SUMMARY: Apixaban (ELIQUIS®) is an oral, direct coagulation factor Xa inhibitor, similar to XARELTO® (Rivaroxaban). In this double blind study, ELIQUIS® was compared with conventional therapy, which included subcutaneous Enoxaparin (LOVENOX®) followed by Warfarin. Five thousand three hundred ninety five (5395) patients with acute deep vein thrombosis, pulmonary embolism or both, were randomly assigned to receive either ELIQUIS® 10 mg BID for one week followed by 5 mg BID for 6 months (n=2691) or conventional therapy with LOVENOX® followed by Warfarin (n=2704). The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death, related to venous thromboembolism. ELIQUIS® was non inferior to conventional therapy (P<0.001). The risk of major bleeding was slightly lower in the ELIQUIS® group. This efficacy and safety of ELIQUIS® was demonstrable in all patient subgroups. ELIQUIS®, similar to XARELTO®, will very likely be approved for the treatment of Venous ThromboEmbolism. Unlike Vitamin K antagonists (Warfarin), the newer oral anticoagulants do not require coagulation monitoring as they have a rapid onset of action, relatively stable pharmacokinetics and are not associated with significant drug interactions. It is important to realize however, that there are no agents presently available to reverse bleeding associated with these new oral anticoagulants. Development of antidotes that bind to factor Xa inhibitors, in order to reverse bleeding complications, are underway. Agnelli G, Buller HR, Cohen A, et al. N Engl J Med 2013; 369:799-808
Author: RR
Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer German AIO study KRK-0306 (FIRE-3)
SUMMARY: It is common practice to combine anti-EGFR agent ERBITUX® (Cetuximab) or anti-VEGF agent AVASTIN® (Bevacizumab) with chemotherapy, in the initial management of patients with metastatic colorectal cancer. There is however a higher likelihood for patients with tumors expressing wild type KRAS (non-mutated KRAS), to respond to ERBITUX®. In this randomized multicenter study, a CAMPTOSAR® (Irinotecan) based backbone, FOLFIRI (folinic acid, fluorouracil and Irinotecan) given along with ERBITUX® (Group A) was compared with FOLFIRI plus AVASTIN® (Group B), in treatment naïve patients with metastatic ColoRectal Cancer (mCRC). Of the 592 patients with wild type KRAS mCRC, 297 patients were randomized to Group A and 295 patients to Group B. The median age was 64 years. The median duration of treatment was 4.7 months and 5.3 months in Group A and Group B respectively. The primary endpoint was Objective Response Rate (ORR). Even though the ORR was comparable in Groups A and B (62% vs 57%), there was a significant improvement in the overall survival (OS) favoring Group A (28.8 vs 25.0 months, HR= 0.77, P=0.0164). The comparable response rates and surprising improvement in OS in the ERBITUX® group suggests that either ERBITUX® or AVASTIN® can be added to FOLFIRI, in the first-line treatment of wild type KRAS mCRC patients. It is however clear that in wild type KRAS mCRC patients, it may be harmful to combine ERBITUX® with FOLFOX chemotherapy regimen, as was seen in the EPOCH trial and based on MRC COIN trial, NORDIC-VII trial and N0147 trial, ERBITUX® should not be combined with FOLFOX chemotherapy regimen as there is no added benefit. It is now well established that mCRC that harbors KRAS mutations in exon 2 (about 40% of the patients) do not benefit from anti-EGFR therapies. The PRIME study has given us aditional insight and it appears that other activating RAS mutations may also predict lack of response to anti-EGFR therapies. With regards to BRAF mutations, they portend a poor prognosis, regardless of treatment. Heinemann V, Weikersthal LF, Decker T, et al. J Clin Oncol 31, 2013 (suppl; abstr LBA3506)
Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities) Final stage 1 results of the CLL11 (BO21004) phase III trial
SUMMARY: Obinutuzumab or GAZYVA® (GA101) is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody (IgG1 monoclonal antibody) that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. It has enhanced antibody-dependent cellular cytotoxicity (ADCC) and strong apoptosis-inducing activity. In contrast, RITUXAN® (Rituximab) is a first generation chimeric anti-CD20 targeted monoclonal antibody. In this phase III trial, LEUKERAN® (Chlorambucil – Clb)) was compared with a combination of GAZYVA® plus LEUKERAN® (GClb) and a combination of RITUXAN® plus LEUKERAN® (RClb). Five Hundred and eighty nine (589) treatment naïve CLL patients over 70 years of age with comorbidities were enrolled of whom 118 patients received Clb, 238 received GClb and 233 received RClb. The primary endpoint was Progression-Free Survival (PFS). Chemoimmunotherapy with both GClb and RClb significantly prolonged PFS compared to Clb alone. The median PFS was 10.8 months with Clb alone compared to 23 months for GClb (HR=0.14, P<0.0001) and 15.7 months for RClb (HR=0.32, P<0.0001). There were no Complete Responses (CR) with Clb alone whereas the CR rates with GClb and RClb were 22% and 8% respectively. This study gives new life to LEUKERAN® when given in combination with CD20 targeted monoclonal antibodies and may be of value when treating elderly patients with comorbid conditions. Goede V, Fischer K, Humphrey K, et al. J Clin Oncol 31, 2013 (suppl; abstr 7004)
Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma
SUMMARY:Lambrolizumab (MK-3475) is a humanized anti–PD-1 monoclonal antibody. The programmed death 1 (PD-1) receptor is an inhibitory receptor expressed on activated T-cells in the tumor micro environment. The anti–PD-1 antibody by blocking the PD-1 receptor essentially unleashes the immune system to fight off cancer cells. One hundred and thirty five patients with advanced melanoma regardless of their prior therapy with YERVOY® (Ipilimumab) received IV Lambrolizumab every 2-3 weeks. There was no difference in the response rates between patients who had prior therapy with YERVOY® and those who did not (38%). Majority of these patients had a rapid and durable response. The median progression-free survival was more than 7 months. The most common adverse events, mostly low grade were, fatigue, rash, pruritus, and diarrhea. The authors concluded that Lambrolizumab can significantly benefit patients with advanced Malignant Melanoma, regardless of their prior therapy with anti-CTLA 4 antibody, YERVOY® and with minimal toxicity. Hamid O, Robert C, Daud A, et al. N Engl J Med 2013; 369:134-144
Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT)
SUMMARY: The FDA recently approved ABRAXANE® ((Paclitaxel albumin-bound particles) for use in combination with GEMZAR® (Gemcitabine) for the first line treatment of patients with metastatic adenocarcinoma of the pancreas. This approval was based on the demonstration of improved overall survival (OS) in a multi-center, international, open-label, randomized trial. Eight hundred and sixty one (861) patients with metastatic pancreatic cancer were randomized to receive either the combination of ABRAXANE® and GEMZAR® (n=431) or GEMZAR® alone (n=430). Patients were stratified based on geographic region, performance status, and presence of liver metastasis. The median age was 63 years. The primary end point was OS and secondary endpoints included progression-free survival (PFS) and overall response rate (ORR. There was a statistically significant prolongation of OS for patients in the combination group with a 28% reduction in the risk of death [HR= 0.72; P < 0.0001]. The median OS was 8.5 months in the combination group and 6.7 months in the single agent GEMZAR® group. There was in addition a significant improvement in the PFS in the combination arm vs the single agent arm (5.5 months vs 3.7 months, respectively.HR= 0.69; P < 0.0001). Objective response rates were 23% in the combination group and 7% in the single agent GEMZAR® group (P<0.0001). Serious adverse reactions in patients receiving combination therapy included fever, vomiting, dehydration and pneumonia. This is clearly a major development in the management of advanced pancreatic cancer patients. Von Hoff DD, Ervin TJ, Arena FP, et al. J Clin Oncol 30: 2012 (suppl 34; abstr LBA148)
ABRAXANE® (Paclitaxel albumin-bound particles)
The FDA on September 6, 2013 approved ABRAXANE® for use in combination with GEMZAR® (Gemcitabine) for the first line treatment of patients with metastatic adenocarcinoma of the pancreas. ABRAXANE® is an injectable suspension and is a product of Celgene Corporation.
Long-Term Survival of Participants in the Prostate Cancer Prevention Trial
SUMMARY: In the landmark Prostate Cancer Prevention Trial (PCPT), Finasteride (PROSCAR®) reduced the risk of Prostate Cancer development and therefore the symptoms associated with it by 33%, compared to Placebo. However, in those who did develop Prostate Cancer while on PROSCAR®, there was an increased risk of high grade tumors. After 18 years of follow up of these patients, it appears that in spite of this set back, there was no difference in the overall survival between the PROSCAR® group and the placebo group. The U.S. Preventive Services Task Force (USPSTF) has been against Prostate Cancer screening, as the consensus is that majority of the Prostate Cancers detected by screening would never become apparent in an individual’s lifetime, if this individual was not screened and therefore would never cause a problem. This long term data begs a very important question – Is it worthwhile taking PROSCAR® for Prostate Cancer prevention? Thompson IM, Goodman PJ, Tangen CM, et al. N Engl J Med 2013;369:603-610
Prostate Cancer – Is Prevention Worthwhile?
