Optimizing collection of adverse event data in cancer clinical trials supporting supplemental indications.

PURPOSE: Although much is known about the safety of an anticancer agent at the time of initial marketing approval, sponsors customarily collect comprehensive safety data for studies that support supplemental indications. This adds significant cost and complexity to the study but may not provide useful new information. The main purpose of this analysis was to assess the amount of safety and concomitant medication data collected to determine a more optimal approach in the collection of these data when used in support of supplemental applications. METHODS: Following a prospectively developed statistical analysis plan, we reanalyzed safety data from eight previously completed prospective randomized trials. RESULTS: A total of 107,884 adverse events and 136,608 concomitant medication records were reviewed for the analysis. Of these, four grade 1 to 2 and nine grade 3 and higher events were identified as drug effects that were not included in the previously established safety profiles and could potentially have been missed using subsampling. These events were frequently detected in subsamples of 400 patients or larger. Furthermore, none of the concomitant medication records contributed to labeling changes for the supplemental indications. CONCLUSION: Our study found that applying the optimized methodologic approach, described herein, has a high probability of detecting new drug safety signals. Focusing data collection on signals that cause physicians to modify or discontinue treatment ensures that safety issues of the highest concern for patients and regulators are captured and has significant potential to relieve strain on the clinical trials system.

Aromatase expression and outcomes in the P024 neoadjuvant endocrine therapy trial.

BACKGROUND: Expression of aromatase by malignant breast epithelial cells and/or the surrounding stroma implies local estrogen production that could influence the outcome of endocrine therapy for breast cancer. METHODS: A validated immunohistochemical assay for aromatase was applied to samples from the P024 neoadjuvant endocrine therapy trial that compared tamoxifen and letrozole. The presence of aromatase expression by tumor or stromal cells was correlated with tumor response, treatment induced changes in proliferation index (Ki67), relapse-free survival (RFS) and breast cancer-specific survival (BCSS). RESULTS: Tumor and stromal aromatase expression were highly correlated (P = 0.0001). Tumor cell aromatase, as a semi-continuous score, also correlated with smaller tumor size at presentation (P = 0.01) higher baseline ER Allred score (P = 0.006) and lower Ki67 levels (P = 0.003). There was no significant relationship with clinical response or treatment-induced changes in Ki67. However, in a Cox multivariable model that incorporated a post-treatment tumor profile (pathological T stage, N stage, Ki67 and ER status of the surgical specimen), the presence of tumor aromatase expression at baseline sample remained a favorable independent prognostic biomarker for both RFS (P = 0.01, HR 2.3, 95% CI 1.2-4.6 for absent expression) and BCSS (P = 0.008, HR 3.76, 95% CI 1.4-10.0). CONCLUSIONS: Autocrine estrogen synthesis may be most characteristic of smaller, more indolent and ER-rich breast cancers with lower baseline growth rates. However, response to endocrine treatment may not depend on whether the estrogenic stimulus has a local versus systemic source.

Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics.

BACKGROUND: Understanding how tumor response is related to relapse risk would help clinicians make decisions about additional treatment options for patients who have received neoadjuvant endocrine treatment for estrogen receptor-positive (ER+) breast cancer. METHODS: Tumors from 228 postmenopausal women with confirmed ER+ stage 2 and 3 breast cancers in the P024 neoadjuvant endocrine therapy trial, which compared letrozole and tamoxifen for 4 months before surgery, were analyzed for posttreatment ER status, Ki67 proliferation index, histological grade, pathological tumor size, node status, and treatment response. Cox proportional hazards were used to identify factors associated with relapse-free survival (RFS) and breast cancer-specific survival (BCSS) in 158 women. A preoperative endocrine prognostic index (PEPI) for RFS was developed from these data and validated in an independent study of 203 postmenopausal women in the IMPACT trial, which compared treatment with anastrozole, tamoxifen, or the combination 3 months before surgery. Statistical tests were two-sided. RESULTS: Median follow-up in P024 was 61.2 months. Patients with confirmed baseline ER+ clinical stage 2 and 3 tumors that were downstaged to stage 1 or 0 at surgery had 100% RFS (compared with higher stages, P < .001). Multivariable testing of posttreatment tumor characteristics revealed that pathological tumor size, node status, Ki67 level, and ER status were independently associated with both RFS and BCSS. The PEPI model based on these factors predicted RFS in the IMPACT trial (P = .002). CONCLUSIONS: Breast cancer patients with pathological stage 1 or 0 disease after neoadjuvant endocrine therapy and a low-risk biomarker profile in the surgical specimen (PEPI score 0) have an extremely low risk of relapse and are therefore unlikely to benefit from adjuvant chemotherapy.

Serum TIMP-1 and response to the aromatase inhibitor letrozole versus tamoxifen in metastatic breast cancer.

