A-L Cheng

A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies

Background:Polo-like kinase 1 (Plk1) has an important role in mitosis. Volasertib (BI 6727), a potent and selective cell cycle kinase inhibitor, induces mitotic arrest and apoptosis by targeting Plk; this phase I study sought to determine its maximum tolerated dose (MTD) in Asian patients with advanced solid tumours.Methods:Patients were enrolled simultaneously into two 3-week schedules of volasertib: a 2-h infusion on day 1 (schedule A) or days 1 and 8 (schedule B). Dose escalation followed a 3+3 design. The MTD was determined based on dose-limiting toxicities (DLT) in the first treatment course.Results:Among 59 treated patients, the most common first course DLTs were reversible thrombocytopenia, neutropenia and febrile neutropenia; MTDs were 300 mg for schedule A and 150 mg for schedule B. Volasertib exhibited multi-exponential pharmacokinetics (PK), a long terminal half-life of ∼135 h, a large volume of distribution (>3000 l), and a moderate clearance. Partial responses were observed in two pre-treated patients (ureteral cancer; melanoma). Volasertib was generally well tolerated, with an adverse event profile consistent with its antimitotic mode of action and a favourable PK profile.Conclusions:These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients.

Abstract OT1-04-03: Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS)

Background For breast cancer (BC) patients with brain metastases (BM) who are not suitable for surgery/radiosurgery, whole brain radiotherapy (WBRT) remained the only standard treatment. Recently, we have demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for BM of BC progressing from WBRT (Clin Cancer Res. 2015;21(8):1851). The CNS objective response rate is 77.1% according to volumetric criteria, and 60% according to RECIST 1.1. It has been demonstrated that enlarged brain tumor size is a predictor of WBRT failure. We hypothesized that, for BC with BM, induction BEEP treatment could decrease the size of brain metastases and thereby enhance effectiveness of WBRT. Methods This is a Phase II, randomized, open-labelled study (NCT02185352). Key inclusion criteria: BC with measurable brain metastatic tumor who had not received WBRT and not suitable for surgery or radiosurgery; KPS ≥30%. Key exclusion criteria: patients who had leptomeningeal metastases; history of disease progression during prior cisplatin treatment. In the experimental arm, patients will be treated by induction BEEP for three cycles followed by WBRT. In the control arm, patients will receive upfront WBRT for brain metastases. The BEEP regimen consist of bevacizumab (15 mg/kg) on Day 1 and, with a 1 day window period, followed by etoposide (70 mg/m 2 /day, Day 2 to Day 4) and cisplatin (70 mg/m 2 , Day 2), in a 21-day cycle. Stratification is based on the Graded Prognostic Assessment (GPA) score. Primary endpoint: brain-specific progression free survival (PFS) according to RECIST 1.1; key secondary endpoint: the 2-month brain-specific objective response rate (BS-ORR) of BEEP alone and WBRT alone. Other secondary endpoints include overall survival, extra-CNS tumor PFS, safety, time-to-improvement of neurological function,brain-specific PFS according to volumetric criteria, and BS-ORR. Approximately 126 patients will be 2:1 randomized. Multi-center recruitment is ongoing. To our knowledge this is the first randomized trial investigating a targeted therapy plus chemotherapy as induction regimen followed by WBRT as first line treatment for BC with BM. Citation Format: Lu Y-S, Tseng L-M, Yu J-C, Rau K-M, Chao T-Y, Chen S-C, Chiu C-F, Chang Y-C, Chen TW-W, Lin C-H, Chang D-Y, Chao T-C, Huang S-M, Huang C-S, Cheng A-L. Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-03.

