SUMMARY: Hairy cell leukemia (HCL) is a relatively indolent disorder with characteristic immunophenotypic findings. In spite of the lack of clear understanding of the molecular biology of HCL, treatment with purine nucleoside analogs has resulted in long term remissions and cure. To under the genetic abnormalities in patients with HCL, Tiacci and colleagues evaluated the peripheral blood of 48 patients with HCL. They noted that all 48 patients had BRAF V600E mutation. This is the same mutation that has been noted in approximately 50% of the patients with melanoma. They further tested the peripheral blood of 5 patients in vitro with BRAF inhibitor vemurafenib. This drug indeed demonstrated efficacy by markedly decreasing phosphorylated ERK and MEK. This interesting finding may help us better understand the pathogenesis of HCL and targeted therapy with BRAF inhibitors may change the way we treat patients with HCL. N Engl J Med 2011; 364:2305-2315
Author: RR
Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600E BRAF-mutated melanoma
SUMMARY: The Mitogen- Activated Protein kinase pathway (MAP kinase pathway) is a key signaling pathway which enables the cell to respond external stimuli. There are a number of MAP kinase pathways which share different proteins at each step. The MAP kinase pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAP kinase pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAS family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6%-8% of all malignancies. The most common BRAF mutations in melanoma is at the V600E site and is detected in approximately 50% of melanomas. Vemurafenib is a novel oral inhibitor of mutated BRAF. Based on the impressive phase I and phase II data, BRIM 3, a randomized, open-label, multicenter, phase III trial was conducted, in treatment naïve patients with unresectable Stage IIIC or Stage IV melanoma with V600E BRAF mutation. Patients in this trial received either Vemurafenib or Dacarbazine. The primary end points were progression- free survival and overall survival . There was a statistically significant improvement both in progression free survival and overall survival in the Vemurafenib group compared to those in the Dacarbazine group.This is a major advance in the field of personalized medicine and molecular targeted therapy. J Clin Oncol 29: 2011 (suppl; abstr LBA4)
Improving Survival in Metastatic Melanoma
Approximately 50% of the patients with melanoma have an activating BRAF mutation, V600E. Vemurafenib is an oral BRAF kinase inhibitor. In a randomized phase III study involving treatment naive patients with unresectable stage III or stage IV melanoma patients with BRAF mutation V600E, Vemurafenib significantly improved progression free survival (PFS) and overall survival (OS) compared to Dacarbazine (DTIC). This is a major advance in the field of personalized medicine and molecular targeted therapy. This information was presented at the 2011 ASCO meeting.
Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer
SUMMARY: Patients with triple negative breast cancer have inherent defects in several DNA repair pathways. These cancer cells therefore become increasing dependent on another DNA damage repair pathway called base excision repair (BER) pathway, for survival. It so happens that PARP 1(PolyAdenosine diphosphate Ribose Polymerase) is an important enzyme regulating the BER pathway. By inhibiting PARP1, the BER pathway is inhibited leading to extreme levels of DNA damage and eventual death of cancer cells. In an article published in the January, 2011 issue of the NEJM, the addition of a PARP inhibitor Iniparib to chemotherapy improved clinical benefit and survival of patients with advanced triple negative breast cancer. A phase II open label trial was conducted, in which 123 patients with metastatic triple negative breast cancer were randomly assigned to receive a combination of carboplatin and GEMZAR® (gemcitabine) with or without iniparib. Patients who received chemotherapy in combination with iniparib demonstrated improved rate of clinical benefit (partial or complete response plus stable disease for 6 or more months) from 34% to 56% (P=0.01). This was the primary end point. The addition of iniparib to chemotherapy also prolonged the median progression free survival from 3.6 months to 5.9 months (HR for progression, 0.59; P=0.01) and median overall survival from 7.7 months to 12.3 months (HR for death, 0.57; P=0.01). These gains were achieved without any significant increase in toxicities. This difficult to treat subtype of breast cancer may soon become extinct. N Engl J Med 2011; 364:205-214
ABIRATERONE ACETATE (AA) PLUS LOW DOSE PREDNISONE (P) IMPROVES OVERALL SURVIVAL (OS) IN PATIENTS (PTS) WITH METASTATIC CASTRATIONRESISTANT PROSTATE CANCER (MCRPC) WHO HAVE PROGRESSED AFTER DOCETAXEL-BASED CHEMOTHERAPY (CHEMO) RESULTS OF COU-AA-301, A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE III STUDY
SUMMARY: Abiraterone acetate (ZYTIGA®) is a novel, targeted, oral androgen biosynthesis inhibitor that decreases androgen production in the adrenal glands, testes and prostate cancer cells by inhibiting a steroidal enzyme CYP17. This agent was approved by the FDA in April, 2011 for use in combination with prednisone for the treatment of patients with metastatic CRPC (Castrate Resistant Prostate Cancer), who have received prior chemotherapy containing docetaxel (TAXOTERE®). This approval was based on a randomized, placebo controlled phase III trial which included 1195 patients with metastatic CRPC, previously treated with one or two chemotherapy regimens, at least one of which contained TAXOTERE®. Patients were randomly assigned (2:1) to receive either ZYTIGA® plus low-dose prednisone (N=797) or placebo plus low dose prednisone (N=398). Treatment was continued until disease progression. The primary endpoint was overall survival. Results from a pre-specified interim analysis demonstrated that patients treated with ZYTIGA® plus low-dose prednisone showed a statistically significant improvement in overall survival as well secondary endpoints such as, time to PSA progression and radiographic progression-free survival. Treatment with ZYTIGA® resulted in a 35 percent reduction in the risk of death and a 36 percent increase in median survival compared with placebo. The most common adverse events were edema, hypertension, joint discomfort, diarrhea, hypokalemia, and hypophosphatemia. This novel therapeutic agent is a major and important medical advance in the management of patients with metastatic CRPC. With the availability of several new agents for the treatment of CRPC, it may be important to properly sequence these available drugs to get the best of each treatment intervention and thus improve overall survival. Annals of Oncology 21 (Supplement 8): viii1-viii12. 2010. Ref Type: Abstract
Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia
SUMMARY: This multicenter international phase III study evaluated the efficacy of Dasatinib (SPRYCEL®) versus Imatinib (GLEEVEC®) in newly diagnosed chronic phase Chronic Myeloid Leukemia patients. Of the 519 patients enrolled, 259 patients received SPRYCEL® at 100 mg daily whereas 260 patients received GLEEVEC® 400 mg daily. The complete cytogenetic response rate after one year for SPRYCEL® and GLEEVEC® was 77% versus 66% respectively and the major molecular response rate at 12 months was 46% vs 28% for the SPRYCEL® group and GLEEVEC® group respectively. Thrombocytopenia and pleural effusions were more often seen in the SPRYCEL® group. It was concluded that SPRYCEL® resulted in a significantly shorter time to achieve complete cytogenetic and major molecular responses. N Engl J Med 2010; 362:2260-2270.
Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors
SUMMARY: Pancreatic neuroendocrine tumors account for approximately 5% of all pancreatic tumors and in general tend to be indolent tumors. In a randomized multicenter phase III trial, 171 patients with advanced, well-differentiated pancreatic neuroendocrine tumors, whose tumors had progressed in the prior 12 months were randomized to receive either Sunitinib (SUTENT®), a multitargeted tyrosine kinase inhibitor, at a dose of 37.5 mg qd or placebo. Following an interim analysis, this study was closed earlier than planned based on the superiority of SUTENT® over placebo. The median progression free survival was longer for those who received SUTENT® than those in the placebo group (11.4 versus 5.5 months). More patients in the SUTENT® group were alive at 6 months compared to the placebo group (92.6% versus 85.2%). N Engl J Med 2011; 364:501-513
Everolimus for Advanced Pancreatic Neuroendocrine Tumors
SUMMARY: Everolimus (AFINITOR®) is an oral mTOR (mammalian target of rapamycin) inhibitor, presently approved for the treatment of advanced renal cel carcinoma. Based on the established efficacy of AFINITOR® in phase II trials, a prospective, randomized, phase III study was conducted in which 410 patients with advanced, low grade or intermediate grade pancreatic neuroendocrine tumors with progression within the previous 12 months were randomized to receive AFINITOR®, at a dose of 10 mg QD (207 patients), or placebo (203 patients).The primary end point, progression free survival (PFS) was met, with a PFS of 11 months in the AFINITOR® group and 4.6 months in the placebo group. These benefits were accomplished with a low rate of grade III and IV toxicities. It appears that the mTOR pathway may play an important role in the molecular pathogenesis of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364:514-523
Anaplastic Lymphoma Kinase Inhibition in Non Small Cell Lung Cancer
SUMMARY:The therapeutic target of interest is an aberrant fusion gene, EML4-ALK. EML4 (echinoderm microtubule-associated protein-like 4) – ALK (anaplastic lymphoma kinase) is a fusion-type oncoprotein and is tyrosine kinase. This oncoprotein/tyrosine kinase is found in 2-7% of all Non Small Cell Lung Cancers (NSCLC) and is generated due to an inversion in the short arm of chromosome 2. This oncoprotein is more prevalent in patients with adenocarcinoma who have little or no exposure to tobacco. Tyrosine kinases normally play an important role in cellular proliferation and differentiation. However with point mutations, translocation/rearrangement and amplifications of their respective genes, these tyrosine kinases can potentially cause malignancy. Such is the case with mutations or translocations of the Anaplastic Lymphoma Kinase gene (ALK). In an article published in the October 28, 2010 issue of the NEJM, Crizotinib an oral small molecule tyrosine kinase inhibitor of ALK tyrosine kinase resulted in an overall response rate of 57% in patients who had progressed on prior therapies. Stable disease was noted in 33% of the patients. This is remarkable considering that the response rates in this patient population treated with second line chemotherapy is around 10-15%. As we move forward, it is very likely that genotyping patients and tailoring therapy accordingly, will become standard practice. N Engl J Med 2010; 363:1693-1703
A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane
SUMMARY: HALAVEN ® (Eribulin) is a non taxane inhibitor of microtubule dynamics and is a synthetic analog of halichondrin B, a product derived from a a sea sponge Halichodria okadai. It triggers apoptosis of cancer cells following prolonged mitotic inhibition. The EMBRACE trial is a randomized open label phase III study involving 762 heavily pretreated patients with locally recurrent or metastatic breast cancer. These patients must have had at least two prior chemotherapy regimens including taxanes and an anthracycline. Patients were randomized to either HALAVEN ® (508 patients) or to an approved treatment of their physician's choice and this could be single agent chemotherapy, hormonal therapy, biological therapy or palliative radiation therapy (254 patients). Nineteen percent of the patients had triple negative disease. There was a statistically significant improvement in overall survival in the HALAVEN ® group 13.1 months compared to 10.7 months in the control group. At one year, 54% of the patients were alive in the HALAVEN ® group compared to 44% in the control group. This statistically significant benefit was also seen in the overall response rates. We now have another agent with a distinct survival advantage for heavily pretreated metastatic breast cancer patients. J Clin Oncol 28:18s, 2010 (suppl; abstr CRA1004)