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Preclinical data have demonstrated that the combination of antihuman epidermal growth factor receptor-2 (anti-HER2) and antivascular endothelial growth factor (anti-VEGF)--targeted agents has antitumor activity; these data indicate certain patients with HER2-overexpressing breast cancer may derive clinical benefit from this combination. The purpose of this single-arm phase II study was to determine the efficacy and safety of the dual-targeting combination of lapatinib and bevacizumab. Women with HER2-overexpressing advanced breast cancer received 1,500 mg oral lapatinib daily plus 10 mg/kg IV bevacizumab every 2 weeks. The primary endpoint was progression-free survival (PFS) at week 12; secondary endpoints included overall tumor response rate (ORR), clinical benefit rate (CBR), duration of response, time-to-response, PFS, and safety. Circulating tumor cells (CTC) and circulating endothelial cells (CEC) were measured at baseline and during study treatment as potential response markers. Fifty-two patients with stage IV disease were enrolled. The 12-week investigator-assessed PFS rate was 69.2% (95% confidence interval [CI]: 54.9, 81.3). Median PFS was 24.7 weeks (95% CI: 20.4, 35.1), and the CBR was 30.8% (95% CI: 18.7, 45.1). Of 45 patients with measurable disease, 6 were determined to have a partial response per Response Evaluation Criteria in Solid Tumors (ORR: 13.3%; 95% CI: 5.1, 26.8). The most common adverse events (AEs) included diarrhea, rash, and fatigue; most of these were either grade 1 or 2. Clinical responses were correlated with decreases in CTC and CEC. Lapatinib plus bevacizumab was active in patients with HER2-overexpressing breast cancer. The AE profile of the combination was consistent with the known profiles for these agents.

Purpose: Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy. Experimental Design: In available breast cancer tissue from EGF30001 (paclitaxel ± lapatinib in HER-2-negative/unknown metastatic breast cancer, n = 579) and EGF100151 (capecitabine ± lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression by HercepTest immunohistochemistry (IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and in a large, high-volume commercial reference laboratory. Results: The HER-2 gene was amplified in 47% (344 of 733) and IHC was 3+ in 35% (279 of 798), with significant correlation (P < 0.01) between FISH and IHC. Positive EGFR immunostaining (IHC 1+, 2+, or 3+) in 28% (213 of 761) correlated with EGFR mRNA levels by RT-PCR (r = 0.59; P < 0.01). HER-2 gene amplification/overexpression was associated with improved clinical outcomes (progression-free survival; P < 0.001) in both trials. A significant improvement in outcome was seen in FISH-positive and IHC 0, 1+, or 2+ patients. HER-2 mRNA expression correlated with HER-2 FISH (r = 0.83) and IHC status (r = 0.72; n = 138). No correlation was found between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER-2 status. Although a significant correlation with lapatinib responsiveness was observed among “HER-2-negative” breast cancer patients in the large, high-volume commercial reference laboratory, this was not confirmed in the academic reference/research laboratory. Conclusions: Women with HER-2-positive metastatic breast cancer benefit from lapatinib, whereas women with HER-2-negative metastatic breast cancer derive no incremental benefit from lapatinib.

Metabolomics, a global study of metabolites and small molecules, is a novel expanding field. In this pilot study, metabolomics has been applied to serum samples from women with metastatic breast cancer to explore outcomes and response to treatment.Pre-treatment and serial on-treatment serum samples were available from an international clinical trial in which 579 women with metastatic breast cancer were randomized to paclitaxel plus either a targeted anti-HER2 treatment (lapatinib) or placebo. Serum metabolomic profiles were obtained using 600 MHz nuclear magnetic resonance spectroscopy. Profiles were compared with time to progression, overall survival and treatment toxicity.Pre- and on-treatment serum samples were assessed for over 500 patients. Unbiased metabolomic profiles in the biologically unselected overall trial population did not correlate with outcome or toxicity. In a subgroup of patients with HER2-positive disease treated with paclitaxel plus lapatinib, metabolomic profiles from patients in the upper and lower thirds of the dataset showed significant differences for time to progression (N = 22, predictive accuracy = 89.6%) and overall survival (N = 16, predictive accuracy = 78.0%).In metastatic breast cancer, metabolomics may play a role in sub selecting patients with HER2 positive disease with greater sensitivity to paclitaxel plus lapatinib.