Abstract P4-14-23: A phase I/II study of the combination of lapatinib and oral vinorelbine in HER2 positive metastatic breast cancer

Background The combination of lapatinib and oral vinorelbine for HER2 positive metastatic breast cancer (MBC) is appealing due to the convenience of oral combinations, but the overlapping toxicities may be of concern. A phase I/II study was designed to understand the tolerability and efficacy of this combination treatment. Methods Female MBC patients (pts) with HER2 positive, but regardless of ER status, were eligible. In the phase I part, pts refractory to HER2-targeted treatment or chemotherapy were eligible. In the phase II part, only pts who had not exposed to HER2-targted treatment in the metastatic setting were eligible. Hormonal treatments were not allowed during the study for ER positive pts. Lapatinib was given once daily and oral vinorelbine was given on days 1 and 8 of a 21-day cycle. A 3+3 standard dose escalation rule was applied in phase I part (Table 1). The maximum tolerated dose (MTD) was the highest dose level with less than 33% of pts experiencing dose limiting toxicity (DLT) and will used as starting dose for phase II part. The primary endpoint of the phase II part was progression-free survival (PFS). Tumor response was assessed according to RECIST 1.1. Pt number estimation in the phase II part was based on Simon 2 stage design. Results From 2009 Jun to 2013 Feb, a total of 46 pts were enrolled in phase I (n=15) and II (n=31) parts. The median age was 52.8 (range 34.3-84.0) and the median follow-up time was 39.2 months (range 6.1-62.2). Twenty-eight (60.9%) pts were ER positive. In the phase I part, 2 pts in dose level III had DLTs (Grade 3 neutropenia and grade 3 diarrhea (n=1), prolonged neutropenia delaying next cycle treatment (n=1)). Other common ≥40% grade 1/2 adverse events (AE) in the first-cycle include diarrhea (80.0%), skin rash (66.7%), fatigue (60.0%), and vomiting (40.0%). The MTD was determined at lapatinib 1000 mg plus oral vinorelbine 50 mg/m2. In the phase II part, 11 pts had intra-patient dose escalation of vinorelbine from 50 to 60 mg/m2 after first-cycle if no major toxicities were noted. Grade 3/4 AEs in the first-cycle include neutropenia, diarrhea, and infection in 12.9%, 3.2% and 3.2%, respectively. Grade 1/2 AEs were similar to the phase I results. Persistent treatment (in 8 cycles) increased the rate of grade 3/4 neutropenia (22.6%) and ALT/AST elevation (6.5%).The median PFS was 5.6 months (95% CI 5.2-5.9); 6 (19.4%) pts had PR, and the clinical benefit rate (CBR) was 38.7%. A higher dose (level III vs. level II) of vinorelbine was not associated with a better CBR (p=0.71), PFS (p=0.73), or OS (p=0.11). Among pts who had disease progression records, 13.2% (5/38) had brain metastasis progression. Long-term disease control (under treatment for more than 2 years) were achieved in 13.0% (6/46, 2 ER positive, 4 ER negative) pts. Conclusion The combination of lapatinib 1000 mg and oral vinorelbine 60 mg/m2 was general tolerable with manageable toxicities. Clinical efficacy was demonstrated with long-term responders observed. Citation Format: Chen TW-W, Yeh D-C, Chao T-Y, Lin C-H, Chow LW-C, Hsieh Y-Y, Huang S-M, Cheng A-L, Huang C-S, Lu Y-S. A phase I/II study of the combination of lapatinib and oral vinorelbine in HER2 positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-23.

742TiPPHASE 3 RANDOMIZED, DOUBLE-BLIND, CONTROLLED STUDY OF CABOZANTINIB (XL184) VS PLACEBO IN SUBJECTS WITH HEPATOCELLULAR CARCINOMA WHO HAVE RECEIVED PRIOR SORAFENIB (CELESTIAL) (NCT01908426)

