Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5.

BACKGROUND: The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). PATIENTS AND METHODS: Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. RESULTS: A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. CONCLUSION: The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations.

Preliminary results of centralized HER2 testing in ductal carcinoma in situ (DCIS): NSABP B-43.

NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at >50 %, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient's pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9 %) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6 %) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3 months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9 %, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust.

Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial.

PURPOSE: Anthracycline- and taxane-based three-drug chemotherapy regimens have proven benefit as adjuvant therapy for early-stage breast cancer. This trial (NSABP B-38; Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer) asked whether the incorporation of a fourth drug could improve outcomes relative to two standard regimens and provided a direct comparison of those two regimens. PATIENTS AND METHODS: We randomly assigned 4,894 women with node-positive early-stage breast cancer to six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), four cycles of dose-dense (DD) doxorubicin and cyclophosphamide followed by four cycles of DD paclitaxel (P; DD AC→P), or DD AC→P with four cycles of gemcitabine (G) added to the DD paclitaxel (DD AC→PG). Primary granulocyte colony-stimulating factor support was required; erythropoiesis-stimulating agents (ESAs) were used at the investigator's discretion. RESULTS: There were no significant differences in 5-year disease-free survival (DFS) between DD AC→PG and DD AC→P (80.6% v 82.2%; HR, 1.07; P = .41), between DD AC→PG and TAC (80.6% v 80.1%; HR, 0.93; P = .39), in 5-year overall survival (OS) between DD AC→PG and DD AC→P (90.8% v 89.1%; HR, 0.85; P = .13), between DD AC→PG and TAC (90.8% v 89.6%; HR, 0.86; P = .17), or between DD AC→P versus TAC for DFS (HR, 0.87; P = .07) and OS (HR, 1.01; P = .96). Grade 3 to 4 toxicities for TAC, DD AC→P, and DD AC→PG, respectively, were febrile neutropenia (9%, 3%, 3%; P < .001), sensory neuropathy (< 1%, 7%, 6%; P < .001), and diarrhea (7%, 2%, 2%; P < .001). Exploratory analyses for ESAs showed no association with DFS events (HR, 1.02; P = .95). CONCLUSION: Adding G to DD AC→P did not improve outcomes. No significant differences in efficacy were identified between DD AC→P and TAC, although toxicity profiles differed.

Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial.

PURPOSE: Premenopausal women with breast cancer receiving adjuvant chemotherapy are at risk for amenorrhea. The National Surgical Adjuvant Breast and Bowel Project B-30 trial included menstrual history (MH) and quality-of-life (QOL) studies to compare treatments on these outcomes. PATIENTS AND METHODS: Patients were randomly assigned to sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T; AC→T), concurrent TAC, or AT, which varied in duration (24, 12, 12 weeks, respectively), and use of C. Endocrine therapy was prescribed for women with hormone receptor-positive tumors. MH and QOL were assessed with standardized questionnaires at baseline; cycle 4, day 1; and every 6 months through 24 months. Prespecified analyses examined rates of amenorrhea by treatment arm, the relationship between amenorrhea and QOL, and QOL by treatment arm. RESULTS: Amenorrhea 12 months after random assignment was significantly different between treatment groups: 69.8% for AC→T, 57.7% for TAC, and 37.9% for AT (P < .001). The AT group without tamoxifen had the lowest rate of amenorrhea. QOL was poorer for patients receiving AC→T at 6 months but similar to others by 12 months. Post-treatment symptoms were increased above baseline for all treatments. Multivariable repeated measures modeling demonstrated that treatment arm, time point, age, and tamoxifen use were significantly associated with symptom severity (all P values < .002). CONCLUSION: Amenorrhea rates differed significantly by treatment arm, with the AT arm having the lowest rate. Patients treated with longer duration therapy (AC→T) had greater symptom severity and poorer QOL at 6 months, but did not differ from shorter duration treatments at 12 months.

Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor alpha proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. METHODS: We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197. FINDINGS: All randomised patients were included in the analysis. At median follow-up of 19.7 months (minimum-maximum 0-56.4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0.35 [0.22-0.53]; one-sided p<0.0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group. INTERPRETATION: Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. FUNDING: US National Institutes of Health and Novartis Pharmaceuticals.

Single-arm, open label study of pemetrexed plus cisplatin in chemotherapy naïve patients with malignant pleural mesothelioma: outcomes of an expanded access program.

