Long-term Results in both First-line and Refractory Settings Seen in Patients with Non-Hodgkin's Lymphoma
PHILADELPHIA, Dec. 8 /PRNewswire/ -- GlaxoSmithKline announced today updated long-term survival data from two Phase II studies of BEXXAR® (tositumomab and iodine I-131 tositumomab) used in either patients with previously untreated cancer of the immune system (follicular lymphoma) or in patients with cancer of the lymphocytes (non-Hodgkin's lymphoma, NHL) that no longer responded to rituximab.
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The first study demonstrated that, among 76 patients with previously untreated follicular lymphoma, the 10-year overall survival rate was 83% and the 10-year progression-free survival rate was 38%. The second study demonstrated that after long term follow-up, heavily pre-treated, rituximab-refractory patients with NHL experienced an overall survival of 6.7 years (median).
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These data were presented at the 51st Annual Meeting of the American Society of Hematology.
"Non-Hodgkin's lymphoma is a serious disease, with more than 65,000 estimated new cases in 2009. These data are exciting because they continue to support that BEXXAR has the potential to provide clinical benefit that translates to long-term survival - ultimately supporting our number one goal of helping patients," said Jeffrey Bloss, MD, Vice President, North American Medical Affairs, GSK Oncology.
The complete prescribing information for BEXXAR contains the following black boxed warnings: hypersensitivity reactions, including anaphylaxis; prolonged and severe cytopenias; pregnancy category X; and special requirements related to the radioactive component of the product. Additional important safety information is provided below and can be found in the complete prescribing information for BEXXAR.
For previously untreated follicular lymphoma: Abstract #3759
In addition to the 10-year overall survival rate of 83%, results showed that the 97% of patients had a response. The overall confirmed response rate was 95%, with 75% of patients in the trial achieving a complete response. The median duration of a complete response was 9.1 years. Finally, the median amount of time follicular lymphoma was responsive to BEXXAR therapy was 6 years.
"Across ten years, we are seeing a consistent result and effect on survival by treating patients with BEXXAR first. Rarely are there data to show a treatment can produce a durable response over a decade, and what's most exciting is that these results were achieved after a single treatment," said Mark Kaminski, MD, Professor of Internal Medicine and Director, Leukemia/Lymphoma Program at the University of Michigan and lead investigator of the study.
This was a single center, single-arm, Phase II trial of previously untreated patients (n=76) with stage III and IV follicular lymphoma.
Five patients (7%) were managed with thyroid hormone replacement therapy from 0.5 to 2.9 years after treatment. Eleven patients (14%) were diagnosed with second malignancies. Malignancies included 4 skin neoplasms (2 basal cell and 2 squamous cell) and 7 visceral neoplasms (3 breast, 2 prostate, 1 endometrial cancer, 1 glioblastoma). In addition, one case of myelodsyplastic syndrome was diagnosed about 8 years after treatment. Hematologic toxicity was common, with grade 4 neutropenia in 5% of patients and no grade 4 thrombocytopenia.
The five-year follow-up data from this study were originally reported in the New England Journal of Medicine in 2005 (NEJM 352:441, 2005). Eight year follow-up data were presented at ASCO 2007.
For non-Hodgkin's lymphoma patients who progressed after treatment with rituximab: Abstract #2732
In addition to the median overall survival of 6.7 years, 72% of patients experienced a response. The overall confirmed response rate was 65% and the complete response rate was 38%. The amount of time patients maintained a response to therapy was 18.9 months (median), with an estimated 40% of patients maintaining a response at five years. There were only two known relapses after two years. Additionally, patients experienced a median of 10.4 months without disease progression, with 28% of patients remaining progression-free at approximately five years.
"It is encouraging to see such long-term durable responses in one of the original patient populations, demonstrating the activity of BEXXAR in patients with rituximab-refractory disease," said Anas Younes, MD, the University of Texas M.D. Anderson Cancer Center. "These results suggest a long-term therapeutic value of BEXXAR for patients with rituximab-refractory, indolent lymphoma."
This study evaluated long-term safety and efficacy data from a Phase II study of patients with slow-growing, follicular large-cell or transformed B-cell lymphoma, which was progressive after rituximab (n=40).
To date, 20 deaths have been reported, 10 without documented disease progression. Six second cancers have occurred: 2 acute leukemia, 1 prostate, 2 skin (1 squamous, 1 Merkel cell), and 1 primary hepatic. The incidence of secondary leukemia remains the same as previously reported in 2005 at 5% (2 of 40 patients). Seven of the 40 patients enrolled in this study had elevated thyroid stimulating hormone (TSH) levels prior to receiving the therapeutic dose of iodine-131 tositumomab and 2 patients did not have baseline TSH data. Of the 31 patients with normal baseline TSH levels prior to treatment, 3 developed elevated TSH as of July 2009 and as reported previously. There were no cases of hypothyroidism reported as an adverse event by investigators as of July 2009.
These data were previously reported in the Journal of Clinical Oncology in 2005 (J Clin Oncol 23:712, 2005).
About the BEXXAR Therapeutic Regimen
BEXXAR pairs the targeting ability of a monoclonal antibody (Tositumomab) and the therapeutic potential of radiation (Iodine-131). Combined, these agents form a radiolabeled monoclonal antibody regimen that is able to bind to the target antigen CD20 found on B cells, including normal B-cells and those that become cancerous in NHL, thereby delivering the dose of radiation. BEXXAR, which is given in four visits over one to two weeks, is specifically dosed based on an individual's drug clearance rate, allowing the delivery of a predetermined amount of radiation to each patient.
