Month: February 2016

FDA Approves VISTOGARD®, an Antidote for 5-FU Overexposure

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SUMMARY: The United States FDA approved VISTOGARD® (Uridine Triacetate) for the emergency treatment of adult and pediatric patients, who had severe or life-threatening toxicities within 4 days of treatment, following an overdose of 5-FluoroUracil (5-FU) or XELODA® (Capecitabine). VISTOGARD® is a Pyrimidine analog and following oral administration is deacetylated by nonspecific esterases, yielding Uridine in the circulation. Uridine is a direct antagonist of 5-FU and competitively inhibits 5-FU from incorporating in normal tissues, thus reducing cell damage and cell death.

The approval of VISTOGARD® was based on two separate trials in which 135 adult and pediatric cancer patients at increased risk for toxicity with 5-FU or XELODA® were included. Risk for toxicity could be due to 5-FU overdose and accidental XELODA® ingestion (N=111) or DihydroPyrimidine Dehydrogenase (DPD) deficiency and/or patients who experienced rapid onset of severe toxicities (N=24). These patients received VISTOGARD® granules 10 grams every 6 hours for 20 doses, starting within 96 hours after the termination of 5-FU therapy. The primary endpoint of the studies was survival at 30 days or until chemotherapy could resume, if prior to 30 days.

Of those who were treated with VISTOGARD® for overdose, 97 percent were still alive at 30 days. Of those treated with VISTOGARD® for early-onset severe or life-threatening toxicity, 89 percent were alive at 30 days. In both studies, 33 percent of patients resumed chemotherapy in less than 30 days. Adverse events were mild and uncommon and included nausea, vomiting and diarrhea.

The authors concluded that VISTOGARD® is a safe and effective antidote for 5-FU overexposure, and can facilitate rapid recovery and resumption of chemotherapy. Patients should take VISTOGARD® as soon as possible after overdose, regardless of symptoms or within 4 days of severe or life threatening toxicity. It should be noted that VISTOGARD® is not recommended for treatment of non-emergency adverse events associated with 5-FU and XELODA®, as this therapy may significantly decrease the efficacy of these chemotherapy agents. Clinical trial experience with uridine triacetate for 5-fluorouracil toxicity. Ma WW, Saif WM, El-Rayes BF, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 655)

Lobectomy Superior to Sublobar Resection in Early Stage Non Small Cell Lung Cancer

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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. Lobectomy is the treatment of choice for resectable Non Small Cell Lung Cancer (NSCLC). Pneumonectomy is rarely performed due to unacceptably high mortality rate. Sublobar resection (Wedge resection or Segmentectomy) is considered a “compromise operation” in selected high risk patients with early stage lung cancer. With the approval of lung cancer screening in high risk individuals and subsequent detection of small tumors, Sublobar resections have been on the rise, even in good-risk patients, in many institutions. Sublobar resection includes Wedge resection and Segmentectomy. In Wedge resection, the lung tumor is removed with a surrounding margin of normal lung tissue, and is not an anatomical resection. Segmentectomy, unlike Wedge resection, is an anatomical resection that usually includes one or more pulmonary parenchymal segments with the dissection of intraparenchymal and hilar lymph nodes. Wedge resection is inferior to anatomic Segmentectomy and is associated with an increased risk of local recurrence and decreased survival in patients with Stage I NSCLC.

The authors in this study analyzed the National Cancer Data Base (NCDB) and the primary goal of this study was to understand practice patterns in the surgical management of patients with clinical Stage IA NSCLC, as well as identify predictors of surgical management with Sublobar resection versus Lobectomy and also evaluate the extent of pathologic lymph node assessment, performed in association with Sublobar resections, in a community practice setting. A secondary goal was to compare long term survival between Sublobar resection versus Lobectomy.

In this large analysis, 39,403 patients from the National Cancer Data Base (NCDB) were included, of whom 75.5% (N=29,736) underwent Lobectomy and 24.5% (N=9667) had Sublobar resection (Wedge resection 84.7%; N = 8192 and Segmental resection 15.3%; N = 1475). Lymph node evaluation was not performed in 2788 (28.8%) of Sublobar resection patients, and 7298 (75.5%) of Sublobar resections were for tumors ≤ 2 cm.

