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
Author: RR
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
Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy
SUMMARY: The FDA in January, 2011 approved rituximab (RITUXAN®) as a maintenance treatment for patients with advanced follicular lymphoma. Follicular lymphomas are a subset of Non Hodgkins Lymphomas and are very responsive to chemotherapy or chemotherapy given along with RITUXAN®. They are however incurable, despite treatment with RITUXAN® plus chemotherapy. This condition can therefore be considered as a chronic disease. For this reason, prolonging remission duration is important, as the length of remission tends to be shorter with each recurrence. The FDA approval was based on the PRIMA trial, which is a phase III study, in which 1217 treatment naive patients with stage III and stage IV disease requiring therapy were initially treated with RITUXAN® and chemotherapy (induction chemotherapy). Patients responding to initial therapy (n = 1018) were randomized to observation alone or maintenance RITUXAN® for 2 years. The first preplanned interim analysis at a median follow up of 25 months demonstrated a progression-free survival (PFS) of 82% in the RITUXAN® maintenance therapy group versus 66% for those in the observation group, which meant that the recurrence rate was 18% with RITUXAN® maintenance versus 34% for those who were observed. This benefit with RITUXAN® maintenance therapy was seen regardless of age, disease severity, and type of induction chemotherapy received. These findings are relevant, as these patients essentially have a chronic disease and are willing to pursue interventions that could potentially delay recurrence of their lymphoma and thus improve their quality of lives. J Clin Oncol 28:15s, 2010 (suppl; abstr 8004))
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
SUMMARY: T lymphocytes play an important role in cell mediated immunity. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) also known as CD 152 is a protein expressed on the surface of T lymphocytes and has an inhibitory role in T cell function. Ipilimumab (YERVOY®) is a CTLA-4 targeted monoclonal antibody which was studied in metastatic malignant melanoma. MDX010-20 is a large double blind placebo controlled trial in which 676 HLA-A*0201–positive patients, with pretreated advanced melanoma, were randomly assigned to one of the three treatment groups- YERVOY® along with a placebo (137 patients), YERVOY® administered along with a peptide vaccine gp 100 (403 patients) or peptide vaccine gp 100 along with a placebo (136 patients). Patients receiving YERVOY® along with a peptide vaccine had a median survival of 10.1 months compared to 6.4 months for those who received the vaccine alone. This survival benefit for YERVOY® plus vaccine compared to vaccine alone was seen at 12 months (46% vs 25% ) and 24 months (24% vs 14%) respectively. Approximately 10-15% of the patients treated with YERVOY® experienced Grade 3 or 4 immune-related adverse events compared to 3% when treated with gp100 alone. This landmark study is a significant advance in the treatment of metastatic malignant melanoma, with an overall survival benefit. N Engl J Med 2010; 363:711-723
Randomized phase III trial comparing FOLFIRINOX (F 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA) Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial
SUMMARY: Adenocarcinoma of the pancreas is one of the hard-to-treat cancers for which chemotherapy has not demonstrated any survival benefit – that is, until now. In a recently presented randomized phase III trial at the ASCO 2010 meeting, 250 patients with metastatic pancreatic cancer were assigned to receive either single agent Gemcitabine (GEMZAR®) or a combination of fluorouracil, leucovorin, Irinotecan (CAMPTOSAR®) , and Oxaliplatin (ELOXATIN®) – (FOLFIRINOX regimen). Following an interim analysis, this trial had to be closed earlier than planned, based on the significantly positive results noted with the combination regimen. The median overall survival for patients in the FOLFIRINOX was 11.1 months compared with 6.8 months for those receiving single agent GEMZAR®. At one year, 48% of patients in the FOLFIRINOX group were alive compared to 20% for those in the GEMZAR® group. The median progression free survival was 6.4 months for the patients treated with FOLFIRINOX compared to 3.3 months for those treated with single agent GEMZAR®. Quality of life was also superior in the FOLFIRINOX group compared to those who were treated with GEMZAR®. For the very first time, we now have a combination chemotherapy regimen for advanced pancreatic cancer that confers survival benefit. J Clin Oncol 28:303s, 2010 (suppl; abstr 4010)
Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC) A Gynecologic Oncology Group study
SUMMARY: The role of Bevacizumab (AVASTIN®) in the treatment of advanced ovarian cancer was evaluated in a large randomized double blind phase III trial. One thousand eight hundred and seventy three (1873) patients with stage III or IV disease, who were treatment naïve, were randomly assigned to one of three treatment groups – standard chemotherapy with paclitaxel and carboplatin given along with a placebo followed maintenance treatment with a placebo, standard chemotherapy given along with AVASTIN® followed by maintenance treatment with a placebo or standard chemotherapy given along with AVASTIN® followed by maintenance treatment with AVASTIN®. Patients receiving standard chemotherapy along with AVASTIN® followed by maintenance AVASTIN® had a median Progression Free Survival of 14.1 months compared to 10.3 months for those who received standard chemotherapy alone. Interestingly, outcomes in patients receiving standard chemotherapy along with AVASTIN® followed by placebo maintenance did no better than those who received standard chemotherapy alone. To date, addition of AVASTIN® to standard chemotherapy followed by AVASTIN® maintenance has not resulted in significant improvement in overall survival. J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1)