ABSTRACT Background: Currently, there are no approved systemic therapies for patients with advanced hepatocellular carcinoma (HCC) who fail sorafenib. Cabozantinib is an oral receptor tyrosine kinase inhibitor (TKI) with activity against tyrosine kinases including MET, RET and VEGFRs. MET and VEGFR signaling have been implicated in tumor neo-angiogenesis and invasion. MET is overexpressed in HCC compared with non-tumor liver tissue, with higher MET expression linked to poor prognosis. Cabozantinib prolonged survival in a MET-driven transgenic mouse model of HCC, and has demonstrated clinical activity in multiple solid tumor types, including 41 subjects with advanced HCC treated in a phase 2 randomized discontinuation study. Trial design: This phase 3, randomized, double-blind study evaluates the efficacy and safety of cabozantinib compared with placebo in subjects with advanced HCC previously treated with sorafenib and have progressed following 1-2 prior systemic treatments for HCC. Subjects must be ≥ 18 year old, have Child-Pugh Score of A and ECOG PS ≤ 1. Subjects are randomized 2:1 to receive either cabozantinib or placebo. Stratification factors are etiology of disease, geographic region and the presence of extrahepatic spread of disease and/or macrovascular invasion. The primary endpoint is overall survival. Secondary endpoints are progression-free survival and objective response rate by RECIST 1.1. Additional endpoints include safety, tolerability, circulating tumor cells, serum bone markers and plasma biomarkers, effects on bony disease assessed by bone scan and health-related quality of life (HRQoL) using the EuroQol Health questionnaire (EQ-5D-5L). Enrollment was initiated in September 2013. Target recruitment is 760 subjects. A total of 621 events planned with 2 interim analyses (at 311 and 466 events) would provide 90% power to detect a 31.6% increase in OS (HR = 0.76). This abstract was accepted and previously presented at ASCO 2014ILCA 2014. Disclosure: G.K. Abou-Alfa: Research Grants: Exelixis Consultancy: Exelixis; A. Cheng, T. Meyer, A.B. El-Khoueiry, M. Ikeda and T. Okusaka: Consultancy: Exelixis; H.G. Chun: Research grant: Exelixis Consultancy: Exelixis E. Janczewska: Research grant: Exelixis; J. Ping: Employee: Exelixis Stock ownership: Exelixis; A.E. Borgman-Hagey: Employee: Exelixis Stock Ownership: Exelixis; R.K. Kelley: Research grant: Exelixis Consultancy: Exelixis. All other authors have declared no conflicts of interest.

744TiPMET-POSITIVE ADVANCED HEPATOCELLULAR CARCINOMA AND CHILD-PUGH CLASS A LIVER FUNCTION IN ASIAN PATIENTS: A RANDOMIZED, MULTICENTER, PHASE IB/II TRIAL OF THE ORAL C-MET INHIBITOR MSC2156119J VS SORAFENIB

ABSTRACT Background: Advanced hepatocellular carcinoma (HCC) is associated with a poor prognosis. Sorafenib is the recommended treatment for HCC patients (pts); however, it is not widely used in Asia due to affordability and unsatisfactory efficacy. The highly selective c-Met inhibitor MSC2156119J showed promising antitumor activity in a phase I trial (Falchook et al. J Clin Oncol 2013:31[Suppl]:2506) with a recommended phase II dose (RP2D) of 500 mg/d. This phase Ib/II, open-label, multicenter trial assesses the efficacy of MSC2156119J monotherapy in first-line treatment vs sorafenib in Met-positive (Met+) advanced HCC pts (NCT01988493). Trial design: Primary objectives include confirmation of the RP2D of 500 mg MSC2156119J in HCC pts (phase Ib) and evaluation of MSC2156119J monotherapy efficacy vs sorafenib, as determined by time to progression (TTP) per independent read (phase II). Secondary objectives are preliminary antitumor activity of MSC2156119J, pharmacokinetics (phase Ib), tolerability, safety, and antitumor activity of MSC2156119J vs sorafenib (phase II: overall survival, objective response, disease control, time to symptomatic progression, progression-free survival, and TTP per investigator read). Main eligibility criteria include: Asian adults with confirmed advanced HCC of BCLC Stage C, Child-Pugh Class A liver function, ECOG status 0–2 (only phase II: Met + , defined as moderate or strong protein overexpression determined by immunohistochemistry, measurable disease according to RECIST v1.1, and eligible for sorafenib treatment), life expectancy >3 mo, no prior systemic anticancer treatment or treatment targeting the HGF/c-Met pathway (phase II only), no neoplasm other than HCC, and no impaired cardiac function, history of liver transplant, or gastrointestinal disease. The Phase Ib part is a “3 + 3” dose-escalation design (300 or 500 mg MSC2156119J p.o./d; 21-d cycle) enrolling up to 18 pts. The phase II part is planned to randomize 140 pts (1:1) who receive MSC2156119J at the RP2D p.o./d or 400 mg sorafenib p.o./twice daily (21-d cycle). Enrollment began on Jan 9, 2014. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting. All rights reserved. Disclosure: L. Xu: Employee of Merck Serono Pharmaceutical RD H. Zheng: Stock ownership: Merck/EMD Serono Employee of EMD Serono, Boston, MA; F. Bladt: Employee of Merck KGaA, Darmstadt, Germany. All other authors have declared no conflicts of interest.

