Division of Oncology Drug Products, Center for Drug Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland, USA

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1 The Oncologist FDA Commentary Velcade : U.S. FDA Approval for the Treatment of Multiple Myeloma Progressing on Prior Therapy ROBERT C. KAE, PETER F. BROSS, A T. FARRELL, RICHARD PAZDUR Division of Oncology Drug Products, Center for Drug Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland, USA Key Words. Multiple myeloma Bortezomib Velcade Accelerated approval The views expressed are independent work and do not necessarily represent the views and findings of the U.S. FDA. LEARIG OBJECTIVES After completing this course, the reader will be able to: 1. Discuss the rationale and requirements for accelerated cancer drug approval by the U.S. Food and Drug Administration (FDA). 2. Identify the current indications for the use of a recently approved agent, bortezomib (Velcade, PS-341), in the treatment of multiple myeloma. 3. Describe the plans for the further clinical development of this agent as part of accelerated approval by the FDA. 4. Explain the mechanism of action of bortezomib and its role in cancer treatment. CME Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com ABSTRACT Bortezomib (formerly PS-341), a promising new drug for the treatment of multiple myeloma, recently received accelerated approval from the U.S. Food and Drug Administration (FDA) for the therapy of patients with progressive myeloma after previous treatment. Two phase II studies of bortezomib used the same schedule of twice-weekly i.v. dosing for the first 2 weeks of each 3-week cycle. In a randomized study of 54 patients, two doses were compared (1.0 and 1.3 mg/m 2 ) and objective responses occurred at both dose levels (23% versus 35%), including one complete response in each arm. In the other phase II study, 202 heavily pretreated patients (median of six prior therapies) all received the same schedule at 1.3 mg/m 2. Of 188 evaluable patients, complete responses occurred in five (3%) and partial responses occurred in 47 (25%). The median duration of response was 365 days. The most clinically relevant adverse events were asthenic conditions, nausea, vomiting, diarrhea, thrombocytopenia, and a peripheral neuropathy that often was painful. This report highlights the FDA analysis supporting the accelerated approval. The Oncologist 2003;8: Correspondence: Robert C. Kane, M.D., F.A.C.P., U.S. FDA, HFD-150, 5600 Fishers Lane, Rockville, Maryland 20857, USA. Telephone: ; Fax: ; kaner@cder.fda.gov Received September 18, 2003; accepted for publication October 14, AlphaMed Press /2003/$12.00/0 The Oncologist 2003;8:

2 509 Velcade Approved for Multiple Myeloma ITRODUCTIO On May 13, 2003, the U.S. Food and Drug Administration (FDA) granted accelerated approval for bortezomib (formerly PS-341), Velcade for Injection (Millenium Pharmaceuticals, Inc.; Cambridge, MA), for use as a single agent for the treatment of patients with multiple myeloma after two prior therapies and progressing on their most recent therapy. In 1998, Millennium Pharmaceuticals, Inc., submitted an Investigational ew Drug Application for bortezomib and in January, 2003, a ew Drug Application (DA) was filed. At the time of the DA submission, melphalan, cyclophosphamide, and carmustine had been FDA approved for myeloma treatment, and pamidronate and zoledronate were approved for reducing skeletal-related events. This commentary reports on the supporting data, the review process, and the standards of evidence employed in the approval of bortezomib. BACKGROUD The clinical development of bortezomib (Fig. 1) followed preclinical observations of its ability to inhibit reversibly the proteolytic (chymotryptic) activity of the proteasome complex in mammalian cells. Inhibition of the intracellular protein degradation pathway (proteasome) alters the levels of numerous intracellular signaling and regulatory proteins as well as other proteins and, in some fashion, then alters the regulation of cellular processes that may lead to growth arrest or apoptosis. Recovery of proteasome activity was nearly complete by hours following bortezomib dosing in preclinical models. At present, the relationship between these or other intracellular effects of bortezomib and the clinical results is uncertain. In the future, pharmacodynamic correlations (proteasome inhibition and/or other proteomic measures) in patients may provide more accurate dosing than the current toxicity end points. CLIICAL DEVELOPMET Criteria to Assess Efficacy of Bortezomib in Multiple Myeloma To describe the effect of bortezomib therapy in myeloma, we examined different systems of classifying response to therapy for myeloma patients. Earlier studies of myeloma variously described treatment benefits as responses, improvements, remissions, and plateaus to refer to reductions in the percent of the monoclonal myeloma protein (M-protein component, paraprotein) or its production rate in serum or urine, marrow plasmacytosis, or immunoglobulin levels. After the introduction of VAD (vincristine, doxorubicin, dexamethasone) chemotherapy and, more recently, with high-dose/stem cell transplant therapy, complete responses have been reported. The original Southwest Oncology Group (SWOG) criteria [1] for objective response ( remission ) required: a decrease in the synthetic index of the serum M-protein component of 75% or more and to <25 g/l, usually measured by serum protein electrophoresis (SPEP); a decrease in urinary light chain excretion of 90% or more and to <200 mg/24 hours; improvements in bone pain and performance status; no increase in bone lesions, and no hypercalcemia. The SWOG classification did not distinguish a complete response category, since it was not considered achievable. To reflect more effective therapy and to provide more consistency, a new system of classifying treatment responses in multiple myeloma has been introduced by an international committee representing the European Group for Blood and Marrow Transplantation, the Autologous Blood and Marrow Transplant Registry, and the International Bone Marrow Transplant Registry the Blade criteria [2]. For a complete response (CR), the Blade criteria require: disappearance of the monoclonal protein in serum and urine by immunofixation electrophoresis (IFE), reconfirmed 6 weeks later (two samples); a bone marrow aspiration (and bone biopsy, if performed) showing less than 5% plasma cells; no increase in bone lesions, and disappearance of any plasmacytomas. A Blade partial response (PR) is defined by: at least a 50% reduction in the level of the serum monoclonal protein, reconfirmed 6 weeks later; reduction in 24-hour urinary light chain excretion by 90% and to <200 mg/24 hours, also sustained for 6 weeks; no increase in bone lesions, and at least a 50% reduction in soft tissue plasmacytomas. In summary, paraprotein response requires both a magnitude and a duration of reduction. Relapse and progressive disease criteria are also described. We chose to report our analysis of bortezomib efficacy using the Blade as well as the SWOG criteria. In applying these criteria, our review process included examining the case report forms, laboratory results including electrophoresis patterns, and reports of the sponsor s independent review committee. For the complete responders, we also examined the bone marrow aspirate and biopsy slides obtained pre- and posttreatment. Response to therapy can be a surrogate marker for clinical benefit such as symptomatic improvement or extended survival. Among the many factors that may influence the relationship between tumor response to a therapy and patient survival, some measurable ones are the kinetics of tumor cell growth, type and toxicities of therapy, use of subsequent therapy, proportion of responding patients, assays used to assess response, statistical methods of analysis, length of follow-up, and duration of disease control. In myeloma, the relationship between response, that is, cytoreduction, as