In the landmark Prostate Cancer Prevention Trial (PCPT), Finasteride (PROSCAR®) reduced the risk of Prostate Cancer development and therefore the symptoms associated with it by 33%, compared to placebo. However, in those who did develop Prostate Cancer while on PROSCAR®, there was an increased risk of more aggressive disease. After 18 years of follow up of these patients (NEJM 2013), it appears that in spite of this set back, there was no difference in the overall survival between the PROSCAR® group and the placebo group. The U.S. Preventive Services Task Force (USPSTF) has been against Prostate Cancer screening, as the consensus is that majority of the Prostate Cancers detected by screening would never become apparent in an individual’s lifetime, if this individual was not screened and therefore would never cause a problem. This long term data begs a very important question – Is it worthwhile taking PROSCAR® for Prostate Cancer prevention?
Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma
SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow. It evolves from a precursor stage called Monoclonal Gammopathy of Unknown Significance (MGUS) to MM. Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. The risk of MGUS transforming into MM is approximately 1% per year. SMM or asymptomatic MM is a precursor to MM and is characterized by at least 10% plasma cells in the bone marrow or a M-spike of at least 3 g/dl, or both, but these patients have no evidence of active symptomatic Myeloma with associated end-organ damage such as hypercalcemia, renal insufficiency, anemia or bone lesions. Even though only 10% of patients with SMM progress to MM annually, over 50% of the SMM patients with high risk features will progress to MM in the first 2 years. The current recommendations for those with SMM are periodic monitoring and treatment intervention only when disease progresses to MM. SMM patients with high risk features include those with at least 10% plasma cells in the bone marrow, a Monoclonal component (IgG monoclonal spike of at least 3g/dL, IgA M-spike of at least 2g/dL or a urinary Bence Jones protein level of more than 1g per 24 hours) or only one of the above two criteria plus at least 95% abnormal plasma cells in the bone marrow, with a reciprocal decrease in one or two uninvolved immunoglobulins of more than 25%, compared to normal values. Identifying those who are at a high risk for progression in the SMM group, is becoming more relevant with the availability of new promising therapies. In a phase III study, 119 patients with high risk SMM were randomly assigned to receive treatment (n=57) or to be observed until progression (n=62).Treatment consisted of Lenalidomide (REVLIMID®) 25 mg given on D1-D21 and Dexamethasone (DECADRON®) 20 mg given on D1-D4 and D12-D15 of a 4 week cycle. Patients received 9 cycles of therapy followed by maintenance therapy with REVLIMID® 10 mg given on D1-D21 every four weeks for 2 years. The median follow-up time was 40 months. The primary end point was time to progression to symptomatic disease. Secondary end points included response rate, overall survival, and safety. The median time to progression was significantly longer in the treatment group compared to the observation group (hazard ratio [HR] = 0.18; P< .001). At 3 years, the survival rate was better in the treatment group than in the observation group (94% vs 80% with a 69% reduction in the risk of death. P =0.03). Treatment related toxicities were grade 2 or lower. The authors concluded that treatment intervention for patients with high risk SMM may be of value, by delaying progression to symptomatic MM and extending overall survival. It remains to be seen if treatment intervention for patients with SMM will become the standard of care. It may also be relevant to include cytogenetics in the SMM definition criteria, as treatment intervention for SMM becomes an acceptable practice. Mateos M-V, Hernandez M-T, Giraldo P, et al. N Engl J Med 2013;369:438-447
Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer
SUMMARY: Radium Ra 223 dichloride (XOFIGO®) is a bone seeking alpha emitter that selectively targets areas of increased bone turnover. It induces double–stranded DNA breaks and has a very limited range path and quickly loses energy within a short distance of its source. This results in less damage to the adjacent healthy tissue. Further, unlike the dreaded Ra 226 which was first isolated by Madame Curie, XOFIGO® has a short half life of 11.4 days and rapidly decays preventing radiation exposure. In a randomized, double-blind phase III trial, 921 patients with Castrate Resistant Prostate Cancer (CRPC) who had progressed on or had not received TAXOTERE® (Docetaxel) for a variety of reasons, were randomly assigned in a 2:1 ratio to receive either XOFIGO®, with best supportive care or PLACEBO with best supportive care. Patients with visceral metastases were excluded. The primary endpoint was overall survival and secondary endpoints included time to first symptomatic skeletal event, time to increase in total alkaline phosphatase level and PSA level. There was a significant increase in the median overall survival in the XOFIGO® group compared to placebo group with a 30% reduction in the risk of death (14.9 months vs 11.3 months, HR=0.70, P<0.001). All secondary endpoints favored XOFIGO® as well. All adverse events were lower in the XOFIGO® group and myelosuppression was minimal. Unlike the bone seeking beta emitters, Strontium-89 and Samarium-153, XOFIGO®, an alpha emitter, is the only agent that has been shown to improve overall survival. Studies are underway evaluating the efficacy of chemotherapy in combination with XOFIGO®, in patients with CRPC with bone metastases. Parker C, Nilsson S, Heinrich D, et al. N Eng J Med 2013;369:213-23