The BEXXAR Therapeutic Regimen has been studied for more than 15 years. It was originally approved by the FDA based on a multicenter, single-arm, clinical trial in 40 patients who had received a median of four prior chemotherapies and whose disease had not responded to or had progressed after at least four doses of Rituximab. In this pivotal registration study, 68% (95% Confidence Interval (C.I.) = 51 to 81%) responded to BEXXAR. The median duration of response was 16 months (range 1 to 38; 95% C.I. = 10 to not reached).
The FDA expanded the indication for BEXXAR based on a multicenter, single-arm, open-label study of 60 chemotherapy-refractory patients. The median age of study participants was 60 years (range 38-82), the median time from diagnosis to protocol entry was 53 months (range 9-334), and the median number of prior chemotherapy regimens was 4 (range 2-13). Fifty-three patients had not responded to prior therapy and 7 patients had responded with a duration of response of less than 6 months. As determined by an independent panel of oncologists and radiologists that reviewed patients' records and radiologic studies, the overall response rate for BEXXAR in this study was 47% (95% C.I.= 34 to 60%), with the median duration of response of 12 months (range 2 to 47; 95% C.I.= 7 to 47); the complete response rate was 20% (95% C.I. = 11 to 32%), with the median duration of response of 47 months (range 9 to 47; 95% C.I.= 47 to not reached), after a median follow-up of 30 months.
The results of these two studies were supported by demonstration of durable objective responses in three single-arm studies enrolling 130 patients evaluable for efficacy with Rituximab-naive, follicular NHL, with or without transformation, who had relapsed following or were refractory to chemotherapy.
Indications
The BEXXAR Therapeutic Regimen (Tositumomab and Iodine I 131 Tositumomab) is indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low-grade, follicular, or transformed NHL, including patients with Rituximab-refractory NHL.
Determination of the effectiveness of the BEXXAR Therapeutic Regimen is based on overall response rates in patients whose disease is refractory to chemotherapy alone or to chemotherapy and Rituximab. The effects of the BEXXAR Therapeutic Regimen on survival are not known.
The BEXXAR Therapeutic Regimen is not indicated for the initial treatment of patients with CD20-positive NHL. The BEXXAR Therapeutic Regimen is intended as a single course of treatment. The safety of multiple courses of the BEXXAR Therapeutic Regimen, or combination of this regimen with other forms of irradiation or chemotherapy, has not been evaluated.
Important safety information
BEXXAR is not for everyone. Serious hypersensitivity reactions, including some with fatal outcome, have been observed with the BEXXAR Therapeutic Regimen. Patients who are allergic to any component of the regimen should not receive BEXXAR. Patients who have previously received mouse proteins should be screened for human anti-mouse antibodies (called HAMA). Patients who are positive for HAMA may be at increased risk for anaphylaxis and serious hypersensitivity reactions. Administration of BEXXAR resulted in the development of antibodies to the mouse antibody (called HAMA). Treatment with BEXXAR resulted in very severe or life-threatening decreases in blood counts (platelets, white blood cells, and red blood cells), in the majority of patients for an extended period of time (about a month). In 7% of patients, these decreases persisted for more than 90 days. BEXXAR can cause fetal harm. Patients who are pregnant should not receive BEXXAR. No long-term animal studies have been performed to establish the potential for BEXXAR to cause cancer or mutation or to determine its effects on fertility in males or females. However, radiation does have the potential to cause cancer or mutation. Effective contraceptive methods should be used during treatment and for 12 months following treatment with BEXXAR. Radioiodine is excreted in breast milk and immunoglobulins are known to be excreted in breast milk. Women should be advised to discontinue nursing before starting treatment with BEXXAR. BEXXAR contains a radioactive component and should only be administered by qualified healthcare professionals.
In patients who received BEXXAR, infections occurred in 45% of patients, bleeding in 12% of patients, and treatment with hematologic supportive care in 27% of patients. Other reactions during or following the infusion included fever, chills, sweating, nausea, low blood pressure, shortness of breath and difficulty breathing. There is also a risk of hypothyroidism following the administration of BEXXAR. All patients must receive thyroid-blocking agents starting at least 24 hours before receiving the dosimetric dose of BEXXAR and continued until 14 days after the therapeutic dose of BEXXAR. Any patient who is unable to tolerate thyroid-blocking agents should not receive the BEXXAR therapeutic regimen. Certain cancer therapies including BEXXAR have been associated with the development of a second type of blood cancer and solid tumors. At a median follow-up of 29 months, 44 cases of myelodysplastic syndrome (a type of pre-leukemia) and/or leukemia and 65 cases of secondary tumors in 54 patients were reported among the 995 patients enrolled in studies with BEXXAR. Patients with impaired kidney function may be at risk for increased exposure to the radioactive component of BEXXAR. The safety of the use of live viral vaccines after treatment with BEXXAR is unknown. The effectiveness of vaccinating during treatment with BEXXAR is also unknown.
Healthcare providers must be specifically trained to administer BEXXAR. Additional information about the BEXXAR Therapeutic Regimen, including safety and complete prescribing information, may be obtained by calling 1-877-423-9927 (1-877-4BEXXAR) or visiting www.BEXXAR.com.
GSK in Oncology
GSK Oncology is dedicated to producing innovations in cancer that will make profound differences in the lives of patients. Through GSK's revolutionary 'bench to bedside' approach, we are transforming the way treatments are discovered and developed, resulting in one of the most robust pipelines in the oncology sector. Our worldwide research in oncology includes collaborations with more than 160 cancer centers. GSK is closing in on cancer from all sides with a new generation of patient focused cancer treatments in prevention, supportive care, chemotherapy, and targeted therapies.
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Cautionary statement regarding forward-looking statements
Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK's operations are described under 'Risk Factors' in the 'Business Review' in the company's Annual Report on Form 20-F for 2008.
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