Tositumomab and iodine I 131 tositumomab (Bexxar ) Corixa Corporation; marketed by GlaxoSmithKline 1

Transcription

1 Generic (Trade Name): Manufacturer: Tositumomab and iodine I 131 tositumomab (Bexxar ) Corixa Corporation; marketed by GlaxoSmithKline 1 NO. 64 OCTOBER 2005 Indication: Current Regulatory Status: In the US, Bexxar is indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low grade, follicular, or transformed non-hodgkin s lymphoma (NHL), including patients with rituximab-refractory NHL. 2 Bexxar was approved in Canada on August 18, 2005, 3 but it is not yet available on the Canadian market. The drug was approved by the US FDA on June 23, Health Canada approved a similar radioimmunotherapeutic agent, Zevalin (yttrium-90 ibritumomob tiuxetan, marketed by Berlex Canada Inc.) on May 10, Description: Bexxar is composed of a monoclonal antibody (tositumomab) and a radiolabelled monoclonal antibody, iodine I 131 tositumomab. Monoclonal antibodies can identify and lock onto certain proteins found on the surface of some cancer cells. Tositumomab attaches itself to a protein called CD20, found on the surface of lymphoma B-cells. The iodine then delivers radiation directly to the lymphoma B-cells, thereby destroying them. 6,7 At the onset of treatment, the patient takes a thyroid-blocking agent (e.g., potassium iodide) and continues to do so for 14 days after the administration of the therapeutic dose. The Bexxar regimen is administered in two steps. The first step, called the dosimetric step, involves infusing tositumomab 450 mg intravenously during a 60-minute period; and then 5.0 mci iodine-131 and 35 mg tositumomab intravenously for 20 minutes. The patient is monitored for seven to 14 days to ensure the appropriate distribution of the compounds. If the distribution is acceptable, the second step, called the therapeutic step, is carried out seven to 14 days after the dosimetric step. It involves infusing tositumomab 450 mg intravenously during a 60-minute period; and then iodine-131 (dosage of iodine-131 is calculated according to a formula that is included in the package insert) and 35 mg tositumomab intravenously for 20 minutes. The patient is pre-medicated with acetaminophen and diphenhydramine during dosimetric and therapeutic steps. 2 Current Treatment: NHL is a disease of the lymphoid system. It is classified as indolent (low grade) or aggressive (intermediate or high grade) B-cell and T-cell neoplasms. 8 Treatment depends on the disease stage and the patient s overall status. Those with localized disease are treated with radiation. Patients with stage I or II low-grade lymphoma can choose from therapeutic options, that include watchful waiting; chlorambucil; a combination of cyclophosphamide, vincristine and prednisone; fludarabine; or rituximab. Most patients present with incurable stage III or IV disease. Patients may respond to chemotherapy, but a relapse usually occurs. Those who relapse are treated with another course of chemotherapy that may include radiation. There is a shorter response with each subsequent course of therapy.

