The FDA on November 22, 2013 approved NEXAVAR® for the treatment of locally recurrent or metastatic, progressive, Differentiated Thyroid Carcinoma (DTC), refractory to radioactive iodine treatment. NEXAVAR® was previously approved for the treatment of Renal Cell Carcinoma in 2005 and HepatoCellular Carcinoma in 2007. NEXAVAR® tablets are a product of Bayer Healthcare Pharmaceuticals Inc.
Month: November 2013
Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer The phase III DECISION trial
SUMMARY: The FDA approved Sorafenib (NEXAVAR®) for the treatment of patients with locally recurrent or metastatic, progressive, Differentiated Thyroid Carcinoma (DTC), refractory to RadioActive Iodine (RAI) treatment. Over 90% of all thyroid cancers are classified as Differentiated Thyroid Cancers with Papillary, Follicular and Hürthle cell histologies. NEXAVAR® inhibits multiple kinases that are involved in cell proliferation and angiogenesis thereby preventing cancer growth. These kinases include Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. The DECISION trial is a randomized, double-blind, multicenter phase III study in which the efficacy and safety of NEXAVAR® was compared with placebo, in patients with progressive RAI-refractory DTC. Four hundred and seventeen patients (417) were randomized to receive either NEXAVAR® 400 mg po BID (n=207) or placebo (n=210). The median age was 63 yrs and only patients who had no prior chemotherapy or targeted therapy and with disease progression within the preceding 14 months, were included. Over 95% of the patients had metastatic disease and the most common sites of spread were lungs and lymph nodes. Treatment was continued until disease progression or until unacceptable toxicity was noted. Upon progression, patients in the placebo group were allowed to crossover and receive open-label NEXAVAR®. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (RR=Complete + Partial Response [PR]), and safety. Approximately 70% of patients in the placebo arm were allowed to crossover to receive open-label NEXAVAR®. The median PFS was 10.8 months with NEXAVAR® compared to 5.8 months with placebo (hazard ratio [HR] = 0.58; P <0.0001). Partial responses were observed in 12.2% of patients receiving NEXAVAR® compared with 0.5% in the placebo arm (P < 0.0001). Further, 42% of patients in the NEXAVAR® group had stable disease for 6 months or more compared to 33% in the placebo group. Median OS has not been reached. The most common adverse events in the NEXAVAR® group included hand–foot skin reaction, diarrhea, rash/desquamation, fatigue and hypertension. The authors concluded that NEXAVAR® extends PFS in a select group of patients with advanced DTC and is the first and only FDA approved therapy for DTC. Brose MS, Nutting C, Jarzab B, et al. J Clin Oncol 31, 2013 (suppl; abstr 4)
Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer The phase III DECISION trial
SUMMARY: The FDA approved Sorafenib (NEXAVAR®) for the treatment of patients with locally recurrent or metastatic, progressive, Differentiated Thyroid Carcinoma (DTC), refractory to RadioActive Iodine (RAI) treatment. Over 90% of all thyroid cancers are classified as Differentiated Thyroid Cancers with Papillary, Follicular and Hürthle cell histologies. NEXAVAR® inhibits multiple kinases that are involved in cell proliferation and angiogenesis thereby preventing cancer growth. These kinases include Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. The DECISION trial is a randomized, double-blind, multicenter phase III study in which the efficacy and safety of NEXAVAR® was compared with placebo, in patients with progressive RAI-refractory DTC. Four hundred and seventeen patients (417) were randomized to receive either NEXAVAR® 400 mg po BID (n=207) or placebo (n=210). The median age was 63 yrs and only patients who had no prior chemotherapy or targeted therapy and with disease progression within the preceding 14 months, were included. Over 95% of the patients had metastatic disease and the most common sites of spread were lungs and lymph nodes. Treatment was continued until disease progression or until unacceptable toxicity was noted. Upon progression, patients in the placebo group were allowed to crossover and receive open-label NEXAVAR®. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (RR=Complete + Partial Response [PR]), and safety. Approximately 70% of patients in the placebo arm were allowed to crossover to receive open-label NEXAVAR®. The median PFS was 10.8 months with NEXAVAR® compared to 5.8 months with placebo (hazard ratio [HR] = 0.58; P <0.0001). Partial responses were observed in 12.2% of patients receiving NEXAVAR® compared with 0.5% in the placebo arm (P < 0.0001). Further, 42% of patients in the NEXAVAR® group had stable disease for 6 months or more compared to 33% in the placebo group. Median OS has not been reached. The most common adverse events in the NEXAVAR® group included hand–foot skin reaction, diarrhea, rash/desquamation, fatigue and hypertension. The authors concluded that NEXAVAR® extends PFS in a select group of patients with advanced DTC and is the first and only FDA approved therapy for DTC. Brose MS, Nutting C, Jarzab B, et al. J Clin Oncol 31, 2013 (suppl; abstr 4)
Hereditary Hemochromatosis Missed Diagnosis or Misdiagnosis?