It was noted that Lobectomy was associated with significantly improved 5-year survival compared to Sublobar resection (66.2% vs. 51.2%; adjusted HR=0.66; P <0 .001). Among patients who underwent Sublobar resection, lymph node sampling was associated with significantly better 5-year survival compared to patients who did not have lymph node sampling (58.2% vs. 46.4%; P < 0.001), although these outcomes were still inferior to Lobectomy.

The authors concluded that for patients with Stage 1A NSCLC, surgical Lobectomy significantly improved survival compared to Sublobar resection. Patients ineligible for Lobectomy and treated with Sublobar resection, should undergo lymph node samplings to help guide appropriate post operative therapy. Sublobar Resection for Clinical Stage IA Non–small-cell Lung Cancer in the United States. Speicher PJ, Gu L, Gulack BC, et al. Clinical Lung Cancer 2016;17:47-55

Cardiac Outcomes of Patients Receiving Adjuvant Weekly TAXOL® and HERCEPTIN®

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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 life time. Approximately, 246,660 new cases of invasive breast cancer were diagnosed in 2016 and 40,450 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 20-25% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2. HERCEPTIN® binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). HERCEPTIN® in combination with chemotherapy has been proven to significantly improve Progression Free Survival and Overall Survival in patients with advanced breast cancer. Adjuvant chemotherapy in combination with HERCEPTIN® has been shown to reduce the relative risk of relapse by 52% and relative risk of death by 33%. The National Comprehensive Cancer Network (NCCN) has recommended adjuvant chemotherapy with HERCEPTIN® for patients with small, HER positive, node-negative tumors, including those with T1bN0 tumors, even though there are little or no data supporting this recommendation, because these patients are generally not included in adjuvant therapy studies. Further, the chemotherapy regimens often recommended (ACTH, TCH) along with HERCEPTIN® are relatively toxic.

In a previously published study, it was noted that a less toxic regimen such as HERCEPTIN®, given along with weekly TAXOL® (Paclitaxel), had significant efficacy in patients with node negative patients with tumors measuring up to 3 cm in greatest dimension, decreasing the risk of recurrence in this patient group, most notable during the first three years after diagnosis. (Tolaney SM, Barry WT, Dang CT, et al. N Engl J Med 2015;372:134-141). Risk risk factors associated with HERCEPTIN® induced cardiotoxicity include, age over 50 years, borderline LVEF (Left Ventricular Ejection Fraction) before HERCEPTIN® treatment, history of cardiovascular disease, cardiovascular risk factors such as diabetes, dislipidemia or elevated body mass index (>30), sequence in which chemotherapy is administered and prior treatment with Anthracyclines (cumulative doses more than 300 mg/m2). However, unlike Anthracycline induced cardiotoxicity, HERCEPTIN® induced cardiotoxicity is reversible and there are no ultrastructural changes noted in cardiomyocytes in HERCEPTIN® induced cardiotoxicity.

This publication is a secondary analysis of the above mentioned previously published study and the authors here reported the cardiac safety data of a HERCEPIN® based nonanthracycline treatment, (TAXOL® with HERCEPTIN®), for patients with early-stage, node negative, HER2 positive breast cancer and the utility of monitoring LVEF in this patient group. This clinical trial enrolled 406 patients with node-negative, HER2 positive breast cancer 3 cm, or smaller with a baseline LVEF of 50% or greater. Treatment consisted of TAXOL® 80 mg/m2 IV weekly administered concurrently with HERCEPTIN® IV for 12 weeks, followed by HERCEPTIN® monotherapy for 39 weeks. HERCEPTIN® could be administered 2 mg/kg weekly or 6 mg/kg every 3 weeks during the monotherapy phase. Radiation and hormone therapy were administered as planned, following completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. Median age was 55 years and 29% of the patients had hypertension, and 7% had diabetes. The median follow up was 4 years.

It was noted that a significant, asymptomatic LVEF decline was seen in 3.2% of the patients and 0.5% developed grade 3 Left Ventricular Systolic Dysfunction. The median LVEF at baseline was 65%, at 12 weeks was 64%, at 6 months was 64%; and at 1 year was 64%. The authors concluded that cardiotoxicity from a combination of TAXOL® and HERCEPTIN® is low and a baseline LVEF assessment may be adequate for the majority of patients although serial LVEF assessments could be considered for patients considered at a higher risk for cardiotoxicity. Cardiac Outcomes of Patients Receiving Adjuvant Weekly Paclitaxel and Trastuzumab for Node-Negative, ERBB2-Positive Breast Cancer. Dang C, Guo H, Najita J, et al. JAMA Oncol. 2016;2:29-36

