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David Cameron,
Michelle Casey,
Michael Press,
Deborah Lindquist,
Tadeusz Pienkowski,
C. Gilles Romieu,
Stephen Chan,
Agnieszka Jagiello-Gruszfeld,
Bella Kaufman,
John Crown, [......],
Vera Gorbounova,
Johannes Isaac Raats,
Dimosthenis Skarlos,
Beth Newstat,
Debasish Roychowdhury,
Paolo Paoletti,
Cristina Oliva,
Stephen Rubin, Steven Stein,
Charles E. Geyer
[show abstract]
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ABSTRACT: Purpose Lapatinib is a small molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal
growth factor receptor type 2 (HER2). Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is
superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy
including trastuzumab. Updated efficacy and initial biomarker results from this trial are reported. Methods Women with HER2-positive, locally advanced or metastatic breast cancer previously treated with anthracycline-, taxane-, and
trastuzumab-containing regimens were randomized to lapatinib 1,250mg/day continuously plus capecitabine 2,000mg/m2 days1–14 of a 21-day cycle or capecitabine 2,500mg/m2 on the same schedule. The primary endpoint was time to progression (TTP) as determined by an independent review panel. Relationship
between progression-free survival (PFS) and tumor HER2 expression and serum levels of HER2 extracellular domain (ECD) were
assessed. Results 399 women were randomized. The addition of lapatinib prolonged TTP with a hazard ratio (HR) of 0.57 (95% CI, 0.43–0.77; P<0.001) and provided a trend toward improved overall survival (HR: 0.78, 95% CI: 0.55–1.12, P=0.177), and fewer cases with CNS involvement at first progression (4 vs. 13, P=0.045). Baseline serum HER2 ECD did not predict for benefit from lapatinib. Conclusion The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive, advanced breast cancer
progressing after treatment with anthracycline-, taxane-, and trastuzumab-based therapy. Biomarker studies could not identify
a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine.
Breast Cancer Research and Treatment 04/2012; 112(3):533-543. · 4.43 Impact Factor
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Stephen Johnston,
John Pippen,
Xavier Pivot,
Mikhail Lichinitser,
Saeed Sadeghi,
Veronique Dieras,
Henry Leonidas Gomez,
Gilles Romieu,
Alexey Manikhas,
M John Kennedy,
Michael F Press,
Julie Maltzman,
Allison Florance,
Lisa O'Rourke,
Cristina Oliva, Steven Stein,
Mark Pegram
[show abstract]
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ABSTRACT: Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC).
Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable.
This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.
Journal of Clinical Oncology 09/2009; 27(33):5538-46. · 18.37 Impact Factor
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[show abstract]
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ABSTRACT: The randomized phase III trial EGF100151 demonstrated that the combination of lapatinib plus capecitabine (L + C) significantly improved time to progression (TTP) compared with capecitabine alone (C) in heavily pretreated patients with HER2+ (ErbB2+) advanced or metastatic breast cancer. This analysis assessed the effects of study treatments on quality of life (QOL) among patients in EGF100151. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQoL (EQ-5D) questionnaires. Patients completed questionnaires during efficacy and safety assessment visits (i.e., at screening visit, every 6 weeks for the first 24 weeks, every 12 weeks thereafter, and at discontinuation of study treatment). Primary analyses compared the treatment groups based on change from baseline QOL. Exploratory analyses compared proportion of patients achieving minimum important differences (MID) in QOL scores and the relationship between QOL and tumor status. Quality of life for patients in both treatment groups was maintained during 24 weeks of follow-up. Adjusted mean changes from baseline in all QOL scores for the L + C arm were comparable to those for the C arm. The between-group differences ranged from 0.7 to 2.2 (FACT-B total) and 0.3 to 1.8 (EQ-5D visual analog scale) and were consistently in favor of the L + C arm, although not statistically significant. Patients with an objective tumor response or stable disease showed clinically meaningful differences in QOL scores compared to patients with progressive disease. A greater proportion of patients receiving L + C versus C achieved the MID for all five QOL scores, although differences were not statistically significant. The addition of lapatinib to capecitabine significantly increases TTP without any evidence of a deleterious effect on patients' QOL, confirming its clinical benefit in this heavily pretreated patient population with advanced HER2+ breast cancer that has progressed on trastuzumab therapy.
Breast Cancer Research and Treatment 02/2009; 117(3):577-89. · 4.43 Impact Factor
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Michael F Press,
Richard S Finn,
David Cameron,
Angelo Di Leo,
Charles E Geyer,
Ivonne E Villalobos,
Angela Santiago,
Roberta Guzman,
Armen Gasparyan,
Yanling Ma,
Kathy Danenberg,
Anne Marie Martin,
Lisa Williams,
Cristina Oliva, Steven Stein,
Robert Gagnon,
Michael Arbushites,
Maria T Koehler
[show abstract]
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ABSTRACT: Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy.
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.
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.
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.
Clinical Cancer Research 01/2009; 14(23):7861-70. · 7.74 Impact Factor
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[show abstract]
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ABSTRACT: Lapatinib is an oral, reversible, dual inhibitor of epidermal growth factor receptor ErbB1 (EGFR) and human epidermal growth factor receptor type 2 ErbB2 (HER2). Results of a phase III study comparing lapatinib plus capecitabine with capecitabine alone in women with ErbB2-overexpressing advanced breast cancer previously treated with an anthracycline, a taxane, and trastuzumab were reported early based on superiority of the combination in prolonging time to tumor progression (TTP). An updated analysis in 399 women supports the earlier findings. In this updated analysis, TTP (hazard ratio [HR] 0.57) favored lapatinib plus capecitabine. Survival trended in favor of the combination. The incidence of cardiac events was numerically higher in the combination arm (5 cases in the combination arm, 2 cases in the monotherapy arm).
Targets & therapy 04/2008; 2(1):61-5.
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Charles E Geyer,
John Forster,
Deborah Lindquist,
Stephen Chan,
C Gilles Romieu,
Tadeusz Pienkowski,
Agnieszka Jagiello-Gruszfeld,
John Crown,
Arlene Chan,
Bella Kaufman,
Dimosthenis Skarlos,
Mario Campone,
Neville Davidson,
Mark Berger,
Cristina Oliva,
Stephen D Rubin, Steven Stein,
David Cameron
[show abstract]
[hide abstract]
ABSTRACT: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients.
Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions.
The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events.
Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).
New England Journal of Medicine 12/2006; 355(26):2733-43. · 53.30 Impact Factor