SUMMARY: The authors in this provocative study reviewed the electronic medical records of patients seen at a tertiary referral center, to evaluate the accuracy of diagnosis of Hereditary Hemochromatosis (HH), an Autosomal Recessive disorder. The HFE gene is located on the short arm of chromosome 6 and modulates iron uptake. HFE genotyping helps differentiate HH from secondary causes of Iron overload syndromes. This differentiation is relevant because of the lack of established guidelines with regards to management of individuals with abnormal iron studies, secondary to liver disease. It is however well known that HH and iron overload related to transfusions, can cause organ damage and this could be prevented by removing the excess iron. In this study, the authors investigated the diagnostic approach, when elevated iron studies were noted, interpretation of HFE genotyping results by physicians in order to accurately diagnose HH and factors contributing to misdiagnosis. This chart review conducted between January 2002 and May 2012 demonstrated that of the 601 patients with disorders of iron metabolism, only 62% were genotyped for mutations in the HFE gene. Of those genotyped, 54% had genotypes consistent with HH (Homozygotes – C282Y/C282Y or Compound Heterozygotes – C282Y/H63D) and the rest of the 46% had non hereditary hemochromatosis genotypes (C282Y heterozygotes, H63D homozygotes and heterozygotes, etc). One half of these non hereditary hemochromatosis genotype patients were misdiagnosed with HH and a third of these patients underwent phlebotomy. Of those who were not genotyped for mutations in the HFE gene, a third of these patients were diagnosed to have HH and majority of these patients underwent phlebotomy. More than 2/3rd of the patients misdiagnosed to have HH in fact had liver disease and 5% had other hematological conditions. The authors concluded that C282Y heterozygotes as well as H63D homozygotes and heterozygotes do not have HH and a majority of patients with iron overload are misdiagnosed to have HH. Aggressive phlebotomy in the absence of an appropriate Hereditary Hemochromatosis genotype, is not indicated and can be potentially harmful, delaying more appropriate therapy. Cherfane CE, Hollenbeck RD, Go J, et al. The American Journal of Medicine 2013;126:1010-1015.
Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma
SUMMARY:The FDA granted accelerated approval to Ibrutinib (IMBRUVICA®), for the treatment of patients with Mantle Cell Lymphoma (MCL), who had received at least one prior therapy. Bruton's Tyrosine Kinase (BTK) is a cytoplasmic protein predominantly expressed in B-cells and is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK is necessary for the proliferation and survival of B-cell tumors. IMBRUVICA® is an oral, irreversible inhibitor of BTK and thereby inhibits cell proliferation and promotes programmed cell death (Apoptosis). The efficacy of IMBRUVICA® was evaluated in a multi-center, international, single-arm Phase II trial in which 111 patients with previously treated MCL, received IMBRUVICA®, at a daily oral dose of 560 mg. The median age was 68 years and patients had received a median of three prior therapies. Patients were stratified into those who had previously received at least 2 cycles of VELCADE® (Bortezomib) therapy and those who had received less than 2 cycles or had no prior therapy with VELCADE®. More than 80% of patients had intermediate-risk or high-risk disease. Treatment was given until disease progression or until unacceptable toxicities were noted. The primary end point was Overall Response Rate (ORR). Secondary end points included duration of response, Progression Free Survival (PFS), Overall Survival (OS), and safety. With a median follow-up of 15.3 months, the ORR was 68%, with a 21% Complete Response and 47% Partial Response rate. The estimated median duration of response was 17.5 months. Prior treatment with VELCADE® had no influence on the Response Rate (RR). The median PFS was 13.9 months and estimated OS was 58% at 18 months. Treatment related toxicities were mild to moderate nausea, diarrhea, fatigue, and cytopenias. Grade 3 bleeding was noted in 5% of the patients, but these patients had a history of falls and were receiving either Aspirin or Warfarin. The authors concluded that IMBRUVICA® given as a single agent has durable efficacy in relapsed or refractory MCL. Studies are underway, combining IMBRUVICA® with TREANDA® (Bendamustine) and RITUXAN® (Rituximab), as front line therapy for patients with MCL. The list of agents for the treatment of relapsed or refractory MCL now include VELCADE®, REVLIMID® and IMBRUVICA®. Wang ML, Rule S, Martin P, et al. N Engl J Med 2013; 369:507-516
IMBRUVICA ® (Ibrutinib)
The FDA on November 13, 2013 granted accelerated approval to IMBRUVICA ® for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. IMBRUVICA ® is an oral capsule and is a product of Pharmacyclics, Inc.
