Tag: Non-Hodgkin Lymphoma

FDA Approves Subcutaneous RITUXAN® Formulation for CD20-Positive Hematologic Malignancies

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SUMMARY: The US FDA on June 22, 2017, granted regular approval to the combination of RITUXAN® (Rituximab) and Hyaluronidase human (RITUXAN HYCELA®) for adult patients with Follicular Lymphoma, Diffuse Large B-Cell Lymphoma, and Chronic Lymphocytic Leukemia. RITUXAN HYCELA® is a combination of RITUXAN® and Hyaluronidase human (ENHANZE® technology), for SubCutaneous (SC) injection in multiple hematological malignancies. ENHANZE® is a drug delivery technology platform which removes limitations on the volume of biologics and drugs that can be delivered SubCutaneously, thereby significantly reducing the time required for drug administration.

RITUXAN® is a first generation type I, chimeric, monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, RITUXAN® mediates B-cell lysis. Possible mechanisms of cell lysis include Complement Dependent Cytotoxicity (CDC) and Antibody Dependent Cell mediated Cytotoxicity (ADCC). Hyaluronan is a polysaccharide present in the extracellular matrix of the subcutaneous tissue and is depolymerized by the naturally occurring enzyme Hyaluronidase. Hyaluronidase human increases permeability of the subcutaneous tissue locally for a period of 24-48 hrs, by temporarily depolymerizing Hyaluronan.

The approval of RITUXAN HYCELA® was based on several randomized clinical trials that demonstrated Non-inferior pharmacokinetics of SubCutaneous RITUXAN HYCELA® compared with IV RITUXAN® as well as comparable efficacy and safety results. The following are the specific trials included in the clinical development program:

MabEase phase III trial is an open label study which evaluated SubCutaneous (N=381) versus IV (N=195) RITUXAN® formulation plus CHOP chemotherapy, in treatment naïve patients with CD20-positive Diffuse Large B-Cell Lymphoma. There was no significant difference noted in the Objective Response Rate, Complete Response rates, Progression Free Survival and Overall Survival, between the two treatment groups.

SABRINA is a randomized phase III study that enrolled a total of 410 patients with previously untreated, CD20-positive Follicular Lymphoma and patients were randomized (1:1) to receive either a SC or IV RITUXAN® formulation in combination with CHOP or CVP chemotherapy. There was again no significant difference noted in the Objective Response Rate, Complete Response rates, Progression Free Survival and Overall Survival, between the two treatment groups

The SAWYER study is a phase Ib open label trial which compared the SC and IV formulations of RITUXAN® in combination with Fludarabine and Cyclophosphamide chemotherapy, in 176 treatment naïve patients with Chronic Lymphocytic Leukemia. There was no significant difference noted in the Objective Response Rate, Complete Response rates, Progression Free Survival and Overall Survival, between the two treatment groups.

SparkThera is a phase Ib study which investigated the pharmacokinetics and safety of SubCutaneous (SC) versus IV RITUXAN® formulations as maintenance therapy, in previously untreated or relapsed Follicular Lymphoma. It was noted that the pharmacokinetics of SC RITUXAN® formulation was Non-inferior to IV RITUXAN® formulation, with a comparable safety profile.

PrefMab is a randomized, open label, phase IIIb study which evaluated patient preference for SC or IV RITUXAN® formulation, in previously untreated CD20-positive Follicular lymphoma and Diffuse Large B-Cell Lymphoma. In this study, most patients preferred SC compared with IV formulation of RITUXAN®, mainly due to reduction in the duration and discomfort of administration.

Treatment with RITUXAN HYCELA® should be initiated only after patients had received at least one full dose RITUXAN® by intravenous infusion. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf

FDA Approves Subcutaneous RITUXAN® Formulation for CD20-Positive Hematologic Malignancies

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The US FDA on June 22, 2017, granted regular approval to the combination of RITUXAN® (Rituximab) and Hyaluronidase human (RITUXAN HYCELA®) for adult patients with Follicular Lymphoma, Diffuse Large B-Cell Lymphoma, and Chronic Lymphocytic Leukemia. This Subcutaneous formulation of RITUXAN® utilizes ENHANZE®, a drug delivery technology platform, which removes limitations on the volume of biologics and drugs that can be delivered Subcutaneously, thereby significantly reducing the time required for drug administration. The approval of RITUXAN HYCELA® was based on several randomized clinical trials that demonstrated Non-inferior pharmacokinetics of Subcutaneous RITUXAN HYCELA® compared with IV RITUXAN®, as well as comparable efficacy and safety results.