Purpose: It has been suggested that a subgroup of human epidermal growth factor receptor 2 (HER2)–negative breast cancer patients with chromosome 17 (Chr-17) polysomy benefit from HER2-directed therapy. This hypothesis was examined using the data from a phase III trial that randomized patients with HER2-negative or HER2-untested metastatic breast cancer to first-line therapy with paclitaxel along with either lapatinib or placebo. Experimental Design: HER2 expression level by immunohistochemistry, fluorescence in situ hybridization (FISH), and mean HER2 ratio of Chr-17 values were determined centrally using archival tissue. Polysomy means of 2.0 and 2.2 served as thresholds. Results: Of 580 patients on the original trial, 406 were HER2 negative by FISH. Progression-free survival (PFS) data were available for 405 patients, of whom 44 (11%) met the definition of polysomy (Chr-17 ≥2.2, FISH negative for HER2). Median PFS in the polysomy group was 20.9 and 24.4 weeks for paclitaxel plus lapatinib and paclitaxel plus placebo, respectively. In the nonpolysomy group, median PFS was 24.6 and 23.1 weeks for paclitaxel plus lapatinib and paclitaxel plus placebo, respectively. Log-rank testing showed no treatment advantage for either group. Similar results were found using a Chr-17 polysomy cutoff of 2.0. Response rates in the polysomy group were 17% for paclitaxel plus lapatinib and 10% for paclitaxel plus placebo. In the nonpolysomy group, response rates were 32% for paclitaxel plus lapatinib and 25% for paclitaxel plus placebo. Neither comparison was statistically significant. Conclusion: This analysis could not confirm the hypothesis that Chr-17 polysomy in HER2-nonamplified patients improved chemotherapy outcome when lapatinib is added as a HER2-targeted treatment. Clin Cancer Res; 16(4); 1281–8

Purpose The HER2 extracellular domain (ECD) is enzymatically cleaved from the cell membrane. Shed ECD in serum has been studied as both prognostic and predictive markers. Lapatinib is a dual inhibitor of HER2 and epidermal growth factor receptor kinases. We examined the prognostic and predictive role of HER2 ECD in a randomized trial of paclitaxel with placebo or lapatinib in women with HER2-negative or -unknown breast cancer. Patients and Methods Patients (n = 579) with newly diagnosed metastatic breast cancer (MBC) were randomly assigned to paclitaxel with placebo or lapatinib. HER2 status was determined centrally. ECD was centrally measured by enzyme linked immunoassay in available samples at baseline (b; n = 472), week 9, and every 12 weeks thereafter. Results were correlated to overall response rate (ORR) and progression-free survival (PFS). Results Elevated baseline ECD (bECD) levels (≥ 16 ng/mL) did not predict HER2 tumor status (sensitivity, 62%; specificity, 75%). In HER2-negative tumors, elevated bECD was not correlated with improved efficacy for lapatinib plus paclitaxel versus placebo plus paclitaxel (ORR: odds ratio, 1.6; 95% CI, 0.1 to 3.8; P = .365; PFS: hazard ratio, 0.94; 95% CI, 0.60 to 1.47; P = .797). ECD levels tended to decrease over time when bECD was elevated. ECD conversion from low to high was associated with worse PFS. Converting from high to low was associated with a better PFS. A consistently low ECD level had better PFS than a consistently elevated ECD. All associations were found to be independent of lapatinib. Conclusion HER2 bECD does not predict lapatinib benefit in patients with HER2-negative MBC. Changes in ECD status correlates with patient outcome regardless of treatment given. Measuring HER2 ECD is not currently recommended for predicting benefit to lapatinib.

