Effectiveness of dabrafenib in the treatment of patients with BRAF V600-mutated metastatic melanoma in a Named Patient Program.

Given the approval of dabrafenib in patients with BRAF-mutant metastatic melanoma, a better understanding of treatment patterns and clinical outcomes with dabrafenib in a clinical setting is warranted. We performed a retrospective chart review of patients who received dabrafenib in a compassionate use setting through the Named Patient Program (DESCRIBE I study) during December 2010-August 2013 in Europe, New Zealand and Australia. Of the 331 Named Patient Program patients included, the majority (95.8%) had stage IV disease at dabrafenib initiation and 39.9% had brain metastases (BMs). Dabrafenib was used first line in 67.7% of patients, and median treatment duration was 6.4 months. Dabrafenib was well tolerated. Common grade 2/3 adverse events were hyperkeratosis (7.6%), pyrexia/fever (6.6%), fatigue (5.1%), hand-foot syndrome (5.4%) and nausea (3.6%). Overall response rate was 45.9%, median progression-free survival was 5.2 months (95% confidence interval, 4.2-6.1 months), and median overall survival was 12.4 months (95% confidence interval, 10.2-15.0 months). In patients with known brain metastases (n = 132) versus patients without (n = 199), overall response rate was 42.4% versus 48.2%, progression-free survival was 3.9 months (95% confidence interval, 3.8-5.5 months) versus 5.9 months (95% confidence interval, 4.8-7.8 months) and overall survival was 9.5 months (95% confidence interval, 6.7-12.4 months) versus 15 months (95% confidence interval, 11.1-20.5 months), respectively. Safety and effectiveness of dabrafenib in patients with unresectable advanced BRAF V600-mutant melanoma treated in an Named Patient Program was similar to the clinical trial experience, demonstrating effectiveness of dabrafenib in a nontrial setting.

Irinotecan/fluorouracil/leucovorin or the same regimen followed by oxaliplatin/fluorouracil/leucovorin in metastatic colorectal cancer.

BACKGROUND: This study reports the long-term follow-up of patients with metastatic colorectal cancer (CRC) participating in a randomised phase II study that compared the efficacy and toxicity of the combination of irinotecan (IRI), fluorouracil (FU) with leucovorin (LV) (arm A) versus sequential chemotherapy with IRI plus FU/LV followed by oxaliplatin (OXA) plus FU/LV (arm B) as first line therapy. MATERIALS AND METHODS: Intent-to-treat analysis was performed on 417 patients (211 in arm A and 206 in arm B). Treatment schedules of weekly IRI 80 mg/m(2) or OXA 45 mg/m(2) plus LV 200 mg/m(2) immediately followed by intravenous bolus FU 450 mg/m(2) for 6 weeks were followed by a 2-week rest period. Treatment continued for 4 cycles. Patients in arm A were treated with IRI/FU/LV for 4 cycles, while patients in arm B were initially treated with IRI/FU/LV for 2 cycles followed by sequential administration of 2 cycles of OXA/FU/LV. RESULTS: No significant difference emerged in overall response rate or overall survival. There was a difference in progression-free survival (median, 7.3 versus 8.2 months, p=0.040) in favour of arm B. Toxicity profiles were similar in both arms. CONCLUSION: IRI/FU/LV and IRI/FU/LV followed by OXA/FU/LV showed comparable activity with a manageable toxicity profile.

Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: We performed a systematic review and meta-analysis to compare treatment outcomes for human epidermal growth factor receptor (HER)-2-positive breast cancer patients receiving adjuvant chemotherapy with or without trastuzumab. METHODS: We identified randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in patients with resectable breast cancer. Fixed-effects meta-analysis was used to combine data. RESULTS: Five eligible trials were identified, reporting outcomes on 13,493 women. Fixed-effects analysis showed disease-free survival to be superior for trastuzumab-treated patients (risk ratio [RR], 0.62; 95% confidence interval [CI], 0.56-0.68). Superiority was also observed for patients receiving trastuzumab with respect to mortality (RR, 0.66; 95% CI, 0.57-0.77), locoregional recurrence (RR, 0.58; 95% CI, 0.43-0.77), and distant recurrence (RR, 0.60; 95% CI, 0.52-0.68). Patients receiving trastuzumab with chemotherapy had a higher risk for congestive heart failure (RR, 7.60; 95% CI, 4.07-14.18) and left ventricular ejection fraction decline (RR, 2.09; 95% CI, 1.84-2.37). A higher risk for central nervous system metastasis as the first recurrence event (RR, 1.60; 95% CI, 1.06-2.40) was also noted in patients receiving trastuzumab. CONCLUSIONS: The use of trastuzumab should be considered an integral part of the adjuvant therapy of HER-2-positive breast cancer patients.

Paclitaxel and carboplatin as first-line chemotherapy combined with gefitinib (IRESSA) in patients with advanced breast cancer: a phase I/II study conducted by the Hellenic Cooperative Oncology Group.

Paclitaxel (Taxol) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m(2) over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35-77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in > or =5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27(kipl) positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27(kipl). The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone.

Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study.

PURPOSE: To evaluate the efficacy of temozolomide (TMZ) combined with cisplatin (CDDP) in terms of response rate, time to progression (TTP) and overall survival (OS), as well as the tolerability of the regimen in patients with brain metastases from solid tumors. PATIENTS AND METHODS: Patients (n=32) with brain metastases were treated with TMZ 150 mg/m2/day (chemotherapy-pretreated) or 200 mg/m2/day (chemotherapy-naive) for 5 days, combined with CDDP 75 mg/m2 on day 1, every 28 days. Primary tumor sites included breast cancer (n=15), lung cancer (n=12) and other (n=5). Twenty-seven patients had received prior chemotherapy for extracranial disease and 17 had prior radiotherapy to the brain. RESULTS: One patient (3.1%) with non-small cell lung cancer (NSCLC) achieved complete response. Nine patients (28.1%; six with breast cancer, two with melanoma and one with NSCLC) achieved a partial response and five patients (16%) had stable disease. Median OS was 5.5 months and median TTP 2.9 months. One patient died from septicemia/neutropenic fever. Grade III-IV toxicities included anemia (9%), leukopenia (6%), thrombocytopenia (3%), renal toxicity (3%), headache (3%), fatigue (3%), nausea (3%), vomiting (3%), and alopecia (6%). CONCLUSIONS: TMZ combined with CDDP is an active and well-tolerated combination in patients with brain metastases from solid tumors.

The effect of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma.

Cerebral metastases from melanoma are correlated with a poor prognosis. Temozolomide is an oral alkylating agent that can cross the blood-brain barrier and in phase II and III trials, patients with advanced metastatic melanoma achieved overall response rates of 13 to 21%. The present study evaluated the efficacy and toxicity of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma. Twenty-five patients (median age 48 years) with histologically confirmed stage IV melanoma and cerebral metastases treated with temozolomide-based chemotherapy. 10 patients received temozolomide plus docetaxel, nine patients temozolomide plus cisplatin and six patients temozolomide as single agent. Six patients achieved an objective response (24%). All responses were partial. The disease was stable in five patients (20%) and 13 patients progressed (52%). The median response duration was 6.9 months (range 1.8 to 16 months). The median time to progression (TTP) for all patients was 2 months, compared with a median TTP of 3.9 months, among responders and a median TTP of 1.8 months, for patients who remained stable or progressed (P<0.0001). The median survival time for the entire patient population was 4.7 months. The median survival for responders was 5.5 months and for non-responders was 3.6 months. The difference was statistically significant (P<0.05). The toxicity was mild. The most frequently reported adverse event were myelotoxicity and nausea and vomiting. Four patients developed grade 3/4 leukopenia, two grade 4 neutropenia, and one patient developed grade 3 thrombocytopenia. There was no treatment discontinuation caused by toxicity. Temozolomide-based chemotherapy may have a role in patients with cerebral metastases from melanoma. Further exploration is required. Toxicity was manageable.