RITUXAN® Maintenance Prolongs Survival in Mantle Cell Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Mantle Cell Lymphomas (MCL) account for approximately 6% of all Non Hodgkin Lymphomas in adults and have a high relapse rate following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease. Maintenance therapy with RITUXAN® (Rituximab) following induction chemotherapy with R-CHOP, prolonged remission and significantly improved Overall Survival in elderly patients with MCL (N Engl J Med. 2012;367:520-531). The role of maintenance RITUXAN® and its impact on Overall Survival in young patients following Autologous Stem Cell Transplant (ASCT) has however not been investigated.

The LyMa trial is a prospective, international, randomized, phase III study that evaluated the benefit of RITUXAN® maintenance following ASCT, in young previously untreated MCL patients. This study enrolled 299 treatment-naïve MCL patients, diagnosed according to WHO 2008 classification, with a median age of 57 years, of whom 277 patients (N=277) were included in the study. Induction chemotherapy consisted of 4 cycles of R-DHAP (RITUXAN®, Dexamethasone, High dose Ara-C, Cisplatin) given every 3 weeks followed by ASCT. Patients who did not respond to R-DHAP received 4 additional courses of R-CHOP-14 before undergoing ASCT (N=20). The conditioning regimen for ASCT was R-BEAM (RITUXAN® BiCNU, Etoposide, Ara-C, and Melphalan). Following ASCT, 240 patients who responded, were randomized in a 1:1 ratio to receive RITUXAN® maintenance at 375 mg/m2 every 2 months for 3 years or no maintenance treatment. The Primary endpoint was Event Free Survival (EFS) calculated from time of randomization and these events included disease progression, relapse, death, severe infection or allergy to RITUXAN®. Secondary endpoints included Progression Free Survival and Overall Survival from time of diagnosis and time of randomization.

In the final analysis, the 4-year Event Free Survival (EFS) was 78.9% with RITUXAN® maintenance compared with 61.4% for those who did not get maintenance therapy (P=0.0012). The EFS duration was significantly superior in the RITUXAN® maintenance arm with a 54% reduction in the risk of events (HR=0.46; P=0.0016). The 4-year Progression Free Survival was 82.2% versus 64.6% with and without RITUXAN® maintenance, respectively (P=0.0005). The Overall Survival at 4 years was 88.7% and 81.4%, for RITUXAN® maintenance and no maintenance respectively (P=0.04). Patients in the RITUXAN® maintenance group had a 60% reduction in the risk of progression (HR=0.40; P=0.0007) and a 50% reduction in the risk of death (HR=0.50; P=0.05).

The authors concluded that RITUXAN® maintenance after ASCT prolongs Event Free Survival, Progression Free Survival and Overall Survival and is a new standard of care for young Mantle Cell Lymphoma patients. Rituximab Maintenance after Autologous Stem Cell Transplantation Prolongs Survival in Younger Patients with Mantle Cell Lymphoma: Final Results of the Randomized Phase 3 LyMa Trial of the Lysa/Goelams Group. Le Gouill S, Thieblemont C, Oberic L, et al. Presented at: 58th American Society of Hematology Annual Meeting & Exposition; December 3, 2016; San Diego, CA. Abstract 145.