Purpose Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) with activity in HER2-amplified metastatic breast cancer (MBC). Its role in non–HER2-amplified MBC remains unclear. EGF30001, a phase III trial of lapatinib and paclitaxel versus paclitaxel and placebo, demonstrated lapatinib does not significantly benefit HER2-negative or HER2-unselected patients with MBC. Published data support interactions between steroid hormone and peptide growth factor signaling. We hypothesized that molecular subgroups may exist within EGF30001 that would benefit from lapatinib. Methods A blinded, retrospective biomarker evaluation was performed using immunohistochemistry to semiquantitate estrogen (ER), progesterone (PR), and EGFR expression. HER2 amplification was determined by fluorescent in situ hybridization. Effects of these biomarkers on event-free survival (EFS) were examined in patients with available tissue (n = 493). Results Lapatinib improved median EFS in HER2-amplified, ER- or PR-positive MBC (n = 36; 5.7 v 4.5 months; P = .351); benefit was greater and statistically significant in HER2-amplified, ER-negative, PR-negative MBC (n = 42; 8.3 v 5.0 months; P = .007). In HER2-negative, ER-positive MBC, median EFS improvement varied by degree of PR expression (H-score): no benefit if PR-strong (n = 133; 9.3 v 7.3 months; P = .373), benefit if PR-weak (n = 50; 7.3 v 2.4 months; P = .026), and potential antagonism if PR-negative (n = 40; 3.7 v 7.2 months; P = .004). No benefit was seen in triple-negative MBC (n = 131; median EFS, 4.6 v 4.8 months; P = .255). EGFR expression was not correlated with benefit from lapatinib. Conclusion Although subgroups are small, these analyses support the hypothesis that semiquantitative determination of hormone receptor status may be a surrogate for EGFR and/or HER2 dependency.

Purpose Lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2–positive locally advanced or metastatic breast cancer (MBC). This phase III trial evaluated the efficacy of lapatinib in HER-2–negative and HER-2–uncharacterized MBC. Patients and Methods Women with MBC were randomly assigned to first-line therapy with paclitaxel 175 mg/m2 every 3 weeks plus lapatinib 1,500 mg/d or placebo. A preplanned retrospective evaluation of HER-2 status was performed using fluorescence in situ hybridization and immunohistochemistry. The primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS), and overall survival (OS). Results In the intent-to-treat population (n = 579), there were no significant differences in TTP, EFS, or OS between treatment arms, although differences in ORR and CBR were noted. In 86 HER-2–positive patients (15%), treatment with paclitaxel-lapatinib resulted in statistically significant improvements in TTP, EFS, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any end point in HER-2–negative patients. The most common adverse events were alopecia, rash, and diarrhea. The incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm. The rate of cardiac events was low, and no difference was observed between treatment arms. Conclusion Patients with HER-2–negative or HER-2–untested MBC did not benefit from the addition of lapatinib to paclitaxel. However, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2–positive patients. Prospective evaluation of the efficacy and safety of this combination is ongoing in early and metastatic HER-2–positive breast cancer patients.

Purpose This study ( EGF20009 ) assessed the efficacy and tolerability of two lapatinib administration schedules as first-line monotherapy in women with ErbB2-amplified locally advanced or metastatic breast cancer. Patients and Methods Patients with ErbB2-amplified, locally advanced or metastatic breast cancer previously untreated in the metastatic setting were randomly assigned to one of two lapatinib dose cohorts and received either 1,500 mg once daily or 500 mg twice daily. Clinical response was assessed at weeks 8 and 12 and every 12 weeks thereafter. Results A total of 138 patients were treated with lapatinib for a median of 17.6 weeks. The overall response rate (complete response [CR] plus partial response [PR]) was 24% in the intent-to-treat population, and 31% of patients derived clinical benefit (CR, PR, or stable disease for ≥ 24 weeks). The median time to response was 7.9 weeks, and the progression-free survival rates at 4 and 6 months were 63% and 43%, respectively. The most common lapatinib-related adverse events (AEs) were diarrhea, rash, pruritus, and nausea, and these events were primarily grade 1 or 2. There were no significant differences in clinical activity or the AE profile between the dosing schedules. Conclusion Lapatinib demonstrated clinical activity and was well tolerated as first-line therapy in ErbB2-amplified locally advanced or metastatic breast cancer. This study supports further evaluation of lapatinib in first-line and early-stage ErbB2-overexpressing breast cancer.