Adjuvant GLEEVEC® Improves Overall Survival in High Risk GI Stromal Tumors

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SUMMARY: The American Cancer Society estimates that in the US, about 4000-5000 cases of Gastro Intestinal Stromal Tumors (GISTs) are diagnosed each year. GI Stromal Tumor (GIST) is one of the most common types of Soft Tissue Sarcoma and can develop anywhere along the GI tract, but are primarily found in the stomach. GISTs originate from the interstitial cells of Cajal or related stem cells and are associated with activating mutations in KIT or PDGFRA (Platelet-Derived Growth Factor Receptor-A). These two mutations are mutually exclusive and are important in the molecular pathogenesis of these tumors. Treatment of patients with advanced or metastatic GIST with Tyrosine Kinase Inhibitor GLEEVEC® (Imatinib) achieves high Objective Response and diseases stabilization rates. Patients with KIT exon 9 mutation have a poor prognosis compared to those with KIT exon 11 mutation and benefit from a higher dose of GLEEVEC® (800 mg daily). It should also be noted that patients with PDGFRA D842V mutation are GLEEVEC® resistant. Approximately two thirds of the patients with GISTs are cured with surgery but recurrences are frequent and this risk of relapse is dependent on the tumor size, mitotic rate and primary tumor site. The risk stratification of GISTs by Joensuu, unlike the NIH criteria, takes into account primary tumor site and tumor rupture as well, which can influence outcomes.

Adjuvant therapy with three years of GLEEVEC®, following curative surgery of high risk GISTs, is recommended and has been shown to improve Recurrence Free Survival (RFS). However, whether adjuvant GLEEVEC® improves overall survival has remained unclear. To address this further the authors in this publication performed a second planned analysis of the SSGXVIII/AIO trial after a longer follow up. In this open label study, 400 patients following surgery were randomly assigned to receive adjuvant GLEEVEC® for either 12 months (N=200) or for 36 months (N=200). Eligible patients had completely resected, KIT-positive GIST, with high risk features, per the modified National Institutes of Health criteria. The median age was 61 years and the primary objective was Recurrence Free Survival (RFS), and the secondary objectives included Overall Survival and Safety.

The second planned analysis was done 3 years after the first analysis of the trial and was intended to compare Overall Survival between the treatment groups, after additional follow up of these patients. The median follow up was 90 months. It was noted that the patients who were treated with 36 months of adjuvant GLEEVEC® had a longer RFS than those who were treated for 12 months (5-year RFS was 71.1% versus 52.3%, HR=0.60; P<0.001). The Overall Survival (OS) also favored the 36 month treatment group compared with the 12 month treatment group (5-year OS was 91.9% versus 85.3%, HR=0.60; P=0.036).

The authors concluded that 3 years of adjuvant GLEEVEC® therapy results in longer Overall Survival than 1 year of adjuvant GLEEVEC®, with a superior 5-year survival rate, in patients with high-risk GIST. Trials are underway evaluating the benefit of adjuvant GLEEVEC® for longer than 3 years. Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial. Joensuu H, Eriksson M, Hall KS, et al. J Clin Oncol 2016;34:244-250

Unique Toxicities of Immunotherapy for the Practicing Physician

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SUMMARY: Immunotherapy in cancer management includes Cancer Vaccines, Cytokine therapy, Adoptive Cell therapy and therapy with Check Point protein inhibitors such as YERVOY®, KEYTRUDA® and OPDIVO®. Toxicities related to these immunotherapeutic interventions are mediated by T cells resulting in exaggerated T cell response and potential damage to normal tissues. A brief summary of the more common adverse events associated with cancer immunotherapy, is listed below-

CANCER VACCINES

PROVENGE® (Sipuleucel-T) is an autologous, cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic Castrate Resistant (hormone-refractory) Prostate Cancer. This product is the only currently approved Cancer Vaccine and consists of autologous CD54+ cells activated with recombinant PAP/GM-CSF (Prostate Acid Phosphatase, an antigen expressed in the prostate cancer tissue, linked to immune cell activator, Granulocyte Macrophage-Colony Stimulating Factor). Vaccine therapies work by promoting type 1 or type 2 immune reactions. In type 1 immune reaction, T helper type 1 (Th1) lymphocytes secrete Interleukin-2 (IL-2), Interferon gamma, and lymphotoxin-alpha and facilitate intense phagocytic activity whereas in type 2 immunity, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and is characterized by high antibody titers. Cancer Vaccines are associated with minimal toxicities because the antigens associated with the tumor are overexpressed in the cancer cells and are not usually detectable in normal cells. Common side effects include local reactions, fever, chills, fatigue, rash, back pain and Melanoma vaccines are associated with vitiligo.

