Month: September 2016

Andexanet Alfa – An Antidote for Acute Major Bleeding Associated with New Oral Anticoagulants

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SUMMARY: There are presently four New Oral Anticoagulants approved in the United States for the treatment of Venous ThromboEmbolism. They include PRADAXA® (Dabigatran), which is a direct thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), which are Factor Xa inhibitors. Compared to COUMADIN® (Warfarin), the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. The half life of these agents can however be prolonged in those with renal insufficiency and may be unsafe and direct oral anticoagulants are ineffective in patients with mechanical heart valves. In several clinical studies, these New Oral Anticoagulants have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN®. Unlike bleeding caused by COUMADIN®, which can be reversed using Vitamin K or Fresh Frozen Plasma, there are no specific agents presently available, for reversing bleeding caused by the New Oral Anticoagulants or for stopping the anticoagulant effects of these drugs, in patients who need urgent surgical intervention. The FDA in October 16, 2015, granted accelerated approval to Idarucizumab (PRAXBIND®), for the treatment of patients treated with Dabigatran (PRADAXA®), a direct thrombin inhibitor, when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. However, the other New Oral Anticoagulants approved in the United States for the treatment of Venous ThromboEmbolism such as XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), are Factor Xa inhibitors and do not have an antidote. As such, some Health Care Providers have discouraged their patients from taking these direct oral anticoagulants until an antidote became available, should their patients need urgent surgical intervention.

Andexanet alfa (AndexXa®) is a recombinant, modified human Factor Xa decoy protein without intrinsic catalytic activity, that binds Factor Xa inhibitors. In a previously published study, AndexXa® reversed the anticoagulant activity of ELIQUIS® and XARELTO® in older healthy participants within minutes after administration, and reduced both the unbound fraction of the plasma level of factor Xa inhibitor and anti-Factor Xa activity, with minimal clinical toxicity (N Engl J Med 2015; 373:2413-242). The AndexXa®, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors (ANNEXA-4) study is an ongoing, multicenter, prospective, open-label, single-group study designed to evaluate the use of AndexXa® in patients with acute major bleeding that was potentially life-threatening.

The authors in this interim report described the outcomes of 67 patients, for whom complete data was available. Patients in this study had acute major bleeding within 18 hours after the administration of one of four Factor Xa inhibitors – ELIQUIS®, XARELTO®, SAVAYSA®, or LOVENOX® (Enoxaparin). Acute major bleeding was defined as potentially life-threatening with signs or symptoms of hemodynamic compromise, decrease in hemoglobin of at least 2 gm/dl, symptomatic bleeding in a critical area or organ. The mean patient age was 77 years, and most patients had a history of cardiovascular disease and thrombotic events and bleeding was predominantly gastrointestinal or intracranial. An independent committee determined hemostatic efficacy on the basis of predetermined criteria. The baseline value for anti-Factor Xa activity was at least 75 ng/ml and 0.5 IU/ml or more for those receiving LOVENOX® and patients had confirmed bleeding severity. All patients received a bolus dose of AndexXa® within 3-6 hours following presentation to the ER followed by a 2-hour infusion of the drug. The two co-primary outcomes were the percent change in the anti-Factor Xa activity and the rate of excellent or good hemostatic efficacy, 12 hours after the AndexXa® infusion. Anti-Factor Xa activity was measured by means of a validated chromogenic assay of Factor Xa enzymatic activity.

It was noted that following the bolus dose of AndexXa®, the median anti-Factor Xa activity decreased by 89% from baseline, among patients receiving XARELTO® and by 93% among patients receiving ELIQUIS® and these levels remained the same during the 2-hour infusion. Four hours after the end of the infusion, the relative decrease in the anti-Factor Xa activity from baseline, among patients receiving XARELTO® was 39% and 30% among those receiving ELIQUIS®. Twelve hours after the AndexXa® infusion, hemostatic efficacy was adjudicated as excellent or good by the independent committee, in 79% of the patients and was consistent across all subgroups. During the 30-day follow up period, thrombotic events occurred in 18% of the patients.

The authors concluded that AndexXa® rapidly reversed anti-Factor Xa activity without significant toxicity, in 79% of the patients, 12 hours after an infusion of AndexXa®. This study also demonstrated that prolonged reversal of Factor Xa inhibition may not be necessary to achieve a good hemostatic response with AndexXa®. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. Connolly SJ, Milling TJ, Eikelboom JW, et al. N Engl J Med 2016; 375:1131-1141

Clinically Localized Prostate Cancer – Treatment or Active Monitoring

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease. The widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on Prostate Specific Antigen (PSA) levels remains controversial and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer. Previously published trials evaluated the effectiveness of treatment, but they did not compare Surgery, Radiotherapy and Active Monitoring.