BACKGROUND: An expanded access program (EAP) provided patient access to pemetrexed prior to its commercial availability. The current report consists of US patients in the EAP who had chemotherapy naïve pleural mesothelioma. METHODS: Eligible patients had a histologic or cytologic diagnosis of malignant mesothelioma that was not amenable to curative treatment with surgery. Study treatment consisted of pemetrexed 500mg/m(2) in combination with cisplatin 75mg/m(2) once every 21 days. Vitamin B12, folic acid, and dexamethasone were administered as prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmacovigilance database for all patients enrolled in the EAP. RESULTS: Of 1056 patients receiving at least one dose of pemetrexed in the EAP, 728 had chemotherapy naïve pleural mesothelioma. Median age of this group was 70 years (range 23-89 years) and 84% were male. Among 615 patients, overall response rate was 20.5%, including 12 complete responses (2.0%) and 114 partial responses (18.5%). An additional 290 patients (47.2%) had stable disease. Median survival for all 728 patients was 10.8 months (95% CI=9.8, 12.3; 60.3% censorship) and 1 year survival was 45.4%. The most commonly reported SAEs in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). CONCLUSIONS: In this large cohort, 67.7% of patients treated with first-line chemotherapy experienced a response or stable disease. Survival time and toxicity from this EAP were promising for this difficult-to-treat disease.

Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program.

BACKGROUND: In a randomized phase III trial, pemetrexed plus cisplatin was associated with improved survival compared with cisplatin alone for patients with malignant pleural mesothelioma (MPM). However, there are limited data available on the efficacy of these and other chemotherapy regimens in patients who have received previous systemic chemotherapy. To gather additional efficacy and safety data of pemetrexed/cisplatin and pemetrexed alone in previously treated patients, we examined patients treated on the Eli Lilly and Company expanded access program (EAP). PATIENTS AND METHODS: Patients with malignant mesothelioma were enrolled in this trial. Of 1056 patients receiving at least one dose of the study drug, 187 (17.7%) were previously treated patients with MPM. Patients were treated every 21 days with pemetrexed 500 mg/m alone (n = 91) or in combination with cisplatin 75 mg/m (n = 96) for a maximum of six cycles. All patients received folic acid and vitamin B12 supplementation and steroid prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmaco-vigilance database for all patients enrolled in the EAP. RESULTS: Median age of the previously treated pleural mesothelioma subset was 66 years (range, 27-87 years). Based on 153 evaluable patients (a subset of the larger intent-to-treat population of 187), the overall response rate was 32.5% for pemetrexed and cisplatin and 5.5% for pemetrexed alone. The disease control rate (response rate + stable disease) was 68.7% for pemetrexed and cisplatin and 46.6% for pemetrexed alone. Median survival was 7.6 months for pemetrexed plus cisplatin (67% censored) and 4.1 months for pemetrexed alone (55% censored). The most commonly reported serious adverse events in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). CONCLUSIONS: The data from this EAP study suggest that patients with previously treated MPM can benefit from treatment with pemetrexed alone or in combination with cisplatin. The treatment is associated with acceptable toxicity.

Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program.

BACKGROUND: To date, few large studies have been reported of patients with peritoneal mesothelioma, and treatment of this disease has been largely extrapolated from the treatment of pleural disease. Hence, it was considered important to study and report on this specific patient population. Before the regulatory approval of pemetrexed, an expanded access program (EAP) provided access to eligible patients with malignant pleural or peritoneal mesothelioma. PATIENTS AND METHODS: Patients received pemetrexed 500 mg/m2 alone or in combination with cisplatin 75 mg/m2 once every 21 days for > or = 6 cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. Serious adverse events (SAEs) were compiled in a pharmacovigilance database, which included all patients in the EAP with pleural or peritoneal mesothelioma. From June 12, 2002 to February 18, 2004, 1056 patients with malignant mesothelioma were enrolled and received > or = 1 dose of treatment at 462 sites in the United States. Of these patients, 98 (9.3%) had peritoneal mesothelioma (57 previously treated, 38 chemotherapy-naive, and 3 with missing data). RESULTS: Response data were available for 73 patients (43 previously treated, 28 chemotherapy-naive, and 2 not classified), indicating response rates of 23.3% for previously treated patients (0 complete responses [CRs], 10 partial responses [PRs], 21 cases of stable disease [SDs], 12 cases of progressive disease [PDs]) and 25% for chemotherapy-naive patients (3 CRs, 4 PRs, 12 SDs, and 9 PDs). Median survival was 13.1 months for previously treated patients and has not been reached for chemotherapy-naive patients. The most commonly reported SAEs for the total EAP were dehydration (7.2%), nausea (5.2%), and vomiting (4.9%). CONCLUSION: Pemetrexed with or without cisplatin had a favorable safety profile, and the disease control rate (CR + PR + SD) of 71.2% in the subset of patients with peritoneal mesothelioma indicated activity in this patient population.