Results of Initial Low-Dose Computed Tomographic Screening for Lung Cancer
SUMMARY: The National Lung Screening Trial (NLST), a federally funded U.S. study, enrolled 53,439 asymptomatic participants, 55 to 74 years of age, with at least 30 pack-year smoking history, and were randomized to undergo annual screening with either low dose CT scan (n=26,715) or a chest X-Ray (n=26,724), for three years. The use of low dose CT scans for 3 years in this high risk, healthy patients, resulted in a 20% reduction in Lung Cancer mortality, compared to screening with a chest X-Ray. Based on these findings, Lung Cancer Screening is recommended for the following groups
1) People 55-74 years of age with no signs or symptoms of Lung Cancer
2) Current or former smoker with a 30 pack year smoking history (Number of years smoked multiplied by the number of packs of cigarettes per day)
3) Current smokers are strongly urged to enter a smoking cessation program
4) Former smokers must have quit smoking within the past 15 years
Lung Cancer screening is performed using a non-contrast, low dose CT scan. People with serious co-morbid conditions, those on home oxygen and individuals with metallic devices or implants in the chest or back (which can interfere with the scan) should be excluded from Lung Cancer screening. It should be noted that Lung cancer screening with low dose CT scan is presently not covered by most insurance plans. The National Lung Screening Trial Research Team. N Engl J Med 2013;368:1980-1991
Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003) a randomised, open-label, phase 3 trial
SUMMARY: Pomalidomide (POMALYST®) is a novel, oral, immunomodulatory agent which is far more potent than Thalidomide (THALOMID®) and Lenalidomide (REVLIMID®). Only 2% of POMALYST® is excreted unchanged through the kidney whereas 80% of REVLIMID® is excreted unchanged via the kidneys. Therefore, POMALYST® may be a consideration for patients with renal insufficiency. Previously conducted phase II trials have shown POMALYST® to be active in Myeloma patients, refractory to REVLIMID® and Bortezomib (VELCADE®). In a multicenter, randomized, phase III trial, the efficacy and safety of POMALYST® given along with low-dose Dexamethasone (LoDEX) (n=302) was compared with high-dose Dexamethasone (HiDEX) (n=153) in Myeloma patients, who were refractory to both REVLIMID® and VELCADE®. The primary endpoint was Progression Free Survival (PFS). The Overall Survival (OS) was only evaluated if PFS was statistically significant. With a median follow up of 10 months, the PFS was significantly longer in the POMALYST® + LoDEX group compared to the HiDEX group (4 month vs 1.9 months; hazard ratio [HR]= 0.48; P <0 .0001). The median OS was significantly longer in the POMALYST® + LoDEX group compared to HiDEX group (12.7 months vs 8.1 months; HR=0.74; P=0.028). The authors concluded that POMALYST® along with low- dose Dexamethasone should be the new standard of care for patients who have Multiple Myeloma refractory to REVLIMID® and VELCADE®. Carfilzomib (KYPROLIS®), a new parenteral proteasome inhibitor is another option for patients with resistant and refractory Multiple Myeloma. San Miguel J, Weisel K, Moreau P, et al. Lancet Oncol 2013;14:1055-1066
Adjuvant Chemotherapy With Gemcitabine and Long-term Outcomes Among Patients With Resected Pancreatic Cancer
SUMMARY: Curative surgical resection has been shown to significantly improve Overall Survival (OS) when compared to Chemoradiation, for resectable Pancreatic Cancer. The standard surgical procedure for tumors of the Pancreatic head is the Pancreaticoduodenectomy (Whipple procedure), whereas distal Pancreatectomy is performed for tumors of the body or tail of the Pancreas. The role of adjuvant chemotherapy following surgery has however remained unclear. In this community based, phase III trial, 368 patients were randomly assigned to receive either adjuvant chemotherapy with GEMZAR® (Gemcitabine) (N=186) or Observation (N=182), following curative resection of the pancreas (Macroscopic complete removal of Pancreatic cancer). Chemotherapy consisted of 6 cycles of GEMZAR® with each cycle consisting of GEMZAR® 1000mg/m2, given weekly, 3 out of 4 weeks. Patients were stratified based on tumor stage (T), nodal status (N) and resection (R) status. The primary endpoint was Disease Free Survival (DFS). Secondary endpoints included OS and safety. With a median follow up of 136 months, the median DFS was 13.4 months in the treatment group vs 6.7 months in the observation group (HR=0.55; P<0.001). The OS in the treatment group was significantly prolonged (HR=0.76; P=0.01), with a 5 year survival of 21% and 10 year survival of 12% compared to 10% and 8% respectively, in the Observation group. The authors concluded that 6 months of GEMZAR® based adjuvant therapy improves Overall Survival for patients with resectable Pancreatic Cancer. There may be added benefit with regimens associated with higher remission rates such as FOLFIRINOX or weekly ABRAXANE® (Paclitaxel albumin-bound particles) and GEMZAR®. Oettle H, Neuhaus P, Hochhaus A, et al. JAMA. 2013;310:1473-1481.
GAZYVA® (Obinutuzumab)
The FDA on November 1, 2013 approved GAZYVA® for use in combination with Chlorambucil (LEUKERAN®), for the treatment of patients with previously untreated Chronic Lymphocytic Leukemia (CLL). GAZYVA® is an injection, for intravenous use and is a product of Genentech, Inc.