Prostate Testing for Cancer and Treatment (ProtecT) study is a prospective, randomized trial, which compared Active Monitoring, Radical Prostatectomy, and External Beam Radiotherapy, for the treatment of PSA-detected clinically localized prostate cancer. A total of 1,643 patients were randomly assigned to Radical Prostatectomy (N=553), Radiotherapy (N=545) or Active Monitoring (N=545). Patients in the Active Monitoring group were evaluated every 3 months for the first year, then every 6-12 months thereafter and radical treatment with curative intent was offered, based on changes in PSA levels. This is different from “watchful waiting”, which has no planned curative radical treatment on disease progression. The median age in this study was 62 yrs, the median PSA level was 4.6 ng/ml, 77% had tumors with a Gleason score of 6 and 76% had Stage T1c disease. The primary end point was prostate cancer mortality at a median of 10 years of follow-up, with prostate cancer-related deaths defined as deaths that were definitely or probably due to prostate cancer or its treatment. Secondary end points included all-cause mortality and the rates of metastases, clinical progression, primary treatment failure, and treatment complications.

At a median follow up of 10 years, prostate cancer-specific mortality was low at approximately 1% irrespective of treatment and all-cause mortality was also low at approximately 10%. However, higher rates of disease progression were seen in the Active Monitoring group (22.9 events per 1000 person-years) compared to the Surgery group (8.9 events per 1000 person-years) or the Radiotherapy group (9.0 events per 1000 person-years). This meant that patients assigned to Active Monitoring were significantly more likely to have metastatic disease than those assigned to treatment (P<0.001 for the overall comparison).

The authors in a companion article (N Engl J Med. DOI: 10.1056/NEJMoa1606221) focused on the patient-reported outcomes after Monitoring, Surgery and Radiotherapy over 6 years of follow up. Prostatectomy had the greatest negative effect on urinary continence and sexual function, whereas Radiotherapy plus neoadjuvant androgen-deprivation therapy had more of a negative effect on bowel function, urinary voiding and nocturia, although patients recovered some function over time. Approximately 44% of the patient’s who were assigned to Active Monitoring, did not receive radical curative treatment and were able to avoid these toxicities.

It was concluded that at a median follow up of 10 yrs, prostate cancer-specific mortality was low, irrespective of the treatment given, with similar efficacy outcomes but with a variable impact on quality of life. However, it should be noted that patients assigned to Active Monitoring were significantly more likely to have metastatic disease than those assigned to treatment. This in turn would warrant salvage treatment, which could result in toxicities as well. Further follow up, evaluating long term survival and the accompanying risk/benefits, will allow patients to make informed decisions, with regards to the treatment options, for clinically localized prostate cancer. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. Hamdy FC, Donovan JL, Lane JA, et al. for the ProtecT Study Group. September 14, 2016DOI: 10.1056/NEJMoa1606220

Proton Beam Therapy May Improve Survival Compared to Conventional Radiation in Stage II and III NSCLC Patients

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SUMMARY: Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2016 about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Even though Photon-based external beam radiation plus concurrent chemotherapy is the current standard of care for patients with unresectable stage III NSCLC, Proton beam therapy is emerging as an alternative to conventional Photon beam therapy for many cancer types. Radiation Therapy involves the use of X-Rays, Gamma rays and charged particles for cancer treatment. External beam radiation therapy is most often delivered using a linear accelerator in the form of Photon beams (either X-rays or Gamma rays). Photons have no mass and are packets of energy of an electromagnetic wave. Electrons and Protons are charged particles and Electrons are considered light particles whereas Protons are considered heavy particles. Electron beams are used to irradiate skin and superficial tumors, as they are unable to penetrate deep into the tissues. The different types of external beam radiation treatments include 3-Dimensional Conformal Radiation Therapy (3D-CRT) meant to deliver radiation to very precisely shaped target areas, IMRT or Intensity Modulated Radiation Therapy which allows different areas of a tumor or nearby tissues to receive different doses of radiation, Image Guided Radiation Therapy (IGRT) which allows reduction in the planned volume of tissue to be treated as changes in a tumor size are noted during treatment, Stereotactic RadioSurgery (SRS) which can deliver one or more high doses of radiation to a small tumor, Stereotactic Body Radiation Therapy (SBRT) or CYBERKNIFE® which is similar to SRS but also takes the normal motion of the body into account while treating malignancies involving the lung and liver and Proton beam therapy. Proton beams unlike Photons, enter the skin and travel through the tissues and deposit much of their energy at the end of their path (known as the Bragg peak) and deposit less energy along the way. This is unlike Photons which deposit energy all along the path through the tissues and the deposited dose decreases with increasing depth. As a result, with Proton beam therapy, normal tissues are exposed to less radiation compared with Photons. Despite this advantage, tissue heterogeneity such as organ motion, tumor volume changes during treatment can have a significant negative impact on target coverage for Proton beam therapy and can result in damage to the surrounding tissues and potential complications.