CYTOKINE THERAPY

Both INTRON® A (Interferon alfa-2b) and ROFERON® A (Interferon alfa-2a) are approved for a variety of malignant conditions as well as for Chronic Hepatitis B and C. In addition to fever, chills and flu like symptoms, two thirds of the patients have nausea and anorexia and up to 45% of the patients may experience symptoms of depression. Patients should be monitored for cytopenias, diarrhea, liver toxicities as well as thyroid dysfunction and autoimmune disorders may be exacerbated with Interferon.

PROLEUKIN® (High dose IL-2) is administered in an inpatient setting with cardiac monitoring, as patients often develop capillary leak syndrome and hypotension in addition to flu like symptoms and liver function abnormalities. This has been attributed to release of Nitric Oxide, IL-1, Tumor Necrosis Factor alpha, and IFN gamma. Patients may also develop autoimmune related thyroid dysfunction, cytopenias as well as neurotoxicity and will therefore require close monitoring.

ADOPTIVE CELL THERAPY

Unlike Cancer Vaccines, Adoptive T cell therapy is a type of passive immunization which involves the transfusion of autologous or allogeneic T cells into patients with malignancies. These tumor reactive T cells can be genetically engineered or grown ex vivo and their efficacy can be enhanced by other immunotherapies, such as Cancer Vaccines, Cytokine administration or in some instances cytotoxic chemotherapy and radiation therapy. BLINCYTO® (Blinatumomab) is a genetically engineered bispecific CD19 directed CD3 T-cell engager, approved by the FDA, that binds to CD19 (expressed on B-cells) and CD3 (expressed on T-cells). It is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor Acute Lymphoblastic Leukemia (ALL). Administration of BLINCYTO® or high dose IL-2 given along with T cells, can cause Cytokine Release Syndrome (CRS), associated with fever, tachycardia, vascular leak, oliguria, and hypotension. This has been attributed to IL-6 and ACTEMRA® (Tocilizumab), an IL-6 receptor antagonist may be of benefit for these patients along with IV fluids, nonsteroidal anti-inflammatory agents and vasopressors. Other toxicities that require monitoring include flu like symptoms, liver function abnormalities, B-cell aplasia, cytopenias and neurotoxicity.

THERAPY WITH CHECKPOINT INHIBITORS

The FDA approved checkpoint inhibitors include, YERVOY® (Ipilimumab) which targets CTLA-4, KEYTRUDA® (Pembrolizumab) and OPDIVO® (Nivolumab), which block checkpoint PD-1. The toxicities associated with YERVOY® are dose dependant. Some common side effects of check point inhibitors include skin rash, flu like symptoms, liver function abnormalities, diarrhea and colitis, cytopenias, thyroid and adrenal function abnormalities. Rare cases of pneumonitis, encephalitis, Guillain-Barré syndrome, and a myasthenia gravis–like syndrome have been reported. With close monitoring, early diagnosis and intervention with Corticosteroids, these toxicities can be alleviated. REMICADE® (Infliximab), a chimeric monoclonal antibody against Tumor Necrosis Factor alpha (TNF-alpha), should be offered to those whose colitis does not resolve within 3 days of high dose steroids or for relapse of colitis with steroid taper.

Toxicities of Immunotherapy for the Practitioner. Weber JS, Yang JC, Atkins MB, et al. J Clin Oncol 2015;33:2092-2099

Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer Improves Overall Survival

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SUMMARY: The American Cancer Society estimates that in the US, about 16,910 new esophageal cancer cases will be diagnosed in 2016 and about 15,690 patients will die of the disease. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in caucasians. Previously published trials comparing neoadjuvant concurrent chemoradiation plus surgery to surgery alone, with Cisplatin and 5-FU chemotherapy, have shown conflicting results and this may have been due to small numbers of patients enrolled in these trials. Based on positive outcomes in phase II studies, the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) was conducted, to compare neoadjuvant chemoradiotherapy plus surgery to surgery alone, in patients with Squamous Cell Carcinoma and Adenocarcinoma of the esophagus or esophagogastric junction. Enrolled patients (N=368) were randomly assigned in a 1:1 ratio and had locally advanced (clinical stage T1N1M0 or clinical stage T2-3N0-1M0) disease. Locoregional sites included mediastinum, supraclavicular and celiac trunk lymph nodes.

