Quantitative ER and PgR assessment as predictors of benefit from lapatinib in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.

PURPOSE: Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 inhibitor, remains unproven in non-HER2-amplified metastatic breast cancer (MBC). EGF30008, a phase III trial of letrozole and lapatinib versus letrozole and placebo, demonstrated that lapatinib significantly improves outcome for postmenopausal women with HER2-amplified, but not HER2-negative, MBC. The hypothesis that low hormone receptor status is associated with benefit in this HER2-negative cohort was tested. EXPERIMENTAL DESIGN: A blinded retrospective biomarker evaluation used immunohistochemistry (IHC) to semiquantify estrogen receptor (ER) and progesterone receptor (PgR) expression (n = 821/952). HER2 status was determined by IHC and confirmed by FISH (n = 326). Effects of these biomarkers on progression-free survival (PFS) were examined in patients with available tissue. RESULTS: In HER2-negative, ER-positive MBC, median PFS was analyzed by ER and PgR expression (H-score) by quartile (Q). There was significant improvement in patients with low ER expression (Q1, H-score <160) with lapatinib and letrozole (13.6 vs. 6.7 months; P = 0.01). No benefit was associated with stronger ER expression (Q2/3, H-score ≥ 160 and <250; 13.6 vs. 14.2 months; Q4, H-score ≥ 250; 11.2 vs. 14.2 months). There was no association between PgR H-score and benefit from lapatinib. CONCLUSION: In postmenopausal patients with advanced hormone receptor-positive disease, weak ER expression is associated with worse outcome with letrozole treatment compared with the combination. The addition of lapatinib significantly improved PFS for this patient subgroup and augments data supporting interaction between steroid hormone and peptide hormone signaling. A prospective study validating this hypothesis is required.

Pathologic complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling.

BACKGROUND: To define protein molecular characteristics of tumor cells prior to, and immediately following, preoperative human epidermal growth factor receptor 2 (HER2)-targeted therapy that correlate with pathologic complete response (pCR) or non response (no pCR) to preoperative HER2-directed therapy and chemotherapy. METHODS: This open-label, phase II study randomized patients with HER2-positive stage II or III invasive breast cancer to trastuzumab, lapatinib, or both, 2 weeks prior to and during chemotherapy with FEC75 for 4 courses; then paclitaxel 80 mg/m2 weekly for 12 courses, then surgery. Core needle biopsies were collected at baseline and after 2 weeks of anti-HER2 therapy prior to chemotherapy. Data were correlated with pCR, defined as absence of invasive tumor in breast and lymph nodes. RESULTS: Of 100 enrolled patients, the analysis population included those who had surgery and received ≥75% chemotherapy (78% [n=78]). pCRs by arm are: trastuzumab (n=26), 54% [n=14]; lapatinib (n=29), 45% [n=13]; trastuzumab plus lapatinib (n=23), 74% [n=17]). Paired biopsy specimens were available for 49 patients (63%). Tumor cells of patients with pCR in the trastuzumab or lapatinib treatment arms showed nonphosphorylated FOXO, phosphorylated Stat5, and sparse signal-transduction protein network crosstalk representing different patterns of connections with PI3K and autophagy proteins compared with no pCR. CONCLUSION: In this exploratory study, pCR with preoperative anti-HER2 therapy and chemotherapy correlated with the levels and phosphorylation status of specific baseline signal pathway proteins in tumor cells. These data may provide candidate biomarkers to stratify initial treatment and potential combination therapies for future study. Tissue preservation technology introduced here makes this procedure widely feasible. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00524303.

An open-label safety study of lapatinib plus trastuzumab plus paclitaxel in first-line HER2-positive metastatic breast cancer.