It has remained unclear whether Proton beam therapy improves Overall Survival (OS) in patients with NSCLC. To address this question, the authors conducted a retrospective analysis using the National Cancer Data Base (NCDB) and analyzed outcomes and predictors associated with Proton beam therapy for NSCLC. This analysis included 140,383 patients with stage I to stage IV NSCLC, treated with thoracic radiation from 2004-2012, of whom 59% had stage II and III disease. Of these patients, 140,035 were treated with Photon beam therapy and 348 with Proton beam therapy. The median age was 68 yrs, 57% were males, 85% were Caucasian, 27% were treated at academic centers and 78% in metropolitan areas. To reduce treatment selection bias, propensity score matching method was implemented.

It was noted that patients were less likely to receive Proton beam therapy in community or comprehensive community centers compared to academic centers (P< 0.001). Further, patients who received Proton beam therapy were more likely to have a higher education and income. On multivariate analysis, it was noted that the risk for death was greater with use of Photon beam therapy compared to Proton beam therapy (HR=1.46; P<0.001). Among patients with stage II and III disease, 5 year OS was superior with Proton beam therapy compared with Photon beam therapy (22.3% versus 15%; P=0.01). Patients with stage II and III disease who received Photon beam therapy had worse OS both in multivariate (HR=1.19; P=0.06) and univariate (HR=1.23; P=0.02) analyses, compared with Proton beam therapy. Proton beam therapy was associated with better 5 year OS compared to Photon beam therapy (23% vs. 14%; P=0.02), on propensity matched analysis. The median OS was 11 months with Photon therapy compared to 19 months with Proton therapy.

The authors concluded that in this retrospective database analysis, thoracic radiation with Proton beam therapy was associated with better survival rates for patients with stage II and III NSCLC. An ongoing randomized phase III trial (NRG Oncology 1308) involving stage III NSCLC patients is evaluating if chemotherapy and Proton beam therapy is superior to chemotherapy and Photon beam therapy. National Cancer Data Base analysis of proton versus photon radiotherapy in non-small cell lung cancer (NSCLC). Behera M, OConnell KA, Liu Y, et al. J Clin Oncol 34, 2016 (suppl; abstr 8501)

STIVARGA® Improves Overall Survival in Advanced Hepatocellular Carcinoma

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SUMMARY: The American Cancer Society estimates that about 39,230 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the US for 2016 and 27,170 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. NEXAVAR® (Sorafenib) was approved by the FDA in 2007 for the treatment of unresectable HepatoCellular Carcinoma (HCC). There are however no proven or approved second line treatment options for patients with advanced HCC. STIVARGA® (Regorafenib) is a small molecule, multikinase inhibitor, that blocks a variety of kinases known to promote angiogenesis (VEGF Receptor Tyrosine Kinases), oncogenesis (c-kit, BRAF, BRAF-V600E) and the tumor microenvironment (PDGFR, FGFR). STIVARGA® demonstrated significant activity as second line treatment in a phase II study, in patients with intermediate or advanced HCC, who had disease progression on NEXAVAR®.

RESORCE (REgorafenib after SORafenib in hepatocellular Carcinoma) is a double-blind, placebo-controlled, multicenter, phase III trial in which 573 patients were randomized in a 2:1 ratio to receive either STIVARGA® (N=379) or placebo (N=194). Enrolled HCC patients had Barcelona Clinic Liver Cancer (BCLC) stage B or C, Child-Pugh A liver function and had received NEXAVAR® for 20 days or more at 400 mg/day or more and had documented radiological progression on NEXAVAR®. Patients received either STIVARGA® 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. All patients received Best Supportive Care and treatment was continued until disease progression, death, or unacceptable toxicity. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS), Time to Progression (TTP), Response Rate (RR), and Disease Control Rate (DCR).