TPS9112 Background: Dabrafenib (D) has clinical activity in patients (pts) with BRAF V600E/K mutation–positive melanoma brain metastases (MBM). The combination of D and trametinib (T) has increased...

1049 Background: A phase III randomized, multicenter, double-blind, placebo-controlled study compared first-line therapy with lapatinib and paclitaxel (L+P) versus paclitaxel alone (P) for MBC. In a sub-group analysis of HER2+ patients, time to tumor progression for L+P was significantly improved, with an emerging trend for survival benefit. This analysis models the QOL data in the subset of the randomized ITT population that overexpressed HER2 (FISH+ or IHC3+). Methods: QOL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. Outcome measures included FACT-B total score, trial outcome index (TOI) score and breast cancer subscale (BCS). Higher scores represent better QOL. Patients completed the FACT-B at the screening visit, week 9, every 12 weeks thereafter, and at discontinuation of therapy. The assessment at discontinuation was applied to the next scheduled visit for analyses. Changes from baseline were analyzed using repeated measures models with baseline score as a covariate. Pattern mixture modeling was implemented as a sensitivity analysis. Results: Of 579 randomized patients, 86 were HER-2+ and 85 completed at least one item from the FACT-B (n = 48 L+P; n = 37 P). The baseline characteristics of this subset were well-matched with regard to age, ECOG status, and prior anthracycline use. More patients in the L+P group than in the P group had visceral disease (69% vs 51%) and more were at stage IV (88% vs 78%).Over the first year, the L+P arm demonstrated stable FACT-B scores over time, whereas average scores for patients on paclitaxel monotherapy decreased (change from baseline: L+P p = 0.99; P p = 0.01). Statistically significant differences were observed between treatment arms on the FACT-B (p = 0.05), TOI (p = 0.03), and BCS (p = 0.01). Pattern mixture models suggested more QOL differentiation between treatments among patients who progressed or withdrew within 6 months of study start. Conclusions: Among patients with HER2+ MBC, treatment with L+P resulted in more stable QOL than with P monotherapy. These findings represent clinically important differences between treatment groups. [Table: see text]

1018 Background: Lapatinib (Lap), an oral, dual inhibitor of EGFR/HER-2, is approved with capecitabine for treatment of HER-2+ MBC for recurrence after taxane, anthracycline, and trastuzumab-based therapy. Letrozole (Let) has activity in hormone-receptor positive (HR+) BC. It has been hypothesized that peptide growth factor signaling and hormone signaling pathways interact and dual targeting of these pathways results in therapeutic synergy. We report a blinded analysis of HER-2, ER, and progesterone receptor (PR) expression for patients (pts) with HR+ MBC at first diagnosis or post-adjuvant relapse and response to Lap + Let versus Let. Methods: 1286 pts were randomized 1:1 to 2.5 mg Let daily plus either 1500 mg Lap daily or placebo. The primary endpoint was PFS in HR+, HER-2+ MBC pts; secondary endpoints included PFS in the intent-to-treat population. Blinded, centralized commerical laboratory analysis of archived tumor tissue for HER-2 (IHC and/or FISH) and academic laboratory semi-quantitative analysis of ER/PR (IHC, H-score) was performed and correlated with clinical outcome. Results: In 219/1286 (17%) HER-2+ (FISH+ or IHC3+) pts, a significant improvement in median PFS was observed for Lap + Let versus Let (8.2 v 3.0 mos, HR = 0.71, 95% CI 0.53, 0.96, p = 0.019). No significant difference in median PFS was seen in 952 (74%) HER-2-negative pts (13.4 v 13.7 mos, HR = 0.90, 95% CI 0.77, 1.05, p = 0.188). 821/952 (86%) HER-2-negative pts had tissue available for quantitative ER and PR analysis. Analysis of ER and PR by quartile identified a subgroup of HER-2-negative pts that benefitted from adding Lap to Let. Pts with the lowest quartile of ER expression (H-score [Table: see text]