BACKGROUND: Recent data support the hypothesis that combining lapatinib and trastuzumab with taxane chemotherapy may offer added clinical benefit to patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). This study examined the safety of the triplet combination in first-line HER2-positive MBC. PATIENTS AND METHODS: Patients were enrolled into three sequential cohorts; the last two cohorts were added by protocol amendment following review of safety data from cohort 1. Patients in cohort 1 received lapatinib (1000 mg/day) plus paclitaxel (80 mg/m(2) per week, 3 of every 4 weeks); cohort 2 received lapatinib (1000 mg/day) plus paclitaxel (70 mg/m(2) per week, 3 of every 4 weeks); and cohort 3 received lapatinib (750 mg/day) plus paclitaxel (80 mg/m(2) per week, 3 of every 4 weeks). All received standard trastuzumab dosing. The primary objective was assessment of dose-limiting toxicities, safety, and tolerability of this combination. RESULTS: The most frequent adverse events (AEs) for all cohorts were diarrhea (89%), rash (79%), fatigue (73%), alopecia (63%), nausea (63%), and vomiting (40%). In cohorts 1 and 2, the incidence of grade 3 diarrhea was 62% and 50%, respectively; in cohort 3, the incidence was 25% (with prophylactic loperamide). Dehydration was the most frequent serious AE (10%). Across cohorts, overall response rate was 75%. CONCLUSIONS: The dose-limiting toxicity of paclitaxel, trastuzumab, and lapatinib in first-line HER2-positive MBC was diarrhea. Of the triplet combinations tested, the cohort receiving 750 mg/day dose of lapatinib had the lowest incidence of diarrhea; therefore, this dose should be used in further studies on the treatment of MBC.

Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study.

PURPOSE: Phase III EGF104900 data demonstrated that lapatinib plus trastuzumab significantly improved progression-free survival (PFS) and clinical benefit rate versus lapatinib monotherapy, offering a chemotherapy-free option for patients with heavily pretreated human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). Final planned overall survival (OS) analysis from EGF104900 is reported here. PATIENTS AND METHODS: Patients with HER2-positive MBC whose disease progressed during prior trastuzumab-based therapies were randomly assigned to receive lapatinib monotherapy or lapatinib in combination with trastuzumab. OS and updated PFS data are presented using Kaplan-Meier curves and log-rank tests stratified for hormone receptor and visceral disease status. Subgroup analyses were conducted to identify characteristics of patients deriving the greatest clinical benefit. RESULTS: In this updated final analysis of all patients randomly assigned with strata (n = 291), lapatinib plus trastuzumab continued to show superiority to lapatinib monotherapy in PFS (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .011) and offered significant OS benefit (HR, 0.74; 95% CI, 0.57 to 0.97; P = .026). Improvements in absolute OS rates were 10% at 6 months and 15% at 12 months in the combination arm compared with the monotherapy arm. Multiple baseline factors, including Eastern Cooperative Oncology Group performance status of 0, nonvisceral disease, < three metastatic sites, and less time from initial diagnosis until random assignment, were associated with improved OS. Incidence of adverse events was consistent with previously reported rates. CONCLUSION: These data demonstrated a significant 4.5-month median OS advantage with the lapatinib and trastuzumab combination and support dual HER2 blockade in patients with heavily pretreated HER2-positive MBC.

Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer.

OBJECTIVE: To evaluate the efficacy and tolerability of letrozole plus lapatinib versus letrozole plus placebo in women with hormone receptor (HR)(+) human epidermal growth factor receptor (HER)-2(+) tumors receiving first-line therapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women (n = 1,286) with HR(+) MBC were randomized to daily oral treatment with letrozole (2.5 mg) plus lapatinib (1,500 mg) versus letrozole (2.5 mg) plus placebo. Of the 1,286 patients enrolled in the phase III study, 219 had HER-2(+) tumors. The primary endpoint was progression-free survival (PFS) in HER-2(+) patients. RESULTS: Results in the HR(+) HER-2(+) population (n = 219) are presented. The addition of lapatinib to letrozole resulted in a significantly lower risk for disease progression than with letrozole alone (hazard ratio, 0.71; 95% confidence interval, 0.53-0.96). The PFS time was 8.2 months, versus 3.0 months. The objective response rate (ORR) (28% versus 15%) and clinical benefit rate (CBR) (48% versus 29%) were also significantly greater in lapatinib-treated women. The most common adverse events in the lapatinib group were diarrhea (68%) and rash (46%), primarily grade 1 and 2. CONCLUSIONS: The addition of lapatinib to letrozole is well tolerated and leads to a significantly greater PFS time, ORR, and CBR than with letrozole alone in women with MBC who coexpress HR and HER-2.

Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer.

PURPOSE: 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). PATIENTS AND METHODS: 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. CONCLUSION: 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.

A randomized, controlled trial of initial anti-retroviral therapy with abacavir/lamivudine/zidovudine twice-daily compared to atazanavir once-daily with lamivudine/zidovudine twice-daily in HIV-infected patients over 48 weeks (ESS100327, the ACTION Study).

BACKGROUND: Traditional first line regimens containing a non-nucleoside reverse transcriptase inhibitor or protease inhibitor may not be suitable for a subset of antiretroviral-naïve patients such as those with certain co-morbidities, women of child-bearing potential, and intolerability to components of standard first line therapy. This study was conducted to determine if alternate treatment options may meet the needs of both general and special patient populations. The ACTION study was a randomized, open-label, multicenter, 48-week trial that compared the safety and efficacy of a triple nucleoside regimen versus a protease inhibitor plus a dual nucleoside regimen in HIV-1 treatment-naïve subjects. RESULTS: 279 HIV-infected subjects with HIV-1 RNA (VL) >5000 but < 200,000 copies/mL (c/mL) and CD4+ count >/= 100 cells/mm3 were randomized (1:1) to receive abacavir sulfate/lamivudine/zidovudine (ABC/3TC/ZDV) twice-daily or atazanavir (ATV) once-daily plus lamivudine/zidovudine (3TC/ZDV) twice-daily. Protocol-defined virologic failure was based on multiple failure criteria.Non-inferiority of ABC/3TC/ZDV to ATV+3TC/ZDV was established with 62% vs. 59% of subjects achieving a VL < 50 c/mL at week 48, [ITT(E), M/S = F, 95% CI: -5.9, 10.4]. Similar results were observed in the 230 (82%) subjects with baseline VL<100,000 c/mL (ABC/3TC/ZDV vs. ATV+3TC/ZDV), 66% vs. 59%; 95% CI: -5.6, 19.5. However, ABC/3TC/ZDV did not meet the non-inferiority criterion compared to ATV+3TC/ZDV in the 48 subjects with baseline VL >/= 100,000 c/mL, 39% vs. 60%; 95% CI: -49.2, 7.4, respectively. Protocol-defined virologic failure was similar between groups. CONCLUSION: ABC/3TC/ZDV demonstrated comparable virologic efficacy to ATV+3TC/ZDV in this population over 48 weeks. In those with a baseline VL >/= 100,000 c/mL, subjects in the ATV+3TC/ZDV showed better virologic efficacy. Both regimens offer benefits in select therapy-naïve subjects. TRIAL REGISTRATION: [Clinical Trials Identifier, NCT00082394].

Abacavir and lamivudine fixed-dose combination tablet once daily compared with abacavir and lamivudine twice daily in HIV-infected patients over 48 weeks (ESS30008, SEAL).

BACKGROUND: Abacavir (ABC) and lamivudine (3TC) administered twice daily were compared with an ABC + 3TC fixed-dose combination (Epzicom, Kivexa; EPZ) administered once daily, both in combination with a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI). METHODS: Two hundred sixty HIV-infected subjects with more than 6 months of ABC and 3TC administered twice daily plus a PI or NNRTI with an HIV-1 RNA level less than 400 copies/mL for more than 3 months and a CD4 count greater than 50 cells/mm were randomized 1:1 to ABC + 3TC administered twice daily or EPZ administered once daily. RESULTS: At baseline, median time on ABC and 3TC administered twice daily was 22 months, and median CD4 count and HIV-1 RNA level were 554 cells/mm and <50 copies/mL, respectively. EPZ administered once daily was established as not inferior to ABC + 3TC administered twice daily based on the proportion of nonvirologic failures (confirmed HIV-1 RNA level > or =1265 copies/mL; 90% confidence interval: -3.4 to 6.4; (intent to treat [ITT]: missing [M] = failure [F]). Proportions with an HIV-1 RNA level <50 copies/mL were 81% of those taking EPZ once daily and 82% of those taking ABC + 3TC twice daily at week 48 (ITT: M = F). Virologic failure was rare (2 patients taking the once-daily regimen, 4 patients taking the twice-daily regimen). There was a low incidence of grade 2 through 4 adverse events (AEs) and no drug-related serious AEs or hypersensitivity reactions. CONCLUSIONS: EPZ administered once daily was established as not inferior to ABC + 3TC administered twice daily in a regimen containing an NNRTI or a PI over 48 weeks. A dual-nucleoside backbone of ABC and 3TC administered once or twice daily is effective, durable, and well tolerated.