After a median of 3.6 months of treatment, the OS was 10.6 months for the STIVARGA® group versus 7.8 months for the placebo group (HR=0.62; P<0.001). The median PFS with STIVARGA® versus placebo was 3.1 months vs 1.5 months (HR=0.46; P<0.001) respectively. These findings meant a 38% reduction in the risk of death and a 54% reduction in the risk of progression or death, compared to placebo. When compared with placebo, median TTP with STIVARGA® was 3.2 vs 1.5 months (HR 0.44; P<0.001), DCR defined as complete and partial responses plus stable disease was 65.2% vs 36.1% (P<0.001) and overall RR (Complete and Partial responses) were 10.6% vs 4.1% (P=0.005), respectively. Grade 3 or higher adverse events occurred more frequently with STIVARGA® when compared with placebo and included hypertension, hand-foot syndrome, fatigue and diarrhea.

The authors concluded that STIVARGA® significantly improved OS in patients with HCC who progressed during treatment with NEXAVAR®, pointing out that we have an effective second-line agent for a very difficult-to-treat cancer. Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: Results of the international, randomized phase 3 RESORCE trial. Bruix J, Merle P, Granito A, et al. Ann Oncol (2016) 27 (suppl 2): ii140-ii141 doi:10.1093/annonc/mdw237.03

Long Term Survival in Advanced Renal Cell Carcinoma with OPDIVO®

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SUMMARY: The American Cancer Society estimates that about 62,700 new cases of kidney cancer will be diagnosed in the United States in 2016 and over 14,000 patients will die from this disease. The understanding of the Immune checkpoints has lead to the development of novel immunotherapies. Immune checkpoints or gate keepers are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as PD-1(Programmed cell Death-1), etc. Following inhibition of PD-1 by specific antibodies, T cells are unleashed, resulting in T cell proliferation and activation with subsequent therapeutic responses. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells.

OPDIVO® was approved by the FDA in November 2015, for the treatment of advanced Renal Cell Carcinoma in patients who have received prior anti-angiogenic therapy. This approval was based on a randomized, open-label, phase III study (CheckMate 025), in which previously treated patients with advanced clear cell RCC, were randomly assigned to receive either OPDIVO® or AFINITOR® (N Engl J Med 2015; 373:1803-1813). It was noted that the median Overall Survival (OS) in the OPDIVO® group was 25 months and 19.6 months in the AFINITOR® group, and this meant a 27% reduction in the risk of death with OPDIVO® (HR=0.73; P=0.002). This survival benefit was seen with a minimum follow up of 14 months.

The authors in this publication reported the long term OS results from phase I and II OPDIVO® studies, leading to CheckMate 025 phase III study. In the phase I open-label study, 34 patients with advanced Renal Cell Carcinoma, with ECOG Performance Status of 2 or less and who had prior systemic treatment with 1-5 regimens, received OPDIVO® at a dose of 1 or 10 mg/kg every 2 weeks (J Clin Oncol 2015;33:2013-2020). At a minimum follow up of 50.5 months, the Objective Response Rate (ORR) was 29% and the median Duration of Response was 12.9 months. The 3 and 5 year OS rates were 41% and 34% respectively. In the phase II study, 167 patients with advanced Renal Cell Carcinoma with KPS of 70% or more and who had prior treatment with 1-3 regimens in the metastatic setting, received OPDIVO® at a dose of 0.3, 2, or 10 mg/kg every 3 weeks (J Clin Oncol 2015;33:1430–37). At a minimum follow up of 38 months, ORR was 21% and the median Duration of Response was 22 months. The 3 year OS rate was 35% and 4 year OS rate was 29%. Long-term survival was observed in MSKCC good, intermediate and poor-risk patients, as well as in patients with excellent or reduced Karnofsky Performance Status.