2 One-third of patients will progress to a higher grade histology with a poorer prognosis. Intermediate-grade lymphomas may be treated with localized radiation; and with chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone; all four of which, in combination is called CHOP). Patients with high-grade lymphomas or patients with relapsed intermediate-grade lymphomas may be treated with autologous stem cell transplantation. 9 Cost: Evidence: In the US, the cost per patient is $26, Treatment is limited to one time only. 2 Trials have been conducted in three populations: treatment-naïve NHL patients 11 (the US FDA has not approved the use of Bexxar in these patients 12 ); patients previously treated with Bexxar 13 (the US FDA has limited the treatment to one course 14 ); and previously treated NHL patients without previous exposure to Bexxar (the review of the evidence is limited to this population). Phase 2 trials Vose et al. conducted an open-label trial of Bexxar in 47 chemotherapy-relapsed and refractory low-grade or transformed-grade B-cell NHL patients. 15 A complete response (defined as the disappearance of all measurable and assessable disease, or a disappearance of all tumour lesions, but with the examination precluding an unequivocal statement that the tumour has disappeared) was obtained in 15 of 47 (31.9%) patients. The median duration of response for the complete responders was 19.9 months (95% CI: 14.3 to not reached) and 9.9 months (95% CI: 4.5 to 17.3) for all patients. The median time to disease progression or death was 11.6 months (95% CI: 6.1 to 19.2 months) for responders and 5.3 months (95% CI: 3.2 to 8.9) for all patients. The median survival duration from study entry was 36 months (95% CI: 28 to 36), with 20 of 47 (42.6%) deaths. Davies et al. conducted an open-label trial of Bexxar in 41 patients at first or second recurrence of indolent or transformed indolent B-cell NHL. 16 A complete remission was defined as resolution of all disease-related radiologic abnormalities, and the disappearance of all signs and symptoms related to the disease. This was achieved in 15 of 41 (36.6%) patients. The median duration of remission for all responders was 1.3 years (95% CI: 0.7 to not reached). The median progression free survival for all patients was 0.8 years (95% CI: 0.5 to not yet reached) and 1.7 years (95% CI: 0.8 to 2.5) for responding patients. Horning et al. evaluated Bexxar in 40 patients with indolent, follicular large-cell, or transformed B-cell lymphoma, with progressive disease after rituximab. 17 A complete response (defined as the disappearance of all disease-related radiographic abnormalities, signs, and symptoms) was seen in 15 of 40 (37.5%) patients, with a median time to complete response of 13 weeks (range: seven to 57 weeks). The median progression free

3 survival was 10.4 months (95% CI: 5.7 to 18.6) for all patients and 24.5 months (95% CI: 16.8 to not reached) for confirmed responders. The overall survival was 24 of 40 (60.0%) at 3.3 years. Phase 3 trials Kaminski et al. completed a non-randomized study of 60 chemotherapy-refractory lowgrade or transformed low-grade B-cell NHL patients. 18 In this study, patients acted as their own control, in comparing the duration of response of their last qualifying chemotherapy (LQC) regimen with Bexxar. A complete response (defined as the disappearance of all disease-related radiologic abnormalities and other assessable disease) was obtained with Bexxar in 12 of 60 (20.0%) patients, compared with two of 60 (3.3%) patients using the data from the LQC regimen (p<0.001). Patients have been observed for 47 months, but the median duration of response on treatment has not been reached. Davis et al. randomized 78 patients with relapsed or refractory, indolent or transformed, CD20-positive NHL to either unlabelled tositumomab (n=36) or Bexxar (n=42). 19 Patients who progressed after treatment with unlabelled tositumomab could cross over to receive Bexxar. A complete response was defined as the disappearance of all diseaserelated physical or radiologic abnormalities, and the disappearance of all signs and symptoms related to the disease. Patients may have had residual radiographic or palpable abnormalities thought to be residual scar tissue. Fourteen patients (33.3%) had a complete response when treated with Bexxar compared with three (8.3%) for patients treated with unlabelled tositumomab (p=0.012). The median duration of complete response has not been reached for patients treated with Bexxar. The median time to progression was 5.5 months (95% CI: 2.9 to 6.0) for the control group and 6.3 months (95% CI: 4.9 to 11.1) for the treatment group (p=0.035). In the control group, 19 (52.8%) crossed over to treatment with Bexxar. Adverse Effects: Commentary: The most common adverse effects include gastrointestinal toxicity [nausea, vomiting, anorexia, diarrhea (38%)]; infusional toxicity, such as hypotension, fever, chills (29%); infections (45%); and anemia (29%). Six per cent of patients may develop hypersensitivity reactions such as an anaphylactoid reaction. Severe neutropenia and thrombocytopenia may occur in 63% and 53% of patients respectively. Some patients may develop myelodysplasia and secondary leukemia. 2 Bexxar will be an option for patients who have failed standard treatments. The high acquisition cost, complex administration regimen, and daunting side-effect profile may be barriers to treatment initiation.