Abstract P2-16-02: Bevacizumab, etoposide, and cisplatin (BEEP) is highly effective in brain metastases of HER2 positive breast cancer progressing from whole brain radiotherapy – Subgroup analysis of a multi-center phase II study

Background: We have recently reported that starting bevacizumab (BE) 1 day before chemotherapy could further induce tumor vascular normalization, thereby significantly enhanced the activity of etoposide (E) and cisplatin (P) in breast cancer patients (pts) with progressing brain metastases after whole brain radiotherapy (WBRT) (ESMO 2013). Lapatinib plus capecitabine is the only proven active regimen for the treatment of brain metastases of HER2 positive breast cancer, with a central nerve system (CNS) objective response rate (ORR) of 18-38% and median time to progression (TTP) of 3.6-5.1 months (mo) in those who had had prior WBRT. Material and methods: Twenty-three HER2 positive breast cancer pts with progressing brain metastases after WBRT were enrolled from Jan 2011 to Jan 2013. Protocol treatment was given in 21 day cycles: BE 15 mg/kg on day 1, E 70 mg/m2/day from day 2 to day 4, and P 70 mg/m2 on day 2 (BEEP regimen), for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS ORR. A CNS objective response was defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. This trial is registered with ClinicalTrials.gov ([NCT01281696][1]). Results: Median age was 55.1 (range 33-75); 9 pts were ER+, 14 pts were ER-; 15 pts were ECOG 0-2 (65.2%), and 8 pts were ECOG 3 (34.8%). All of them had previous exposure to trastuzumab, and 20 (87.0%) of them had received trastuzumab containing regimen for the treatment of metastatic disease. Eleven pts (47.8%) received lapatinib treatment before enrollment into this trial. The median lines of chemotherapy for the treatment of metastatic disease were 3 (range 1-8). The median BEEP treatment cycles were 6 (range 1-6). Sixteen of 23 pts (69.6%; 95%CI 47.1-86.8) achieved CNS objective response, including 6 pts (26.1%) with ≥80% and 10 pts (43.5%) with 50-80% CNS volumetric reduction, respectively. Five pts (21.7%) had 20-50% CNS volumetric reduction. Seven of 11 (63.6%) who were refractory to lapatinib treatment had CNS tumor response, and 9 of 12 (75.0%) who were lapatinib naive had CNS ORR. With median follow-up of 12.1 months (mo), the median time to progression was 7.7 mo (95% CI 6.6-8.8), and overall survival was 11.8 mo (95% CI 7.0-16.6) among the 23 pts. Only 3 pts (13.0%) had disease progression during protocol treatment. Grade 3/4 toxicities (≥1%) included neutropenia, leukopenia, thrombocytopenia, infection, anemia, and in 32.7%, 14.0%, 8.4%, 8.4%, and 5.6% per cycles, respectively. Ten pts (43.5%) needed dose reduction of E to 60 mg/m2 and P to 60 mg/m2, and 2 pts discontinued from treatment due to toxicity. Conclusions: BEEP regimen has a significant anti-tumor effect for HER2 positive breast cancer with brain metastasis which progresses after WBRT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-02. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01281696&atom=%2Fcanres%2F73%2F24_Supplement%2FP2-16-02.atom

Abstract P3-06-02: Genetic polymorphisms from genome-wide association study associated with the metabolic and cell proliferation pathways affect the time to distant metastases of hormone receptor-positive and Her2-negative early breast cancer