Abstract #58 Background: Identification of molecular predictors of response is an important aspect of individualized cancer treatment. Responses to lapatinib (L), an oral inhibitor of HER2 and EGFR, approved in combination with capecitabine for HER2+ metastatic breast cancer (MBC), were evaluated in a panel of BC cell lines. Computational approaches were used to identify transcripts that quantitatively associate with response to L in the cell line panel that were then tested in 2 clinical trials. Methods: The clinical utility of a 6-gene predictor was tested retrospectively using a branched-chain DNA assay in paraffin-embedded archival tumor tissue from patients (pts) with HER2 negative or untested MBC tumors enrolled in a phase III trial of paclitaxel (P) vs. P+L, and from pts with HER2 positive MBC enrolled in a L monotherapy trial. Expression of HER2 transcript using the branched-chain assay was compared with HER2 fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) status; discordant cases were analyzed. Response patterns for pts with HER2+ tumors and a computational model that predicts L sensitivity or resistance is described. Results: Ingenuity analysis of the mRNA predictors of response to L identified in the BC cell line panel revealed saturated gene networks with HER2 as a major node. The 6-gene predictor of response was comprised of 2 genes associated with sensitivity to L: HER2 and GRB7; 4 genes associated with resistance to L: CRK, ACOT9, FLJ31079, and DDX5. Expression results for the 6 genes and progression-free survival (PFS) data were available for 159 pts on L+P. Median PFS in the branched-chain HER2+ group was 32.9 wks vs. 22.4 wks in the HER2-negative group. The 6-gene predictor was used to predict response to L in the HER2+ pts. Comparison of PFS in the 24 “L sensitive” tumors vs. 25 “L resistant” tumors indicated that the predictor, derived from cell-line analyses, had the potential to predict clinical response to L in pts treated with L+P (HR=0.58; 95% CI=0.30-1.11; p=0.07). The 6-gene predictor was further tested in an independent L monotherapy study in pts with HER2 FISH+ MBC. Comparison of PFS in the 24 “L sensitive” tumors vs. 28 “ L resistant” tumors reconfirmed the potential of the 6-gene predictor to enrich for HER2+ pts most likely to experience clinical benefit from L (HR=0.40; 95% CI=0.19-0.84; p=0.015). Further testing is ongoing. Conclusions: This study suggests that molecular predictors of clinical response can be developed through an analysis of response from a collection of 50 BC cell lines. The identification of a L specific 6-gene assay is promising as a clinical predictor of benefit from L in pts with HER2+ BC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 58.