FDA Approves IMBRUVICA® for Marginal Zone Lymphoma

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SUMMARY: The FDA on January 18, 2017 granted accelerated approval to IMBRUVICA® (Ibrutinib) for the treatment of patients with Marginal Zone Lymphoma (MZL), who require systemic therapy and have received at least one prior anti-CD20 based therapy. The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B-cell lymphoproliferative disorders and include Follicular Lymphomas, Small Lymphocytic Lymphomas (SLL), LymphoPlasmacytic Lymphomas (LPL) and Marginal Zone Lymphoma subtypes such as Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL)/Mucosa-Associated Lymphoid Tissue (MALT) lymphoma and Splenic Marginal Zone Lymphoma (SMZL). Marginal Zone Lymphoma is an indolent B-cell lymphoma originating in the lymph nodes as well as in organs including the stomach, salivary glands, thyroid gland, lungs and spleen. It accounts for approximately 10% of all cases of Non Hodgkin Lymphomas (NHL) in adults and is often linked to chronic infection. When treatment is indicated, patients are often treated with a RITUXAN® (Rituximab) based regimens with improved outcomes. Relapses however are common and there is presently no therapy, specifically approved for the treatment of Marginal Zone Lymphoma.

Normal B-cell activation and proliferation is dependent on B-Cell Receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® is presently approved by the FDA for the treatment of patients with Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma including those with del-17p, patients with Mantle Cell Lymphoma who had received at least one prior therapy, and patients with Waldenstrom’s Macroglobulinemia.

The approval of IMBRUVICA®, in MZL was based on results from a multicenter, open-label, single-arm, phase II trial, in which the safety and efficacy of IMBRUVICA® was evaluated in 63 patients with Marginal Zone Lymphoma. Enrolled patients had previously received one or more prior therapies including at least one anti-CD20 targeted monoclonal antibody -containing regimen or monotherapy RITUXAN®. The subtypes of Marginal Zone Lymphomas included, Extra Nodal MZL (N=32), Nodal MZL (N=17) and Splenic MZL (N=14). The median number of prior systemic therapies was 2 and 35% of the enrolled patients had 3 or more prior therapies. Treatment consisted of IMBRUVICA® 560 mg orally once daily until progression or unacceptable toxicity. The primary study endpoint was Overall Response Rate (ORR). Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS), and safety.

The Overall Response Rate as assessed by an independent review committee was 46%,of whom with 3.2% of patients had a Complete Response and 42.9% achieved a Partial Response. This benefit was observed across all three subtypes of Marginal Zone Lymphomas (Overall Response Rate was 46.9%, 41.2%, and 50.0% for ENMZL/MALT, NMZL, and SMZL subtypes, respectively). The median time to response was 4.5 months and the median duration of response was not reached (range, 16.7 months – Not Reached). The most common adverse events were fatigue, diarrhea, cytopenias, nausea, peripheral edema, cough, arthralgia and dyspnea.

The authors concluded that single agent IMBRUVICA® achieved high Response Rates and durable responses in patients with Relapsed/Refractory Marginal Zone Lymphoma. IMBRUVICA® addresses an unmet need for previously treated Marginal Zone Lymphoma patients, who are in need of non-chemotherapy treatment options. Single-Agent Ibrutinib Demonstrates Efficacy and Safety in Patients with Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open-Label, Phase 2 Study. Noy A, de Vos S, Thieblemont C, et al. Presented at: ASH 2016 Annual Meeting and Exposition. Abstract 1213.

GAZYVA® Superior to RITUXAN® in Follicular Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 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), 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 is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years.

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 (natural killer cells, macrophages and neutrophils), Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular phagocytosis are significantly enhanced, but induces very little Complement-Dependent Cytotoxicity. This is in contrast to RITUXAN® 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.

GAZYVA® along with Bendamustine in the phase III GADOLIN study, prolonged PFS, compared with Bendamustine alone, in patients with relapsed/refractory indolent Non Hodgkin lymphoma. Based on this promising data, the GALLIUM phase III trial was conducted in treatment naïve patients with Follicular Lymphoma. This study included 1,202 patients with newly diagnosed Follicular Lymphoma, who had Grade I-IIIa tumors and had an ECOG PS of 2 or less. Patients were randomized to receive either GAZYVA® plus chemotherapy, followed by GAZYVA® maintenance (N=601), or RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance (N=601). The chemotherapy regimens used were CHOP, CVP or Bendamustine, based on the discretion of the treating physician. Patients received either RITUXAN® 375mg/m2 IV on day 1 of each cycle or GAZYVA® 1000 mg IV on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles, for either eight 21-day cycles (CHOP and CVP) or six 28-day cycles (Bendamustine). Patients who achieved a complete response (CR) or partial response (PR) at the end of induction therapy, received maintenance therapy with RITUXAN® or GAZYVA® every 2 months for 2 years or until disease progression. The median age was 59 years and 57.1% of patients received Bendamustine, 33.1% received CHOP, and 9.8% received CVP. The primary endpoint was PFS and secondary endpoints included Response Rate, Overall Survival (OS), Disease Free Survival and safety. Upon recommendations from the Independent Monitoring Committee, the study was unblinded after a preplanned interim efficacy analysis.