The authors concluded that with this longest follow up data reported to date with any anti-PD-1/PD-L1 agent in advanced Renal Cell Carcinoma, about 33% of patients treated with OPDIVO® are alive at 5 years in the phase I study and at 3 years in the phase II study. Potential predictors of long term survival with OPDIVO® are being explored, in this previously treated patient population. Long-term overall survival (OS) with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies. McDermott DF, Motzer RJ, Atkins MB, et al. J Clin Oncol 34, 2016 (suppl; abstr 4507)

New NCCN Guidelines for the Diagnosis and Treatment of Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, about 30,330 new cases will be diagnosed in 2016 and 12,650 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. With a record number of regulatory approvals for Myeloma treatment over the past 12 years, the median survival for patients with Myeloma is over 10 years. The recent new drugs approved for the treatment of relapsed/refractory Multiple Myeloma include a Histone Decetylase inhibitor (FARYDAK®) and 2 monoclonal antibodies, Daratumumab (DARZALEX®) and Elotuzumab (EMPLICITI®). The two most important determinants of Myeloma patient outcomes include, Performance Status and tumor genomics. Performance Status can be assessed using currently validated instruments and patients can be defined as Fit, Intermediate Fit, or Frail. Patients with chromosomal abnormalities t(4;14), t(14;16), t(14;20) or del 17p are considered to fall in the high risk group.

The updated Multiple Myeloma guidelines were presented at the National Comprehensive Cancer Network (NCCN) 21st Annual Conference on April 1, 2016. These guidelines include the use of the Revised International Staging System for Multiple Myeloma, treatment of asymptomatic patients even if they do not fit the CRAB criteria (Calcium elevation, Renal insufficiency, Anemia, or Bone abnormalities) and incorporation of a triplet instead of doublet for newly diagnosed Fit Myeloma patients, regardless of transplant eligibility.

Revised International Staging System for Multiple Myeloma

The revised ISS (R-ISS) combines the International Staging System (ISS) with chromosomal abnormalities detected by interphase Fluorescent In Situ Hybridization after CD138 plasma cell purification and serum Lactate DeHydrogenase (LDH).

R-ISS I: ISS stage I (serum β2-microglobulin level less than 3.5 mg/L and serum albumin level 3.5 g/dL or more), absence of high risk cytogenetics and normal LDH level (less than the upper limit of normal range)

R-ISS III: ISS stage III (serum β2-microglobulin level more than 5.5 mg/L) and high-risk cytogenetics or high LDH level

R-ISS II: Includes all the other possible combinations

New Definition of Active MM in Asymptomatic Patients Qualifying for Treatment

• Bone marrow plasmacytosis 60% or more

• Abnormal free light chain ratio 100 or more (involved kappa) or less than 0.01 (involved lambda)

• Focal bone marrow lesions detected by functional imaging such as a PET scan or a MRI

New Treatment Options

For newly diagnosed patients, who are transplant candidates or Fit non-transplant candidates, Lenalidomide/Bortezomib/Dexamethasone should be incorporated as the preferred regimen based on a phase III randomized trial showing superiority of this triplet therapy over a doublet. This triplet improved Complete Response (CR) rates (including molecular CR), Progression Free Survival (PFS), and Overall Survival (OS) compared with Lenalidomide/Dexamethasone doublet. (Blood. 2015;126:25). Another all oral triplet included in the guidelines is a combination of Lenalidomide, Ixazomib and Dexamethasone. Ixazomib (NINLARO®) is an oral proteasome inhibitor and has a half-life of 3 to 4 days and requires only once weekly administration. The combination of Carfilzomib/Lenalidomide, and Dexamethasone was included in the new guidelines as a category 2A front-line treatment, based on a phase 1/2 study (Blood. 2012;120:1801-1809). Maintenance therapy is now considered standard of care regardless of transplantation and for newly diagnosed non-transplant candidates, a new standard of care is continuous Lenalidomide/Dexamethasone, which was found to improve PFS significantly, with a favorable safety profile (N Engl J Med. 2014;371:906-917). Three drug maintenance therapy may benefit high risk patients and should be considered.

In conclusion, these latest updates reflect the rapid advances in the diagnosis and treatment of Multiple Myeloma. National Comprehensive Cancer Network (NCCN) 21st Annual Conference. Presented April 1, 2016, Hollywood, FL.

Anthracycline Regimen Superior in High Risk Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. The superiority of Anthracycline based chemotherapy regimens for the treatment of breast cancer was demonstrated in the mid 1980’s. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) overview analysis published in the Lancet in 1998 concluded that there was a 12% proportional reduction in the risk of recurrence and 11% proportional reduction in mortality with Anthracycline containing regimens versus non-Anthracycline containing chemotherapy regimens. There is however a small risk of cardiotoxicity even with cumulative doses of Doxorubicin of less than 550 mg/m2. Jones and colleagues in 2009 published the results of US Oncology Research Trial 9735 which compared TC with AC and concluded that TC is superior to AC chemotherapy regimen and would be a reasonable option for both younger and older patients requiring chemotherapy, who are hormone receptor positive or negative with either node negative disease or have 1-3 positive lymph nodes.