Treatment consisted of PARAPLATIN® (Carboplatin) at AUC-2, IV and TAXOL® (Paclitaxel) 50 mg/m2 IV, given weekly for 5 weeks, on days 1,8,15,22 and 29 with concurrent radiotherapy (41.4 Gy, given in 23 fractions of 1.8 Gy, 5 days per week) followed by surgery (N=180), or surgery alone (N=188). The median age was 60 years and patients in the surgery alone group underwent surgery as soon as possible, whereas those receiving neoadjuvant chemoradiation underwent surgery 4-6 weeks following completion of chemoradiation. The primary endpoint of this study was Overall Survival (OS) and secondary endpoints included Progression Free Survival (PFS).

After a median follow up of 84.1 months, the median Overall Survival (OS) for all histologies was 48.6 months in the neoadjuvant chemoradiation plus surgery group and 24 months in the surgery alone group (HR=0.68; P=0.003). The median OS for patients with Squamous Cell Carcinomas was 81.6 months in the neoadjuvant chemoradiation plus surgery group and 21.1 months in the surgery alone group (HR=0.48; P=0.008) and for patients with Adenocarcinomas was 43.2 months in the neoadjuvant chemoradiotherapy plus surgery group and 27.1 months in the surgery alone group (HR=0.73; P=0.038). It is of interest to note that the improvement in distant disease control occurred within the first 2 years following treatment initiation, whereas improvement in locoregional control continued for a longer period of time.

The authors concluded that in patients with resectable, locally advanced, esophageal or esophagogastric junctional cancer, neoadjuvant chemoradiotherapy when added to surgery, confers Overall Survival benefit for both Squamous Cell Carcinoma and Adenocarcinoma histological subtypes and should therefore be regarded as the standard of care, for this patient population. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Shapiro J, van Lanschot JB, Hulshof MM, et al. The Lancet Oncology 2015;16:1090-1098

VARUBI® Now Approved for Delayed Chemotherapy Induced Nausea and Vomiting

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SUMMARY: The U.S. Food and Drug Administration on September 2, 2015, approved VARUBI® (Rolapitant) to prevent delayed phase Chemotherapy Induced Nausea and Vomiting (CINV). 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. The development of effective antiemetic agents has facilitated the administration of majority of the chemotherapy agents in an outpatient setting avoiding hospitalization. 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. VARUBI® is a substance P/Neurokinin-1 (NK-1) receptor antagonist.

The safety and efficacy of VARUBI® were established in three randomized, double-blind, controlled clinical trials where VARUBI® in combination with KYTRIL® (Granisetron) and Dexamethasone was compared with placebo, KYTRIL® and Dexamethasone (control therapy), in more than 2500 patients receiving a moderately or highly emetic chemotherapy regimen. HEC Study 1 and HEC Study 2 included Cisplatin Based Highly Emetogenic Chemotherapy (HEC). Chemotherapy regimens included more than 60 mg/m2 of Cisplatin. In HEC Study 1, 532 patients were randomized to receive either antiemetic regimen with VARUBI® (N =266) or control therapy (N =266). In HEC Study 2, a total of 555 patients were randomized to receive either antiemetic regimen with VARUBI® (N =278) or control therapy (N =277). MEC Study 3 included Moderately Emetogenic Chemotherapy and combinations of Anthracycline and Cyclophosphamide chemotherapy. A total of 1369 patients were randomized in this study to receive either antiemetic regimen with VARUBI® (N =684) or control therapy (N =685). Patients in these trials received either VARUBI® 180 mg PO or placebo at 1 to 2 hours before administration of Highly Emetogenic Chemotherapy. All patients received intravenous KYTRIL® 10 μg/kg IV and Dexamethasone 20 mg PO on day 1 and Dexamethasone 8 mg PO twice daily on days 2 to 4 for up to six cycles, with each cycle lasting a minimum of 14 days. The primary endpoint in all three studies was complete response (defined as no emetic episodes and no rescue medication) in the delayed phase (25 to 120 hours) post chemotherapy.