Background: Single nucleotide polymorphisms (SNPs) identified from genome-wide association study (GWAS) have been found to be associated with breast cancer risk. We hypothesized that candidate genes and genes derived from GWAS involving in the Estrone/Estradiol (E2)/Tamoxifen biosynthesis may influence the adjuvant hormonal therapy effect and the survival. In this study, we sought to investigate whether these SNPs are associated with prognosis of hormone receptor (HR)-positive breast cancer patients, especially in HER2-negative patients. Patients and methods: We selected breast cancer susceptibility SNPs identified by GWAS, SNPs in tamoxifen metabolizing related genes, and SNPs in estrogen receptor genes and estrogen metabolism genes, and genotyped for variations of above genes, including ALDH3A1 , CYP2C19 , COMT , CYP19 , MAP3K1 , FGFR2 , TNRC9 , HCN1 , ERCC4 , CYP3A5 , UGT1A1 , ER , ABCG2 , CYP2B6 , CYP2D6 , 5p12 in 171 hormone receptor-positive, and Her2-negative early breast cancer patients (127 with negative lymph node [LN], and 44 with 1–3 positive LN). All patients received adjuvant hormonal therapy. The associations were examined between SNPs and distance disease-free survival (DDFS), and overall survival (OS) by using the log-rank test and Cox9s proportional hazard model. Furthermore, we combined clinicopathologic features and SNPs into the risk score analysis to further validate above identified genetic markers. Results: We found that SNPs of CYP2B6 (rs3211371), FGFR2 (rs2981582), and MAP3K1 (rs889312) were significantly associated with DDFS and OS. Furthermore, in lymph node-negative patients, CYP2B6 (rs3211371), FGFR2 (rs2981582), MAP3K1 (rs889312) and 5p12 (rs10941679 and rs4415084) were significantly associated with DDFS and OS, while CYP3A5 (rs776746) was significantly associated with OS but not DDFS. We further assessed the associations of disease prognosis with the number of high-risk genotypes in CYP3A5 , FGFR2 , and MAP3K1 , and showed significant dose-response relationships between the number of high-risk alleles at these 3 loci and DDFS ( P = 0.005 for trend) and OS ( P = 0.0008 for trend). When combining the clinicopathologic features and SNPs into the risk score analysis, patients were divided into 3 subgroups (subgroup 1, risk score 1.708, n=43 [LN-positive, n=11]). We found that around 20 % of subgroup 3 patients had early development of distant metastases (DM) in the upfront 3 years (the trend of DM appeared to persist at least 10 years), and subgroup 2 patients had higher risk of DM after 5 years, whereas subgroup 1 patients had no development of DM even after 12 years. Conclusion: Our results indicate that in addition to drug metabolic genes, genes related to cell proliferation, anti-apoptosis, and signaling transduction, for example, CYP3A5 , CYP2B6 , FGFR2 , and MAP3K1 genes were associated with DDFS and OS in HR-positive/Her2-negative breast cancer patients. These findings provide additional insight that the genetic variants, or host factors, may affect the prognosis of breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-02.

Abstract P6-05-15: Glucocorticoids has diverse effect on the tumorigenicity in estrogen receptor positive and estrogen recptor negative cancer cells