The ABC (Anthracyclines in early Breast Cancer) adjuvant phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49) done in sequence, were developed by USOR and NSABP to determine if a regimen of TC for 6 cycles was non-inferior to combination regimens of Doxorubicin/Cyclophosphamide with Docetaxel or Paclitaxel (TaxAC), in patients with resected, high risk, HER2-negative breast cancer. The final analysis set from these collective trials known as ABC included 4130 patients, of whom 2078 patients were randomized to TC and 2052 patients to TaxAC. The treatment groups were well balanced. Sixty nine percent (69%) were hormone receptor positive, 41% were node negative and 51% had high grade tumors. The Primary Endpoint was invasive Disease Free Survival (iDFS) and the median follow up was 3.2 years.

At the time of pre-planned analysis with 399 invasive Disease Free Survival events, the 4 year DFS was significantly higher with TaxAC (90.7%) compared to 88.2% with TC (P=0.04). TaxAC provided little or no added benefit in hormone receptor positive and node negative patients. There was some benefit for patients with hormone receptor positive disease with 1-3 positive lymph nodes and those with hormone receptor negative disease with negative nodes. The most benefit was seen with TaxAC in patients with hormone receptor positive disease with 4 or more positive lymph nodes and in those with hormone receptor negative disease with positive nodes. The 4 year Overall Survival was comparable in both treatment groups although longer follow up is needed.

It can be concluded based on these findings that in early stage breast cancer, Anthracycline containing regimens are superior to non-Anthracycline regimens in patients with triple negative breast cancer and for those hormone receptor positive patients with 4 or more positive lymph nodes. There may be some benefit in select group of hormone receptor positive patients with 1-3 positive lymph nodes and in some patients with node negative, hormone receptor negative disease. Non-Anthracycline regimen such as TC is appropriate in node negative, hormone receptor positive patients. Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide (TC) v anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer. Blum JL, Flynn PJ, Yothers G, et al. J Clin Oncol 34, 2016 (suppl; abstr 1000)

Long Term Data Confirms Durable Efficacy and Safety of JAKAFI® in Myelofibrosis

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SUMMARY: MyeloFibrosis (MF) is a MyeloProliferative Neoplasm (MPN) characterized by a ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET). The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.

JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor and exerts its mechanism of action by targeting and inhibiting the dysregulated JAK2-STAT signaling pathway. The FDA approval of JAKAFI® for the treatment of Intermediate and high risk Myelofibrosis was based on two phase III trials – COMFORT (Controlled Myelofibrosis Study with Oral JAK1/JAK2 Inhibitor Treatment)-I and COMFORT-II studies. JAKAFI® in patients with Myelofibrosis, demonstrated rapid and durable improvements in splenomegaly and symptoms as well as improved survival in both phase III COMFORT studies. The authors now reported the final long term efficacy and safety results after 5 years of treatment with JAKAFI® in the COMFORT-I study. In COMFORT-I study, 309 intermediate or high risk patients were randomized to receive either JAKAFI® (N=155) or Placebo (N=154). The Primary end point was a 35% or more reduction in spleen size at 24 weeks. The preplanned 5- year analysis occurred when all patients reached the 5-year visit or discontinued treatment. Patients in the placebo group could crossover to the JAKAFI® group after the primary analysis (when all patients completed week 24) or at any time if they had pre-specified worsening of splenomegaly. Of the 154 patients randomized to placebo, 111 patients crossed over to the JAKAFI® group and the median time to crossover was 41 weeks.

It was noted that at week 24, patients in the JAKAFI® arm had a mean Spleen Volume reduction of 32% from baseline and this response was durable for patients who continued treatment, with a mean Spleen Volume reduction of 38% at week 264 (5 years). At 5 years, 18.5% of patients on JAKAFI® had a 35% or more, reduction in Spleen Volume from baseline. Median duration of this spleen response (35% or more reduction in Spleen Volume) in the JAKAFI® group was 168 weeks. Overall Survival was significantly better for patients originally randomized to JAKAFI® compared to placebo (HR=0.69; P=0.025). The mean hemoglobin and platelet count remained stable through 5 years, after week 24. Adverse events included anemia, thrombocytopenia, Herpes Zoster and Basal Cell Carcinomas