It was noted that a significantly greater proportion of patients receiving antiemetic regimen with VARUBI® had complete responses in the delayed phase than did patients in the control therapy group – HEC Study 1: 72.7% vs 58.4% (P<0.001), HEC Study 2: 70.1% vs 61.9% (P=0.043) and MEC Study 3: 71.3% vs 61.6% (P<0.001). The most common adverse events in patients treated with VARUBI® included neutropenia, hiccups, decreased appetite and dizziness. It was concluded from these three trials that VARUBI® when combined with a 5-HT3 receptor antagonist such as KYTRIL® and a corticosteroid, significantly prevented delayed Chemotherapy Induced Nausea and Vomiting.

1) Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Rapoport BL, Chasen MR, Gridelli C, et al. The Lancet Oncology 2015;16:1079-1089

2) Phase 3 trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (MEC). Schnadig ID, Modiano MR, Poma A, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 9633)

FDA Approves HALAVEN® for Advanced Liposarcoma

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SUMMARY: The FDA on January 28, 2016, approved HALAVEN® (Eribulin) for the treatment of patients with unresectable or metastatic Liposarcoma, who have received a prior Anthracycline-containing regimen. The American Cancer Society's estimates that in the United States, approximately 11,930 new Soft Tissue Sarcomas were diagnosed in 2015 and 4,870 patients died of the disease. The most common types of sarcoma in adults are, Undifferentiated Pleomorphic Sarcoma ( Malignant Fibrous Histiocytoma), Liposarcoma, and Leiomyosarcoma. Leiomyosarcomas often present as abdominal sarcomas, whereas Liposarcomas and Undifferentiated Pleomorphic Sarcomas develop in the extremities. There are close to 50 different types of Soft Tissue Sarcomas. Liposarcomas are malignant tumors of the adipose tissue.

The approval of HALAVEN® was based on an open-label, randomized, multicenter, phase III trial in which 446 patients with unresectable, locally advanced or metastatic Liposarcoma or Leiomyosarcoma were randomly assigned in a 1:1 ratio to receive either HALAVEN® (N=225) or Dacarbazine (N=221). Eligible patients had received at least two prior systemic chemotherapies (one of which must have included an Anthracycline) and had disease progression within 6 months of randomization. Randomized patients received either HALAVEN® 1.4 mg/m2 on days 1 and 8 of a 21-day cycle or Dacarbazine 850 mg/m2, 1000 mg/m2, or 1200 mg/m2 chosen by the investigator prior to randomization, on day 1 of a 21-day treatment cycle. Treatment was continued until disease progression or unacceptable toxicity. Patients were stratified by histology (Liposarcoma vs. Leiomyosarcoma) and 68% (N=303) had Leiomyosarcoma and 32% (N=143) had Liposarcoma. Majority of the patients had received more than two prior systemic chemotherapies. The median age was 56 years. The primary endpoint of this study was Overall Survival and secondary endpoints included Progression Free Survival and Safety.

The trial met its primary endpoint with a statistically significant improvement in Overall Survival (OS) in the HALAVEN® group compared to the Dacarbazine group. The median OS was 13.5 months in the HALAVEN® arm and 11.3 months in the Dacarbazine arm (HR=0.75; P=0.011). There was no improvement noted in the Progression Free Survival (PFS) or Objective Response Rates in the overall study population. In the pre-planned, exploratory subgroup analyses of OS and PFS, the benefit with HALAVEN® treatment was limited to the subgroup of patients with Liposarcoma (N=143), with a median OS of 15.6 versus 8.4 months for the Dacarbazine group (HR=0.51). There was no treatment benefit with HALAVEN® compared to Dacarbazine treatment, for patients with Leiomyosarcoma (median OS of 12.8 vs 12.3 months; HR=0.90 and median PFS of 2.2 vs 2.6 months; HR=1.05).

The most common adverse reactions associated with HALAVEN® treatment were fever, fatigue, nausea, alopecia, constipation, peripheral neuropathy and neutropenia. Thrombocytopenia was more frequent in the Dacarbazine group than HALAVEN® group. It was concluded that HALAVEN® significantly improves Overall Survival in patients with advanced, pretreated Liposarcoma and is the first drug approved for this patient population. Schöffski P, Maki RG, Italiano A, et al. Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI). J Clin Oncol. 2015;(suppl; abstr LBA10502).