PURPOSE: To determine the effect of elevated serum TIMP-1 on the response of patients with metastatic breast cancer to an aromatase inhibitor versus tamoxifen. PATIENTS AND METHODS: Five hundred twenty-two patients estrogen receptor-positive metastatic breast cancer were randomly assigned to receive first-line hormone therapy with letrozole or tamoxifen. Serum tissue inhibitor of metalloproteinases-1 (TIMP-1) levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Pretreatment serum TIMP-1 was elevated in 120 (23%) of 522 patients. Patients with elevated serum TIMP-1 had a significantly reduced objective response rate (19.2% v 30.6%; odds ratio, 0.54; P = .01), duration of response (median, 15.5 v 26.2 months; P = .001), time to treatment progression (TTP; median, 4.5 v 9.2 months; HR, 1.78; P = .0001), time to treatment failure (median, 3.5 v 9.0 months; HR, 1.77; P = .0001), and overall survival (median, 20.3 v 35.8 months; HR, 1.77; P = .0001) compared with patients with normal pretreatment TIMP-1 levels. Letrozole was superior to tamoxifen in both the normal serum TIMP-1 group (median TTP, 11.8 v 8.6 months; P = .003) and in the elevated serum TIMP-1 group (median, 6.1 v 3.2 months; P = .03) In multivariate analysis, elevated serum TIMP-1 remained an independent predictor of both shorter TTP (HR, 1.46; P = .002) and survival (HR, 1.44; P = .002), as did serum HER-2. Combined analysis of both serum TIMP-1 and HER-2/neu conferred additional ability to predict significantly different clinical outcomes compared to using either biomarker alone. CONCLUSION: Patients with elevated pretreatment serum TIMP-1 had a significantly reduced response and survival. Serum TIMP-1 was an independent predictive and prognostic factor. Blockade of TIMP-1 and HER-2/neu activity may be beneficial in a subset of patients with breast cancer.

Conditional approval: discussion points from the PSI conditional approval expert group.

The European Agency for the Evaluation of Medicinal Products has recently completed the consultation of a draft guidance on how to implement conditional approval. This route of application is available for orphan drugs, emergency situations and serious debilitating or life-threatening diseases. Although there has been limited experience in implementing conditional approval to date, PSI (Statisticians in the Pharmaceutical Industry) sponsored a meeting of pharmaceutical statisticians with an interest in the area to discuss potential issues. This article outlines the issues raised and resulting discussions, based on the group's interpretation of the legislation. Conditional approval seems to fit well with the accepted regulatory strategy in HIV. In oncology, conditional approval may be most likely when (a) compelling phase II data are available using accepted clinical outcomes (e.g. progression/recurrence-free survival or overall survival) and Phase III has been planned or started, or (b) when data are available using a surrogate endpoint for clinical outcome (e.g. response rate or biochemical measures) from a single-arm study in rare tumours with high response, compared with historical data. The use of interim analyses in Phase III for supporting conditional approval raises some challenging issues regarding dissemination of information, maintenance of blinding, potential introduction of bias, ethics, switching, etc.

Serum epidermal growth factor receptor/HER-2 predicts poor survival in patients with metastatic breast cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR, HER-1, and erbB1) is overexpressed in primary breast cancer and had been identified as a poor prognostic factor. METHODS: Pretreatment serum EGFR levels were quantified by using an enzyme-linked immunoadsorbent assay in a Phase III first-line trial of letrozole and tamoxifen and were correlated with patient outcomes. RESULTS: Serum EGFR levels in a control group of 117 healthy, postmenopausal women measured 64.1 +/- 13.3 ng/mL (mean +/- standard deviation). Using a cutoff EGFR level of 44.1 ng/mL from the control group (5% nonparametric method), 53 of 535 patients (10%) had decreased serum levels of EGFR. Patients with decreased serum EGFR had no significant difference in objective response rate (ORR), clinical benefit rate (CBR), time to progression (TTP), or time to treatment failure (TTF); however, they did have significantly reduced survival compared with patients who had normal serum EGFR levels (median survival, 23.3 months vs. 30.9 months; P = .007). A combined analysis of pretreatment serum EGFR and HER-2 yielded no additional predictive information for ORR, CBR, TTP, or TTF compared to serum HER-2 alone. However, in the current analysis, a subgroup of patients who had decreased serum EGFR and normal serum HER-2 was identified (n = 39 of 535 patients; 7.3%) that had significantly reduced survival compared with patients who had normal serum levels of both EGFR and HER-2 (median survival, 23.5 months vs. 37.1 months; P = .005). In multivariate analysis, a decreased serum EGFR level remained a significant independent prognostic factor for decreased survival (hazards ratio, 1.58; P = .007). CONCLUSIONS: In patients who had metastatic breast cancer, decreased serum EGFR/normal serum HER-2 predicted shorter survival compared with patients who had normal levels of serum EGFR/HER-2. This patient subgroup deserves further study to assess their response to and selection for anti-EGFR-directed therapies.