The authors concluded that after a median follow up of over 5 years, patients with Myelofibrosis randomized to receive JAKAFI® in the COMFORT-I study, had a superior Overall Survival compared to placebo, as well as durable spleen response, while on long term therapy with JAKAFI®. Long-Term Outcomes of Ruxolitinib(RUX) Therapy in Patients(PTS) with Myelofibrosis(MF): 5-Year Final Efficacy and Safety Analysis from COMFORT-I. Verstovsek S, Mesa RA, Gotlib JR, et al. Presented at 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark. Abstract:S452

GAZYVA® in Combination with TREANDA® for RITUXAN® Refractory Indolent Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2016, about 72,580 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,150 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT) lymphoma, Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL are not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life (QoL), has been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach, whereas those with B symptoms (fever, night sweats, and weight loss), painful lymphadenopathy/splenomegaly, organ compromise and cytopenias are generally considered candidates for therapy.

GAZYVA® (Obinutuzumab) 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. By virtue of binding affinity of the glycoengineered Fc portion of GAZYVA® to Fcγ receptor III on innate immune effector cells such as natural killer cells, macrophages and neutrophils, Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular phagocytosis is significantly enhanced, whereas it induces very little Complement-Dependent Cytotoxicity. This is in contrast to RITUXAN® (Rituximab), which is a first generation type I, chimeric anti-CD20 targeted monoclonal antibody that kills lymphoma cells primarily by Complement-Dependent Cytotoxicity and also ADCC.

GADOLIN is a pivotal multicenter, open-label, phase III study in which TREANDA® (Bendamustine) alone was compared with TREANDA® plus GAZYVA® followed by GAZYVA® maintenance, in patients with indolent NHL (iNHL), refractory to RITUXAN®. Patients with RITUXAN® refractory iNHL (N=396) were randomly assigned to receive either TREANDA® 120 mg/m2 IV on days 1 and 2 every 28 days for a total of 6 cycles (N=202) or TREANDA® 90 mg/m2 IV on days 1 and 2 every 28 days for 6 cycles and GAZYVA® 1000mg IV days 1, 8 and 15 every 28 days of cycle 1 and on day 1 of cycles 2-6 (N=194). In patients with non-progressive disease in the combination arm, GAZYVA® was continued (maintenance) every 2 months for up to 2 years. Both treatment groups were well balanced and the median age was 63 years, with a median of two prior lines of therapy. More than 90% of patients in each treatment group were refractory to their previous therapy and between 76% and 81% were double-refractory to both RITUXAN® and an alkylating agent. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival and Response Rate.

The study was unblinded at the time of planned interim analysis and had to be halted early, upon recommendations from the Independent Data Monitoring Committee, as the primary end point was reached. After a median follow up of 21 months, the Progression Free Survival with GAZYVA® and TREANDA® combination was superior (median not reached) compared to a PFS of 14.9 months with TREANDA® monotherapy (HR=0.55; P<0.0001). This meant a 45% reduction in the rate of disease progression. There was however no difference in the Response Rates between the treatment groups and the best Overall Response Rate up to 12 months from start of treatment, was 77% in the TREANDA® alone group and 79% in the TREANDA® plus GAZYVA® group. Median Overall Survival has not yet been reached in either arm and longer follow up is needed. The combination experimental group experienced more grade 3 adverse events such as infusion related reactions and neutropenia whereas the TREANDA® alone group experienced more thrombocytopenia and anemia.

The authors concluded that GAZYVA® in combination with TREANDA® is superior to TREANDA® alone, in patients with RITUXAN® refractory indolent Non Hodgkin Lymphoma, with a significant improvement in Progression Free survival. The lack of difference in the Response Rate between the two treatment groups begs the question if the improvement in PFS benefit in the combination treatment group was derived from the quality of remission related to improved minimal residual disease negativity versus continuous maintenance treatment with GAZYVA® or both. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Sehn LH, Chua N, Mayer J, et al. Lancet Oncol 2016;17:1081-1093

FDA Approves SUSTOL® for the Prevention of Chemotherapy-Induced Nausea and Vomiting