Background: Glucocorticoids (GCs) exerts its biologic effects via GC receptor (GR), which has been linked to signal transduction pathways inducing apoptosis in many hematological malignancies. Generally, GCs are considered not affecting the growth of gross tumor of most non-hematological solid tumor. However, a recent study using meta-analysis of primary breast tumor gene expression from 1378 early breast cancer patients with long-term follow-up, showing that high levels of GR expression significantly correlated with shorter relapse-free survival in estrogen receptor (ER) negative patients. On the contrary, in ER+ breast cancer patients, high levels of GR expression in tumors were significantly associated with better outcome relative to low levels of GR expression. (Cancer Res. 2011, 15;71: 6360–70). We hypothesized that GC has differential effect on the tumorigenicity in ER+ and ER− breast cancer cells. Methods: Twelve ER− breast cancer cell lines and 5 ER+ breast cancer cell lines were tested. MTT assay, clonogenic assay and soft agar assay was performed with cancer cells treated with or without dexamethasone (DEX). Flow cytometry were applied to detect the effect of DEX on the expression of cancer stem cell markers after treatment with DEX. Nude mice tail vein injection assay of cancer metastasis was performed to evaluate the in vivo tumorigenicity. Transfection with ER expression vector to MDA-MB231, a triple negative cancer cell, by lipofectamine was carried to determine the role of ER in this scenario. Results. DEX significantly enhanced colony forming ability and/or tumorigenicity in 12 ER− breast cancer cell lines. However, DEX did not affect the proliferation rate of these cancer cells according to MTT assay. We further explored whether DEX could affect the population of cancer stem-like cell, and thereby resulted in increase of tumorigenicity. By flow cytometry study, we found treatment of DEX significantly increased the number stem cell marker + (for examples, ALDH+) cells in ER− cancer cell lines, but not in ER+ cell lines. Sorting and collection of these stem cell marker + cells demonstrated that they had much higher colony forming efficiency and tumorigenicity. Further, in nude mice model by tail vein injection with MDA-MB-231-Lu2 (derived from lung metastasis of MDA-MB-231 cells after two in vivo passages in nude mice using intracardiac injection), treatment of DEX significantly increased the lung metastatic foci number and size. In contrast, DEX significantly decreased the colony forming ability and tumorigenicity in 5 ER+ cancer cell lines. Short term exposure (72hr) of DEX resulted in increased p21 expression and cell cycle G1 arrest in MCF7, an ER+ cancer cell. Prolong incubation of MCF7 cells with DEX (more than 10 days) induced cell apoptosis. When MDA-MB231 cells were stably transfected with ER, MDA-MB231/ER cells showed similar phenotype as those of ER+ cancer cell lines, i.e., DEX decreased the clonogenic and tumorigenicity ability. Studies on underlying mechanisms are ongoing, and preliminary result showed that there is cross talk between ER and GR. Conclusions: GC increased tumorigenicity in ER− breast cancer cells, but decrease tumorigenicity in ER+ cancer cells. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-15.

Abstract P3-14-18: Result of Phase I Part of a Phase I/II Study of Lapatinib (L) Plus Oral Vinorelbine (oVNR) in Metastatic Breast Cancer (MBC) Patients Overexpressing ErbB2

Background: Lapatinib(L) is effective in overexpressing ErbB2 MBC patients. Oral vinorelbine (oVNR) has similar efficacy to that of the injection formulation and has demonstrated generally favorable tolerability. Oral medications provide convenient treatment and satisfactory life quality. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies. Methods: This open-label, single-center, single-arm phase I study aimed to determine the maximum tolerated dose (MTD) and recommended dose of L+oVNR to women with ErbB2+ MBC, in progression after trastuzumab-taxane based treatment. Patients refractory to any line of anticancer treatment including vinorelbin was allowed to join in this study, except lapatinib. Cohorts of 3 patients received oral vinorelbine at escalating doses of 30-80 mg/day on day 1 and day 8 every 3 weeks (q3w) combined with lapatinib at escalating doses of 1000-1250 mg/day given po continuously, with each successive cohort until the MTD (2/3, 2/6 patients experiencing dose-limiting toxicity [DLT]) was reached. Additional patients received repeated administration at the recommended dose. G-CSF as primary prophylaxis of febrile neutropenia was not permitted. Results: 15 patients have been enrolled. During dose escalation, 2 of 3 experienced DLT at dose level of oral vinorelbine 60mg/kg day 1 and day 8 q3w plus lapatinib 1000mg/day. One with grade 3 diarrhea and the other with prolonged grade 3 neutropenia. This dose level was declared as MTD. Therefore we stop recruiting patient into next dose level of oral vinorelbine 60mg/kg plus lapatinib 1250mg/day. Recommended dose was lapatinib 1000mg/day with oral vinorelbine 50mg/kg day 1, day 8 q3w. There is no DLT experienced in 12 patients with the dose level below MTD. The most frequent treatment-related adverse events included diarrhea, skin rash, and fatigue, mostly grade 1-2. As of June 2010, 6 patients are still on treatment. Efficacy signals in other 9 patients included 2 maintained stable disease (SD) > 6 months (both of them had unconfirmed PR during treatment), 1 unconfirmed partial response (PR), 1 SD Conclusions: The combination of lapatinib and oral vinorelbine is tolerable and has antitumor activity in heavily pretreated ErbB2+ MBC. Further phase II study is underway. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-18.