4 References: 1. For immediate release: Corixa and Glaxosmithkline enter into license and supply agreement for Bexxar therapy in Canada [news release]. Research Triangle Park (NC): GlaxoSmithKline; 2003 May 28. Available: 2. BEXXAR : tositumomab and iodine I 131 tositumomab [product monograph]. Research Triangle Park (NC): GlaxoSmithKline; Available: (accessed 2005 Sep 16). 3. Bexxar therapy. In: Notices of compliance [database online]. Ottawa: Therapeutic Products Directorate, Health Canada; Available: 4. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. BL /0. In: BEXXAR [FDA product approval information]. Rockville (MD): The Center; Available: 5. Zevalin. In: Notices of compliance [database online]. Ottawa: Therapeutic Products Directorate, Health Canada; Available: 6. Monoclonal antibody therapy: Bexxar. In: Lymphoma Information Network: your comprehensive guide to Hodgkin's and non-hodgkin's lymphoma: Lymphoma Information Network; Available: 7. Iodine 131 tositumomab (BEXXAR). In: CancerBACUP: helping people live with cancer. London: CancerBACUP; Available: 8. Hennessy BT, Hanrahan EO, Daly PA. Non-Hodgkin lymphoma: an update. Lancet Oncol 2004;5(6): Johnston CB, Lyons WL, Covinsky KE. Blood: lymphomas. In: Tierney LM, McPhee SJ, Papadakis MA, editors. Current medical diagnosis & treatment. 43rd ed. New York: Lange Medical Books/McGraw-Hill; p Bexxar vs. Zevalin. In: Lymphomation.org. Reigelsville (PA): Patients Against Lymphoma; Available: Press OW, Unger JM, Braziel RM, Maloney DG, Miller TP, LeBlanc M, et al. A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood 2003;102(5): Kaminski MS, Tuck M, Estes J, Kolstad A, Ross CW, Zasadny K, et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005;352(5): Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, Tuck M, et al. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 2000;96(4): Wahl RL, Leonard JP, Kaminski MS, Goldsmith SJ. Can patients with non-hodgkin's lymphoma (NHL) who have been treated with and responded to the BEXXAR therapeutic regiment (tositumomab and iodine I 131 tositumomab) be retreated [abstract]. J Nucl Med 2004;45(Suppl):143P.

5 15. Vose JM, Wahl RL, Saleh M, Rohatiner AZ, Knox SJ, Radford JA, et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-hodgkin's lymphomas. J Clin Oncol 2000;18(6): Davies AJ, Rohatiner AZ, Howell S, Britton KE, Owens SE, Micallef IN, et al. Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-hodgkin's lymphoma. J Clin Oncol 2004;22(8): Horning SJ, Younes A, Jain V, Kroll S, Lucas J, Podoloff D, et al. Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol 2005;23(4): Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non- Hodgkin's lymphomas. J Clin Oncol 2001;19(19): Davis TA, Kaminski MS, Leonard JP, Hsu FJ, Wilkinson M, Zelenetz A, et al. The radioisotope contributes significantly to the activity of radioimmunotherapy. Clin Cancer Res 2004;10(23): This series highlights medical technologies that are not yet in widespread use in Canada and that may have a significant impact on health care. The contents are based on information from early experience with the technology; however, further evidence may become available in the future. These summaries are not intended to replace professional medical advice. They are compiled as an information service for those involved in planning and providing health care in Canada. These summaries have not been externally peer reviewed. Production of this report is made possible by a financial contribution from Health Canada s Health Care Strategies and Policy, federal, provincial and territorial partnership grant program. CCOHTA takes sole responsibility for the final form and content of this report. The statements, conclusions and views expressed herein do not necessarily represent the view of Health Canada or any provincial or territorial government. ISSN (online only)