) and shorter survival time (P = 0.008) in patients who had received first-line trastuzumab and in patients with estrogen receptor- (P = 0.029) and progesterone receptor-negative tumors (P = 0.033). p-AKT-Ser473 and p-p70S6K-Thr389 each had a limited correlation with trastuzumab response. When these markers were combined with PTEN loss, an increased correlation with patient outcome was observed. In conclusion, PI3K pathway activation plays a pivotal role in trastuzumab resistance. Our findings may facilitate the evaluation of tumor response to trastuzumab-based and targeted therapies.

Phase II Trial of Weekly Nanoparticle Albumin-Bound Paclitaxel With Carboplatin and Trastuzumab as First-line Therapy for Women With HER2-Overexpressing Metastatic Breast Cancer

Purpose This multicenter phase II trial evaluated the efficacy and safety of weekly nanoparticle albumin-bound paclitaxel with carboplatin and weekly trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer (MBC). Patients and Methods We treated 32 patients who had measurable MBC that was HER2-positive defined by an immunohistochemical staining score of 3+ or gene amplification by fluorescence in situ hybridization, required for those with an IHC of 2+. Patients were treated with albumin-bound paclitaxel 100 mg/m 2 and carboplatin at area under the curve (AUC) = 2 on days 1, 8, and 15 of a 28-day cycle. Trastuzumab was administered at 2 mg/kg weekly after a loading dose of 4 mg/kg. Because of hypersensitivity reactions occurring during carboplatin infusion numbers 6–8 in 4 of the first 13 patients with this premedication-free regimen, the protocol was amended for carboplatin and dosed at AUC = 6 day 1 each 28-day cycle, in lieu of introducing steroid prophylaxis. Patients were treated with 6 cycles and allowed to continue with all 3 drugs or trastuzumab alone if free of progression and unacceptable toxicity after 6 cycles. Results The overall response rate (ORR) was 62.5% (95% CI, 45.7%–79.3%) with 3 confirmed complete responders (CRs; 9%) and 17 confirmed partial responses (PRs; 53%). An additional 6 patients (19%) had stable disease (SD) for greater than 16 weeks for a clinical benefit rate (ORR + SD > 16 weeks) of 81%. As of April 16, 2009, 20 patients (63%) had progressed with a median progression-free survival (PFS) of 16.6 months (95% CI, 7.5-26.5 months). Antitumor activity was similar for patients treated with weekly carboplatin and every-4-week carboplatin (ORR, 65% vs. 67%, respectively). Hematologic toxicities were the only grade 4 toxicities noted and were infrequent with grade 4 neutropenia in 3 patients (9%) and 1 febrile neutropenia. Grade 2/3 peripheral neuropathy was uncommon (13%/3%). Conclusion Weekly albumin-bound paclitaxel with carboplatin and trastuzumab is highly active in HER2-overexpressing MBC. In the absence of corticosteroid premedication, which we avoided with albumin-bound paclitaxel, carboplatin seems best dosed every 4 weeks rather than weekly because of carboplatin-associated hypersensitivity reactions. The regimen was very well tolerated with few grade 3 and 4 nonhematologic toxicities experienced, and severe hematologic toxicity and peripheral neuropathy were infrequent.

Trastuzumab Single-Drug Therapy after Failure of Cytotoxic Treatment for Metastatic Breast Cancer

Background: Trastuzumab is an established component of breast cancer combination regimens, but data on the safety and efficacy of single-agent therapy is sparse. Patients and Methods: 70 patients with HER2-overexpressing breast cancer after failure of at least one chemotherapy regimen for metastatic disease were recruited from 28 institutions. HER2 overexpression was 3+ in 96% and 2+/FISH+ in 4%. Treatment consisted of a loading dose of 4 mg/kg trastuzumab in the first week and 2 mg/kg per week thereafter, continued until progression. Results: Trastuzumab treatment duration ranged from 1 to 66 weeks (median: 12). Objective responses (complete response (CR)/partial response (PR)) were seen in 12/62 fully evaluable patients (19%; 2 CR) while another 29% showed stabilization of the disease. Half of the patients had experienced progression after 13 weeks while median duration of response reached 44 weeks. Median survival was 68 weeks with nearly one-third of the patients still alive after more than 3 years. The most frequent adverse reaction was infusion-related syndrome arising during the first administration. Significant cardiovascular problems were detected in 3 cases, all with anthracycline pretreatment. Conclusions: Patients with metastatic breast cancer overexpressing HER2 may benefit from trastuzumab single-drug treatment, predominantly due to its favourable safety profile.