Comparison of HIV type 1 protease inhibitor susceptibility results in viral samples analyzed by phenotypic drug resistance assays and by six resistance algorithms: an analysis of a subpopulation of the CHORUS cohort.

Drug resistance testing is increasingly used to guide treatment decisions in patients infected with HIV-1. A number of rules-based algorithms have been designed to predict drug resistance profiles based on the HIV-1 genotypic data. Drug-resistance mutations in 206 viral samples from protease inhibitor (PI)-experienced subjects with HIV-1 infection were assessed, and the level of susceptibility of the samples predicted using seven unique algorithms. kappa scores were used to compare agreement of results obtained using each of the predictive algorithms with the phenotypic assay results. Good overall agreement between the different algorithms and the phenotypic results was observed. Good or excellent agreement was observed between the results obtained by the predictive algorithms and the phenotypic assay results for ritonavir, indinavir, saquinavir, and nelfinavir. For amprenavir and lopinavir, there were marked differences between the different algorithms, with poor agreement (kappa < 0.40) obtained with four of the seven algorithms for amprenavir. For lopinavir, poor agreement was obtained with three of seven algorithms using the 2.5-fold biological cut-off and four of seven with the clinical cut-off of 10. Atazanavir susceptibility was evaluated for concordance among six algorithms, with a range of 23-50% of the samples maintaining susceptibility. Although this cohort of patients included many who were highly antiretroviral experienced, predictive algorithms demonstrated good agreement with phenotype for several Pls. For those where discordance among algorithms existed, further improvement will likely occur as drug resistance pathways for the more recently approved PIs are elucidated.

A direct comparison of drug susceptibility to HIV type 1 from antiretroviral experienced subjects as assessed by the antivirogram and PhenoSense assays and by seven resistance algorithms.

HIV-1 drug resistance methodologies are being increasingly utilized to guide treatment decisions; however, information comparing the various assays is limited. Duplicate plasma samples from 70 ART-experienced subjects were analyzed by both the Antivirogram and PhenoSense phenotypic assays and the results compared. HIV genotypes were also obtained and analyzed using seven different resistance algorithms. These results were also compared with the phenotypic assay results. Concordances between the phenotypic tests and between each algorithm, and between the two phenotypic assays were calculated and kappa coefficients (KC) determined. Overall agreement between the two phenotypic assays was good (86.9% concordance; KC 0.621). The highest concordance by drug class was seen for protease inhibitors (93.4%; KC 0.679) and the lowest (79.8%; KC 0.549) for nucleoside reverse transcriptase inhibitors. Concordance between the two phenotypic assays, when evaluating individual drugs, was good for all drugs tested except for abacavir, zalcitabine, and indinavir. Agreement between the seven algorithms and each phenotypic assay was variable, though most had good or excellent agreement. The highest overall level of agreement for an individual drug was observed when comparing lamivudine susceptibility to either assay. Concordance for abacavir, didanosine, zalcitabine, and saquinavir was generally problematic when comparing one or more phenotypic assays to the drug resistance predictive algorithms. In conclusion, results comparing these two phenotypic tests were mostly similar, but comparisons of the predictive resistance algorithms for specific drugs, as well as to specific phenotypic assays, were more inconsistent.