Abstract #3154 Background: Overexpression of both HER2 and VEGF is associated with worse outcome than overexpression of either receptor alone. In preclinical models, combination anti-HER2 and anti-VEGF therapy has been shown to be more effective than either treatment alone. Bevacizumab (B) plus trastuzumab and lapatinib (L) plus pazopanib have shown activity in patients (pts) with HER2+ MBC. We evaluated the combination of L+B in a phase 2 trial in HER2+ MBC pts. To explore new biomarkers of treatment effect, we measured circulating tumor cells (CTCs) with two different methods of CTC enumeration: CellSearch (Veridex LLC), and immunomagnetic enrichment followed by flow cytometry (IE/FC), as well as circulating endothelial cells (CECs) in pts receiving study treatment. Methods: This study evaluated L (1500 mg PO daily) plus B (10 mg/kg IV q2wk) in 50 HER2+ MBC pts. The primary endpoint is crude progression-free survival (PFS) at 12 wks. Serial evaluation of CTC and CEC was performed. Blood was obtained from consenting pts at baseline, weeks 2, 6 then every 12 weeks until end of study. CellSearch assay was performed as previously described using 7.5 cc blood in a CellSave tube and the CellSpotter analyzer. For IE/FC, 20 ml of blood was subjected to IE using anti-EpCAM ferrofluid, followed by FC for EpCAM, CD45, and nucleic acid content. CTC data were correlated with assay method and with best response. CECs were defined as CD34/31+, CD45-, or CD34/146+, CD45-, and were assayed by FC. Results: Enrollment to this study ended in March 2008 (n=52). Clinical data is presented at this meeting (Dickler et al). 47 patients have evaluable CTC and CEC data at baseline and/or first follow-up; 32 patients have response data. CTC determined by CellSearch or IE/FC showed significant correlation at baseline (R=0.58; P=0.012). CTC by CellSearch at first followup correlated with treatment response (P=0.01) with levels above 5 CTC/sample associated with progression; there was no correlation with baseline values. There were too few positive IE/FC values to evaluate correlation with outcome. The change in CEC/CD146 from baseline to first followup for is of borderline significance in this preliminary analysis (P=0.07) between PR (N=2, Mean Change Score/MCS=-4.345) and SD/PD (N=18, MCS=0.8); a decrease of CEC/CD146 from baseline to first followup suggests greater likelihood of response. Conclusions: L+B is an active regimen in pts with MBC. CTC measurements correlated between two separate methodologies, and for the CellSearch assay predicted response to therapy. A decrease in CEC from baseline to first followup correlated with response to this combined targeted therapy, consistent with our previous results with other B-based therapy. PFS and response correlations for the full study cohort will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3154.

1007 Background: Lapatinib (L), an oral small molecule tyrosine kinase inhibitor of EGFR and HER2, is approved in combination with capecitabine for the treatment of women with HER2+ metastatic breast cancer (MBC). The optimal method to select patients (pts) for L therapy has not been determined. To address this issue, selected biomarkers were analyzed in pts from two randomized phase III MBC trials. Methods: In available BC tissue from EGF30001 pts (paclitaxel ± L in HER2-negative/unknown MBC, N=579) and EGF100151 pts (capecitabine ± L in HER2+ MBC, N=399), HER2 gene amplification was evaluated by fluorescence in situ hybridization (FISH), HER2 messenger RNA (mRNA) by reverse transcriptase-polymerase chain reaction (RT-PCR), protein expression by HercepTest immunohistochemistry (IHC), EGFR mRNA level by RT-PCR, and EGFR protein by IHC. HER2 and EGFR status was compared with clinical outcome across treatment arms to assess potential marker associations. Results: HER2 was amplified in 47% (345/733) and had ...

1017 Background: It has been hypothesized that women with HER2-negative MBC respond to HER2-targeted drugs if the circulating baseline HER2 ECD is >16 ng/ml. Lapatinib, an oral, dual inhibitor of HER2 and EGFR, is effective in women with HER2+ MBC. We retrospectively examined this hypothesis using tissue and serum data from women with MBC who were enrolled in a randomized clinical trial of lapatinib and paclitaxel. Methods: Patients (pts, n=579) with newly diagnosed MBC were randomized to paclitaxel with placebo (P) or lapatinib (L+P). HER2 status was evaluated by fluorescence in situ hybridization or immunohistochemistry in archival tissue. Serum ECD was centrally measured by ELISA in available samples at baseline (bECD, n=473), Week 9, and every 12 weeks thereafter. Pts were stratified by HER2 and bECD status. Results: bECD was positive only in 62% (50/81) of HER2+ pts and in as many as 24% (96/392) of HER2-negative pts. It is known that PFS increased in L+P in HER2+ patients. In HER2-negative pts, bECD...