Survival benefits from lapatinib therapy in women with HER2-overexpressing breast cancer: a systematic review

Breast cancer is the second cause of cancer mortality worldwide and there is an unmet need for novel anticancer agents. Lapatinib is a novel tyrosine kinase inhibitor for treatment of breast cancer with human epidermal growth factor receptor 2 (HER2) amplification. Given promising results in clinical studies, we investigated the survival benefits of lapatinib use in patients with HER2-overexpressing advanced or metastatic breast cancer. We searched MEDLINE, EMBASE, American Society of Clinical Oncology Meeting proceedings, San Antonio Breast Cancer Symposia proceedings, and the Cochrane Library between 2000 and 2008 for randomized controlled trials where lapatinib was used as single agent or in combination with or following other therapies. Three trials (n=704) met the inclusion criteria. Study quality was assessed by two independent reviewers and meta-analyses were conducted. Significant differences were observed between lapatinib-containing treatments to those without lapatinib in terms of survival. Pooled estimates suggested the hazard ratios of 0.61 [95% confidence interval (CI): 0.50-0.74] for progression-free survival and 0.76 (95% CI: 0.60-0.97) for overall survival. Objective response rate and clinical benefit rate also showed significant differences in favoring the use of lapatinib with odds ratios of 2.15 (95% CI: 1.48-3.11) and 2.23 (95% CI: 1.59-3.12), respectively. Heterogeneity between studies was not observed. In conclusion, addition of lapatinib to conventional anticancer treatment might offer superior survival benefit to patients with advanced metastatic HER2-overexpressing breast cancer. Further investigations on the use of lapatinib in combination with anticancer agents are warranted.

Oral vinorelbine (NVBO) in combination with trastuzumab (HER) in metastatic breast cancer (MBC): Data on efficacy and safety when administered in first- or second-line treatment.

e11508 Background: Vinorelbine plus HER is an active and well-tolerated regimen in HER2-overexpressing MBC. When HER is administered every 3 weeks, the use of oral vinorelbine can increase the patient's convenience avoiding local toxicity. We report the retrospective results of our clinical experience on the combined regimen of HER and NVBO as first- or second-line treatment in HER2+ MBC. Methods: Between April 2005 and March 2009, 18 patients (p) with histologically confirmed, measurable MBC were treated in 8 Spanish institutions. Tumors scored as +3 positive for HER2 by inmunohistochemistry or FISH+. P could have received a prior treatment line with HER plus chemotherapy (CT). Treatment consisted of HER 8 mg/kg as a loading dose, then 6 mg/kg i.v. every 3 weeks, plus NVBO 80 mg/m2 days 1 and 8, with a prior test of myelosensitivity at 60 mg/m2 for the first cycle (cy), every 3 weeks. Treatment was continued until progression or unacceptable toxicity. Results: Patient's characteristics were: PS 0-1, 94%; visceral involvement in 100%; >2 metastatic sites in 50%. Prior (neo)adjuvant CT in 11 p (61%); type of CT: anthracycline 63%, anthracycline+taxane 27%. Prior hormonetherapy, 9 p (50%). Treatment was administered as first-line CT in 8 p (44%); second-line CT in 10 p (56%). Median number of cy 6 (range 3-12). We analyzed 121 cy. NVBO dose reduction was performed in 2.9% cy on D1 and 1.6% cy on D8. Hematological toxicities (%cy): grade (g) 3 anemia, 0.8%; no g3-4 neutropenia was reported. Nonhematological toxicities (%cy): g3 asthenia, 0.8%; g3 diarrhea, 3.3%; g3 nausea/vomiting 1.7%. All patients were evaluable for response. 5 CR (28%), 6 PR (33%), and 5 SD (28%) were reported. Objective response (OR) rate 61%. Median follow-up was 4.3 months (range 2.3-17.03), At the time of analysis, 3 p presented PD and 1 p had died. Conclusions: The findings of this retrospective analysis when compared to the reported data in the literature in this population suggest that the combination of three-weekly HER plus oral vinorelbine (80 mg/m2 D1 and 8) has a similar efficacy when compared to i.v. vinorelbine while avoiding venous toxicity and adding comfort to the day 8 administration. No significant financial relationships to disclose.