After a median follow-up of 34.5 months, patients in the GAZYVA® group had a 34% reduction in the risk of progression or death compared with those in the RITUXAN® group (HR=0.66; P=0.001). There was however no difference between the two treatment groups in the 3-year Overall Survival (OS) rate (P=0.21). Response rates were similar in both GAZYVA® and RITUXAN® treatment groups. Patients treated with GAZYVA® had more serious adverse events, 46.1% versus 39.9% in the RITUXAN® group, but the discontinuation rate was similar in both treatment groups.

The authors concluded that for treatment naïve Follicular Lymphoma patients, combining GAZYVA® with chemotherapy resulted in a clinically meaningful improvement in PFS compared with RITUXAN® plus chemotherapy and should therefore be the new standard of care for this patient population. Obinutuzumab-Based Induction and Maintenance Prolongs Progression-Free Survival (PFS) in Patients with Previously Untreated Follicular Lymphoma: Primary Results of the Randomized Phase 3 GALLIUM Study. Marcus RE, Davies AJ, Ando K, et al. Presented at the 58th American Society of Hematology (ASH) Annual Meeting. December 3-6, 2016; San Diego, CA. Abstract 6.

Late Breaking Abstract – ASH 2016 Dramatic Responses in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL) with anti-CD19 CAR T Cells

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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. Patients with refractory DLBCL have poor outcomes with chemotherapy, and have a response rate of 20%-30% and median overall survival of approximately 6 months (J Clin Oncol 34, 2016, suppl; abstr. 7516), and thus represents a significant unmet medical need. Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy in which T cells are collected from the patient’s own blood and are genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR’s). The cytotoxic T cells with these chimeric antigen receptors on their surface are now able to recognize a specific antigen on tumor cells. These engineered CAR T-cells which are grown in the lab are then infused into the patient and they in turn proliferate in the patient’s body and the engineered receptor on their surface help recognize and kill cancer cells that expresses that specific antigen. CD19 antigen is expressed by majority of the B cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies such as Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL) and Non Hodgkin lymphoma (NHL), such as Diffuse Large B-Cell Lymphoma (DLBCL).

The KTE-C19 (anti-CD19 Chimeric Antigen Receptor (CAR) T cells) construct consists of an extracellular domain which recognizes and targets the CD19 antigen on the surface of tumor cells, and the intracellular domains to avoid activation of hidden signals to the T-cells. ZUMA-1 is a multicenter phase I/II trial of anti-CD19 Chimeric Antigen Receptor (CAR) T cells (KTE-C19) in refractory, aggressive NHL and this study included patients with Diffuse Large B-Cell Lymphoma (DLBCL), Primary Mediastinal B-Cell Lymphoma (PMBCL), and Transformed Follicular Lymphoma (TFL). In the phase I component of this study, 43% of the patients had ongoing Complete Responses at 12 months.

Phase II of ZUMA-1 included 2 patient cohorts based on the tumor type. Cohort 1 included DLBCL and patients in cohort 2 had PMBCL or TFL. Refractory disease was defined as progressive or stable disease as best response to last line of therapy, or disease progression 12 months or less after Autologous Stem Cell Transplant (ASCT). All included patients received a prior anti-CD20 antibody and an Anthracycline-containing regimen. The median age was 58 years, 78% were refractory to 2 or more lines of therapy, 20% relapsed less than 12 months after ASCT. Patients received a low-dose conditioning regimen of Cyclophosphamide 500 mg/m2 IV and Fludarabine 30 mg/m2 IV, daily for 3 days followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The primary endpoint was Objective Response Rate (ORR) and secondary endpoints include Duration of Response, frequency of adverse events (AEs), and levels of CAR T cells and serum cytokines. The authors presented the results of a pre-specified interim analysis from cohort 1 and 51 patients in cohort 1 were eligible for analysis.