1042 Background: In a preclinical HER2+ BC model, combination anti-HER2 and anti-VEGF therapy was more effective than either treatment alone, and increased VEGF expression is associated with worse outcome in HER2+ disease. B plus trastuzumab (T) has shown promising activity in patients (pts) with HER2+ MBC, however the cardiac toxicity of this regimen requires further evaluation. L, an oral dual inhibitor of EGFR and HER2, is approved in combination with capecitabine after T-based therapy for HER2+ MBC. L may have less cardiac toxicity and may be a safer and more effective alternative to T+B. This hypothesis was evaluated in a phase 2 trial of L+B in HER2+ MBC pts. Methods: This 50-patient single-arm study evaluated L (1,500 mg PO daily) plus B (10 mg/kg IV q2wk). The primary endpoint is progression-free survival (PFS) at 12 weeks with 84% power to detect a clinically significant PFS rate of 60%; secondary endpoints include toxicity and response per RECIST. Efficacy was assessed at Week 6, 12, and q12wks ...

1006 Background: Patients with polysomy of Chr-17 have been suggested as a FISH-negative subpopulation that might benefit from HER2-directed therapy, due to an increase in HER2 gene expression without HER2 specific amplification. A recent phase III clinical trial studied lapatinib (L) in combination with paclitaxel (P) as 1st-line therapy for HER2-negative or HER2-untested MBC. We examined the hypothesis that HER2 FISH-negative patients with Chr-17 polysomy may be sensitive to HER2 inhibitors using data from this trial. Methods: Patients (n=579) with newly diagnosed MBC were randomized to P with placebo or L (P+L). Response rate (RR) using RECIST and progression-free survival (PFS), were evaluated. HER2 expression level by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and mean HER2 ratio of Chr-17 values were determined in a central laboratory using archival tissue. Tumors with a HER2:Chr-17 ratio < 2.0 were considered HER2-negative by FISH. Chr-17 centromere averages of 2.0 and 2....

1043 Background: Identification of molecular predictors of response is an important aspect of efforts to individualize cancer treatment. Responses to lapatinib (L), an oral, dual inhibitor of HER2 and EGFR approved in combination with capecitabine for HER2+ metastatic breast cancer (MBC), were evaluated in a panel of BC cell lines. Computational approaches were then used to identify a 6-gene predictor of quantitative response to L. Methods: The clinical utility of the 6-gene predictor was tested retrospectively using a Panomics assay in tumor tissue samples from HER2-negative or HER2-untested MBC patients (pts) enrolled in a phase III trial of paclitaxel (P) or P+L. Panomics results were compared with HER2 fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) status and discordant cases were analyzed. Dichotomous response patterns of HER2+ pts and a computational model that predicts L sensitivity or resistance is described. Results: Tissue samples from 302 pts were tested using the bran...

10562 Background: Lapatinib is a potent inhibitor of both EGFR and HER2 tyrosine kinase activity. Results of the phase II trial EGF20009 in advanced or metastatic breast cancer (MBC) indicated an overall response rate of 24% to monotherapy L as first line (1L) treatment in 138 patients. In an effort to better define predictive biomarkers of response, we evaluated correlations between baseline tumor biomarker expression levels and clinical response to L. Methods: Response rate (RR) was defined as either complete response (CR) or partial response (PR). Tumor blocks were available on 118 patients from the time of most recent biopsy, and mRNA was extracted from 65 individual patient blocks for this preliminary analysis. Using qRT-PCR Taqman analysis, tumors were evaluated for expression of ERBB1- 4, PTEN, c-MYC, as well as two comparator genes for normalization. DecisionTree analysis using SpotFire software was performed to determine the genes most significantly associated with RR. Results: For the initial 65 patient samples analyzed, an elevation of ERBB2 expression was significantly associated with response to treatment with L (p=0.02) and a longer time to progression following treatment with L (p No significant financial relationships to disclose.