Everolimus in combination with weekly paclitaxel and trastuzumab in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) with prior resistance to trastuzumab and taxanes: A multicenter phase II clinical trial.

1013^ Background: Resistance to trastuzumab (H) may be associated with deregulation of PTEN or mutations in PI3K/AKT pathway. Preclinically, everolimus (E), an oral inhibitor of mTOR, enhances activity, reverses resistance to H and demonstrates synergistic activity with paclitaxel (T). The objective of this phase II study was to evaluate the efficacy of E combined with T and H in heavily pretreated HER2-positive MBC pts. Methods: A multicenter, Novartis sponsored, phase II trial was conducted using: T 80mg/m2, IV on days 1, 8 and 15 q4w; H 4mg/kg IV loading dose, then weekly 2mg/kg; E daily 10mg in patients whose disease is resistant to both H (progression on or within 3 months of the end of H therapy for metastatic cancer or within 12 months after the end of neoadjuvant or adjuvant H) and taxanes (progression on or within 4 months of the end of taxane therapy for metastatic cancer or within 12 months after the end of neoadjuvant or adjuvant therapy.) Treatment continued until progression or unacceptable toxicity. Results: The study completed enrollment (n=55). Analyses were performed on 37 evaluable pts. Median treatment duration is 12 weeks (2-43) with19 pts still on treatment and 6 beyond 6 cycles. Pt characteristics were median age 56 y; visceral disease in 33 pts (89%) with lung and liver involvement in 18 pts (49%) and 21 pts (57%), respectively; median no. of prior chemo lines for metastatic disease 3 (range 0-8); prior anthracyclines in 25 pts (68%); prior lapatinib in 23 pts (62%). Twenty-five pts were evaluable for efficacy. We observed 5 (20%) confirmed PRs, 14 (56%) SDs and 6 (24%) PDs. Treatment was well tolerated. G3-4 neutropenia occurred in 12 pts (32%) with 1 case of febrile neutropenia, G3 stomatitis in 5 pts (13%) and G3 asthenia/fatigue in 2 pts (5%). Conclusions: These preliminary results confirm a previous phase I study showing that E in combination with T and H has an acceptable safety profile and promising anticancer activity in HER2-positive MBC pts pretreated with trastuzumab and taxanes. Updated safety, efficacy, and PFS results will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis, Pfizer Novartis Novartis, Pfizer Genentech, Novartis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.

Improved Prognosis by Trastuzumab of Women With HER2-Positive Breast Cancer Compared With Those With HER2-Negative Disease