Serum HER-2/neu conversion to positive at the time of disease progression in patients with breast carcinoma on hormone therapy.

BACKGROUND: Prolonged exposure of breast carcinoma cells in vitro to tamoxifen results in tamoxifen resistance. Tamoxifen-resistant cells express increased HER-2/neu mRNA and protein. The objective of this study was to determine whether patients with metastatic or locally advanced breast carcinoma who have negative serum HER-2/neu status at the initiation of first-line hormone therapy with letrozole or tamoxifen convert to positive serum HER-2/neu status at the time of disease progression and to determine whether serum HER-2/neu conversion to positive status is associated with response to therapy and overall survival. METHODS: Serum samples were obtained at baseline and at the time of disease progression from 240 patients who initially had negative serum HER-2/neu status (< 15 ng/mL). A manual microtiter, enzyme-linked immunosorbent assay that was specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to quantitate serum levels. RESULTS: Among 240 patients, 61 patients (26%) converted from serum HER-2/neu negative to positive (> 15 ng/mL) at the time of disease progression. Thirty-two of 129 patients (25%) who were treated with tamoxifen and 29 of 111 patients (26%) who were treated with letrozole became converted to positive serum HER-2/neu status at the time of disease progression. The response rate and the time to disease progression on first-line hormone therapy were not affected by serum HER-2/neu conversion. The survival of patients who converted to positive serum HER-2/neu status was significantly shorter compared with the survival of patients who remained negative for serum HER-2/neu. A multivariate analysis revealed that conversion to positive serum HER-2/neu status was an independent prognostic variable for survival. CONCLUSIONS: Conversion to positive serum HER-2/neu status occurred in approximately 25% of patients who received first-line hormone therapy. Conversion to serum HER-2/neu-positive status occurred with equal frequency in antiestrogen and aromatase-inhibitor therapy. The current results showed that serum conversion to HER-2/neu-positive status was an independent risk factor for decreased survival in patients with breast carcinoma.

Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status.

BACKGROUND: The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated by analyzing tumor proliferation and expression of estrogen-regulated genes before and after the initiation of therapy. METHODS: Tumor samples were obtained at baseline and at the end of treatment from 185 patients participating in a double blind randomized Phase III study of neoadjuvant endocrine therapy. These paired specimens were simultaneously analyzed for Ki67, ER, progesterone receptor (PgR), trefoil factor 1 (PS2), HER1 (epidermal growth factor receptor), and HER2 (ErbB2 or neu) by semiquantitative immunohistochemistry. RESULTS: The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole (87%) than tamoxifen (75%; analysis of covariance P = 0.0009). Differences in the average Ki67 reduction were particularly marked for ER-positive tumors that overexpressed HER1 and/or HER2 (88 versus 45%, respectively; P = 0.0018). Twenty-three of 92 tumors (25%) on tamoxifen and 14 of 93 on letrozole (15%) showed a paradoxical increase in Ki67 with treatment, and the majority of these cases was HER1/2 negative. Letrozole, but not tamoxifen, significantly reduced expression of the estrogen-regulated proteins PgR and trefoil factor 1, regardless of HER1/2 status (P < 0.0001). ER down-regulation occurred with both agents, although levels decreased more with tamoxifen (P < 0.0001). CONCLUSION: Letrozole inhibited tumor proliferation to a greater extent than tamoxifen. The molecular basis for this advantage appears complex but includes possible tamoxifen agonist effects on the cell cycle in both HER1/2+ and HER1/2- tumors. A pattern of continued proliferation despite appropriate down-regulation of PgR expression with estrogen deprivation or tamoxifen was also documented. This observation suggests the estrogenic regulation of proliferation and PgR expression may be dissociated in endocrine therapy resistant cells.

Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group.

PURPOSE: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: This multicenter phase III trial randomly assigned 916 patients with hormone receptor-positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician's discretion. This report updates efficacy at a median follow-up of 32 months. RESULTS: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P <.0001), time to treatment failure (median, 9 v 5.7 months, respectively; P <.0001), overall objective response rate (32% v 21%, respectively; P =.0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not significant, survival was improved in the randomized letrozole arm over the first 2 years of the study. Approximately one half of the patients in each arm crossed over. Total duration of endocrine therapy ("time to chemotherapy") was significantly longer (P =.005) for patients initially on letrozole (median, 16 months) than for patients initially on tamoxifen (median, 9 months). Time to worsening of Karnofsky performance score was significantly delayed with letrozole compared with tamoxifen (P =.001). CONCLUSION: This study documents the superiority of letrozole over tamoxifen in first-line endocrine therapy in postmenopausal women with advanced breast cancer.