The study met its primary endpoint and with a minimal follow up of three months, the ORR was 76% compared with ORR of 20% in historical controls (P<0.0001). Complete Responses were noted in 47% of the patients and Partial Response rate was 29%. Majority of the responses (92%) occurred within the first month, and the Complete Response Rate at 3 months was 33% and 39% of the patients had ongoing responses at 3 months. The treatment benefit was consistent across all subgroups of patients. The most frequent more than grade 3 toxicities were cytopenias, encephalopathy and hypophosphatemia. Grade 3 or more Cytokine Release Syndrome (CRS) and neurologic events occurred in 20-30% of the patients.

The authors concluded that this is the first reported multicenter trial of CAR T cell therapy in patients with refractory aggressive NHL and therapy with KTE-C19 induced a nearly six fold higher Complete Response Rate compared to historical outcomes and efficacy was strongly associated with peak CAR T levels. KTE-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA-1.Neelapu SS, Locke FL, Bartlett NL, et al. Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract LBA6.

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

GAZYVA® (Obinutuzumab)

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The FDA on February 26, 2016 approved GAZYVA® for use in combination with Bendamustine followed by GAZYVA® monotherapy for the treatment of patients with Follicular Lymphoma (FL) who relapsed after, or are refractory to, a RITUXAN® (Rituximab) containing regimen. GAZYVA® was previously approved for use in combination with Chlorambucil for the treatment of patients with previously untreated Chronic Lymphocytic Leukemia. GAZYVA® injection is a product of Genentech, Inc.

FDA Approves GAZYVA® in Combination with TREANDA® for Follicular Lymphoma

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SUMMARY: The FDA on February 26, 2016, approved GAZYVA® (Obinutuzumab) for use in combination with TREANDA® (Bendamustine) followed by GAZYVA® monotherapy for the treatment of patients with Follicular Lymphoma (FL) who relapsed after, or are refractory to, a RITUXAN® (Rituximab) containing regimen. GAZYVA® was previously approved for use in combination with Chlorambucil for the treatment of patients with previously untreated Chronic Lymphocytic Leukemia. 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®. Four hundred and thirteen (N=413) RITUXAN® refractory iNHL were randomized and patients in the control arm received TREANDA® 120 mg/m2 IV on days 1 and 2 every 28 days for a total of 6 cycles. Patients in the experimental arm received 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. In patients with non-progressive disease in the experimental 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. The median Progression Free Survival was 29 months with GAZYVA®/ TREANDA® plus maintenance GAZYVA® versus 14 months with TREANDA® monotherapy and no maintenance (HR=0.52; P<0.001). 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, 76.6% in the TREANDA® alone group and 78.6% 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, anemia and pneumonia.

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 begs the question, if the improvement in PFS was predominantly contributed by the continuous maintenance treatment with GAZYVA®. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. Sehn LH, Chua NS, Mayer J, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA8502)

Superior Outcomes with GAZYVA® and TREANDA® Combo in Indolent Non Hodgkin Lymphoma

RR

SUMMARY: The American Cancer Society estimates that in 2015, about 71,850 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,800 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®, in patients with indolent NHL (iNHL), refractory to RITUXAN®. Four hundred and thirteen (N=413) RITUXAN® refractory iNHL were randomized and patients in the control arm received TREANDA® 120 mg/m2 IV on days 1 and 2 every 28 days for a total of 6 cycles. Patients in the experimental arm received 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. In patients with non-progressive disease in the experimental 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. The median Progression Free Survival was 29 months with GAZYVA®/ TREANDA® plus maintenance GAZYVA® versus 14 months with TREANDA® monotherapy and no maintenance (HR=0.52; P<0.001). 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, 76.6% in the TREANDA® alone group and 78.6% 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, anemia and pneumonia. 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 begs the question, if the improvement in PFS was predominantly contributed by the continuous maintenance treatment with GAZYVA®. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. Sehn LH, Chua NS, Mayer J, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA8502)