TO THE EDITOR: We have read with great interest the article by Dawood et al, and we think that the findings reported by the authors deserve some comments. Between June 2000 and January 2004, we consecutively enrolled 68 women with metastatic breast cancer: 33 patients received vinorelbine alone, while 35 patients were given trastuzumab plus vinorelbine according to human epidermal growth factor receptor-2 (HER2) expression determined by immunohistochemistry. This was formally a phase II study, which demonstrated that women with HER2-overexpressing metastatic breast cancer when treated with trastuzumab and vinorelbine had a better prognosis than those with HER2-negative disease treated with vinorelbine alone. In our study, the vast majority of patients received chemotherapy for metastatic disease. No one had previously received vinorelbine and only three women with HER2-positive disease had previously received trastuzumab for metastatic disease. Thus, by our findings, we provocatively suggested that the assumption that HER2positive tumors have a worse prognosis could be no longer valid when treated with trastuzumab. In fact, with the use of trastuzumab, women with HER2-positive disease appeared to do far better than did patients with HER2-negative tumors, exhibiting consistently higher rates of response, longer time to progression, and improved overall survival. Given that HER2-positive breast cancer is being treated as a distinct clinical entity, we cannot include women with HER2-positive breast cancer in trials recruiting patients regardless of HER2 status. Our study was criticized because it lacked a randomization plan. But, because in HER2-positive tumors chemotherapy alone as first-line treatment has been replaced with a combination of chemotherapy and trastuzumab, a trial without trastuzumab in HER2-positive patients with breast cancer would be ethically inappropriate. Thus, a prospective comparison between patients treated for HER2-positive disease and women treated for HER2-negative breast cancer can be formally performed only as a phase II study, in which consecutively enrolled patients with metastatic breast cancer are treated with chemotherapy with or without trastuzumab, according to HER2 status. Decades of randomized clinical trials on the first-line treatment of metastatic breast cancer have never been able to show so remarkable differences in time to progression and overall survival as the three fundamental randomized trials comparing chemotherapy with chemotherapy plus trastuzumab in women with HER2overexpressing metastatic breast cancer have been able to do. The merit of the study by Dawood et al is to have retrospectively compared the prognosis of three groups of patients: women with metastatic HER2-positive breast cancer with and without the addition of trastuzumab with women with HER2-negative disease. We agree with the authors that trastuzumab has not only beneficially changed the natural history of HER2-positive breast cancer, but it has also improved the prognostic outcomes of women with HER2overexpressing tumors beyond those of women with HER2negative disease.

436 Trastuzumab- (H) and everolimus- (RAD001) containing regimens are safe and active when reintroduced in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) pre-treated with lapatinib

436 Trastuzumab- (H) and everolimus- (RAD001) containing regimens are safe and active when reintroduced in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) pre-treated with lapatinib

493 Prognostic factors to predict outcomes in patients with HER2-overexpressing metastatic breast cancer treated with trastuzumab containing chemotherapy as first or second line therapy: prognosis grouping according to the prognostic factors

493 Prognostic factors to predict outcomes in patients with HER2-overexpressing metastatic breast cancer treated with trastuzumab containing chemotherapy as first or second line therapy: prognosis grouping according to the prognostic factors

Promising Novel Approaches for Metastatic HER2-Overexpressing Breast Cancer Progressing on Trastuzumab: (1) Pertuzumab+Trastuzumab Active after Failed Sequential Therapy; (2) Adding Lapatinib & Continuing Trastuzumab Better than Lapatinib Alone, Reinforcing Trastuzumab Use Beyond Progression; (3) Trastuzumab+Ridaforolimus Effective in Heavily Pretreated Patients; (4) T-DM1 Shrinks Tumors after Multiple Previous Treatments

Promising Novel Approaches for Metastatic HER2-Overexpressing Breast Cancer Progressing on Trastuzumab: (1) Pertuzumab+Trastuzumab Active after Failed Sequential Therapy; (2) Adding Lapatinib & Continuing Trastuzumab Better than Lapatinib Alone, Reinforcing Trastuzumab Use Beyond Progression; (3) Trastuzumab+Ridaforolimus Effective in Heavily Pretreated Patients; (4) T-DM1 Shrinks Tumors after Multiple Previous Treatments

Trastuzumab-DM1: A Review of the Novel Immuno-Conjugate for HER2- Overexpressing Breast Cancer

Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-expressing breast cancer, the majority of patients with metastatic HER2 overexpressing breast cancer who initially respond to trastuzumab develop resistance within one year of initiation of treatment, and in the adjuvant setting, progress despite trastuzumab-based therapy. The immuno-conjugate Trastuzumab- DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1, a maytansine derivative, to HER2-expressing breast cancer cells. T-DM1 is the first immuno-conjugate with a non-reducible thioether linker in clinical trials. Here, we summarize evidence from pre-clinical studies, analyze clinical data, and discuss the potential clinical implications of T-DM1.