1011 Background: L is an oral tyrosine kinase inhibitor of EGFR/HER2, active as monotherapy and in combination for HER2-overexpressing advanced/metastatic breast cancer (BC). A Phase I study of L with paclitaxel (P) indicated no unexpected adverse events (AEs). PK profile indicated no relationship between peak plasma concentration of P+L and neuropathy, neutropenia, diarrhea, rash or myalgia. We report here blinded efficacy and safety data for patients (pts) with incurable Stage IIIb/IIIc/IV BC at first diagnosis or relapse, untested or negative (0/1+ IHC or FISH neg) for HER2. Unblinded data will be presented at ASCO 2007. Methods: Between Jan 2004 and Jul 2005, 580 pts from 24 countries were stratified by metastatic site and randomized 1:1 to L 1500 mg QD + 175 mg/m2 P q3w or placebo QD + 175 mg/m2 P q3w. Primary endpoint was TTP; secondary endpoints were AEs, ORR, PFS, CBR, RFS, and OS. Tumor tissue was obtained from the most recent biopsy of 451 (78%) pts and was centrally analyzed in blinded fashion for biomarker patterns. Serum samples were collected for central EGFR and HER2 ECD analysis. Results and Conclusions: 579 pts were analyzed; 87% presented with Stage IV BC. 55% received prior adjuvant chemotherapy or anti-hormonal therapy. No pts received previous trastuzumab. At the time of analysis, 561 (97%) pts progressed or otherwise withdrew. Most common AEs were alopecia (58%), neurological (55%, gr=3:8%), diarrhea (42%, gr=3:9%), nausea (32%), and rash (32%, gr=3:2%). Neutropenia and thrombocytopenia AEs related to study treatment were 18% and [Table: see text]

Abstract #3133 Background: HER2 overexpression has been shown to upregulate VEGF expression in pre-clinical breast cancer models. Overexpression of both HER2 and VEGF has been associated with worse clinical outcome than overexpression of either receptor alone. In pre-clinical models, combination anti-HER2 and anti-VEGF therapy has been shown to be more effective than either treatment alone. B plus trastuzumab (T) has shown promising activity in patients (pts) with HER2+ MBC, however the cardiac toxicity of this regimen requires further study. L, an oral dual tyrosine kinase inhibitor of EGFR and HER2, is approved in combination with capecitabine after T-based therapy for HER2+ MBC. L may have less cardiac toxicity and may be a safer and more effective alternative to T. This hypothesis was evaluated in a phase 2 trial of L+B in HER2+ MBC pts. Methods: This single-arm study was designed to evaluate L (1500 mg PO daily) plus B (10 mg/kg IV q2wk) in 50 HER2+ MBC patients. The primary endpoint is crude progression-free survival (PFS) rate at 12 weeks with 84% power to detect a clinically significant PFS rate of 60%; secondary endpoints include toxicity and response per RECIST. Efficacy was assessed at Week 6, 12, and q12wks thereafter. HER2-overexpression was defined as local FISH-positive or IHC 3+ results. Serial evaluation of circulating tumor and endothelial cells and HER2 extracellular domain was performed. Results: Enrollment to this study ended in March 2008 (n=52). Data are presently available on 32 of 52 pts enrolled before January 1, 2008. Pts received a median of 5 prior MBC therapies (range 0-15); 88% received prior T (median 19.7 months; range 1.2-56.8 months). The most frequently reported AEs included diarrhea (81%), rash (66%), nausea (56%), fatigue (56%), and emesis (46%). Four asymptomatic LVEF declines were reported (three grade 2 events; one grade 1 event), as were nine cases of hypertension (eight grade 1 or 2 events; one grade 3 event) and one grade 3 GI hemorrhage. 27/32 patients were evaluable for response; five withdrew prior to first radiologic assessment (two due to toxicity, three due to investigator/pt request). The crude 12-week PFS rate was 63% (20/32 did not progress by Week 12); overall response rate (complete/partial response) was 13%, and the clinical benefit rate (complete/partial response or stable disease for ≥ 24 weeks) was 34%. Conclusions:L+ B is well tolerated and has shown promising activity in heavily pretreated HER2+ MBC pts. Final efficacy and safety data will be presented on the full study cohort. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3133.