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SUMMARY: The FDA on August 10, 2016 approved SUSTOL® (Granisetron) extended- release injection, for use in combination with other antiemetics in adults, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of Moderately Emetogenic Chemotherapy (MEC) or Anthracycline and Cyclophosphamide (AC) combination chemotherapy regimen. Chemotherapy Induced Nausea and Vomiting (CINV) is one of the most common adverse effects of chemotherapy and is experienced by about 80% of patients receiving chemotherapy. Acute CINV begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment, whereas delayed nausea and vomiting occurs more than 24 hours after chemotherapy administration and can persist for several days. Delayed CINV is often underestimated and a third of the patients receiving chemotherapy may experience delayed nausea and vomiting without prior acute nausea or vomiting. Acute nausea and vomiting is dependent on Serotonin (5-hydroxytryptamine-5HT3) and its receptors, with the chemotherapeutic agents stimulating the release of Serotonin from the enterochromaffin cells of the small intestine. 5-HT3 receptors are located on vagal afferent pathway, which in turn activates the vomiting center to initiate the vomiting reflex. 5-HT3 receptors are also located centrally in the Chemoreceptor Trigger Zone of the area Postrema. Delayed nausea and vomiting is associated with the activation of Neurokinin 1 (NK1) receptors by substance P. NK1 receptors are broadly distributed in the central and peripheral nervous systems.

Granisetron is a first-generation serotonin-3 (5-HT3) receptor antagonist commonly used to treat CINV, but has a short half-life of approximately 8 hours. SUSTOL® is a novel formulation of 2 % Granisetron and a bioerodible tri(ethylene glycol) polymer, designed to provide slow, controlled hydrolysis, resulting in slow and sustained release of Granisetron, thereby preventing both acute and delayed CINV associated with MEC and Highly Emetogenic Chemotherapy (HEC). With a plasma half-life of 24-34 hours, this novel preparation formulation can maintain therapeutic levels of Granisetron for 5 or more days.

The FDA approval of SUSTOL® was based on the efficacy data from a multicenter double-blind trial which included 733 patients who received MEC or AC combination chemotherapy. Patients were randomized to receive either SUSTOL® 10 mg Subcutaneous injection (N=371) or ALOXI® 0.25 mg IV (N=362). This study was structured to compared SUSTOL® with ALOXI® (Palonosetron), which is also a serotonin-3 (5-HT3) receptor antagonist because, ALOXI® is not approved by the FDA to prevent delayed-onset CINV in patients who receive HEC. The trial was designed to allow for the evaluation of non-inferiority of SUSTOL® to ALOXI® in the acute and delayed phases. Antiemetics were administered 30 minutes before chemotherapy on Day 1. Dexamethasone was also administered IV at 8 or 20 mg on Day 1, depending on the chemotherapy regimen administered and those who received Dexamethasone 20 mg IV, were also given an 8 mg oral dose of the drug twice daily on Days 2, 3, and 4. The mean age was 57 years and 79% the patients were female. Approximately 55% of the patients received MEC regimen and 45% of the patients received AC combination chemotherapy. The most frequently used MEC regimen was Carboplatin and Paclitaxel combination (31%). The primary endpoint of the study was Complete Response (CR), which was defined as no emetic episodes or rescue medication during the acute phase (0-24 hours) and the delayed phase (more than 24 to 120 hours) after chemotherapy administration in cycle 1.

The results demonstrated that SUSTOL® was noninferior to ALOXI® . It was noted that among patients receiving MEC (N=406) the CR rate in the acute phase was 83% in the SUSTOL® group compared with 89% in the ALOXI® group. The CR rates in the delayed phase were 69% and 70% respectively. For those patients who received AC chemotherapy (N=327), the CR rate in the acute phase for the SUSTOL® group was 70% compared with 64% in the ALOXI® group. The CR rates in the delayed phase were 50% and 47% respectively. The safety of the FDA recommended dose of SUSTOL® (10 mg Subcutaneous dose), was evaluated in 924 patients across two double-blind, randomized active-controlled studies and it was noted that SUSTOL® was associated with a higher incidence of injection site reactions and constipation.

The authors concluded that SUSTOL® by virtue of its Biochronomer polymer-based drug delivery technology, represents a novel and convenient alternative to intravenous ALOXI® for the prevention of acute and delayed Chemotherapy Induced Nausea and Vomiting. Randomized phase III trial of APF530 versus palonosetron in the prevention of chemotherapy-induced nausea and vomiting in a subset of patients with breast cancer receiving moderately or highly emetogenic chemotherapy. Boccia R, O’Boyle E, Cooper W. BMC Cancer. 2016;16:166. doi:10.1186/s12885-016-2186-4.