3 Kane, Bross, Farrell et al. 510 measured by the various response indices noted above, and survival prolongation remains uncertain [3]. Following VAD therapy [4], CRs, based on various criteria, were described in up to 25% of patients, but these CRs did not convey longer survival than lesser degrees of response using SWOG criteria [5]. Achieving a plateau phase (stable disease) has also been suggested to confer benefit similar to that of responders [6]. The traditional evaluation of myeloma treatment has relied heavily on measurements of the myeloma paraprotein, one of the earliest biomarkers in clinical oncology. One problem with use of the protein biomarker is that its level cannot be assumed to predict the myeloma tumor mass throughout the course of the disease process. Another variable is the sensitivity of the assay technique. IFE, a more recent assay method, is a more sensitive indicator [7] of M-protein component disappearance than SPEP but has not consistently been used to determine CR status; both may eventually be replaced by polymerase chain reaction-based assays for residual disease following therapy [8]. As progressively more sensitive assays of the biomarker protein are employed in assessing response, longer durations of benefit may be reflecting greater magnitudes of cytoreduction achieved following treatment. Early efforts to link response to clinical benefits such as survival [9] were flawed by the use of invalid statistical methods and trial designs to compare the survival rate of responders with that of nonresponders. Various suggestions have been proposed to address this, such as the Mantel-Byer or landmark time analysis [10] or the nonparametric method of Simon and Makuch [11]. Survival benefits are usually the primary end points of current phase III comparative trial designs in which all patients receiving one therapy are compared with those receiving an alternative treatment. With this study design, interim demonstration of superiority in response rate and time to progression over standard therapy using objectively defined response and progression end points can provide a high degree of credibility of clinical benefit and is likely to predict a survival advantage as well. Following transplantation for myeloma, CRs have been reported to convey prolonged disease control [12, 13]. In the report of Attal et al. [12], newly diagnosed patients with myeloma were prospectively randomized to receive either conventional chemotherapy or autologous transplantation. A 1-year (after diagnosis) landmark analysis procedure was used to show a survival advantage for complete responders. More recently, patients who achieved a CR with negative IFE results were reported to have a survival advantage over those with positive IFE results or partial responders [7]. Phase I Results Phase I studies tested weekly and twice-weekly i.v. bolus (3-5 seconds) schedules for 2-4 weeks (Table 1). Toxicity patterns paralleled the preclinical findings. Hypotension and syncope occurred as higher weekly single doses approached 2.0 mg/m 2 [14]. Diarrhea and neuropathy were the dose-limiting toxicities (DLTs) with a schedule of twice-weekly treatment for 2 weeks followed by 1 week without treatment in each 3-week cycle [15]. Dosing twice weekly for 4 weeks out of 6 established a lower maximum-tolerated dose (MTD), 1.04 mg/m 2, with DLTs of hyponatremia, hypokalemia, and malaise [16]. During phase I trials, some pharmacokinetic studies were completed. The mean elimination half-life of bortezomib after the first dose ranged from 9-15 hours at doses ranging from mg/m 2 in patients with advanced malignancies. The pharmacokinetics of bortezomib as a single agent have not been fully characterized at the recommended dose in multiple myeloma patients. In vitro studies indicate that bortezomib is primarily oxidatively metabolized via multiple cytochrome P450 enzymes. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several inactive metabolites. The effects of age, gender, race, hepatic impairment, and renal impairment on the pharmacokinetics of bortezomib have not been evaluated. Table 1. Phase I and II clinical studies reviewed by the FDA in the approval of bortezomib Study Phase n Bortezomib dose (mg/m 2 ) Schedule Cycle Results (mg/m 2 ) Papandreou et al. [14] I Weekly 4 6 weeksmtd = 1.6* Aghajanian et al. [15] I Twice weekly 2 3 weeksmtd = 1.3* Orlowski et al. [16] I Twice weekly 4 6 weeksmtd = 1.04 Jagannath et al. [17] II or 1.3 Twice weekly 2 3 weeks Richardson et al. [18] II Twice weekly 2 3 weeks *In the publication of this study, the MTD of 1.56 mg/m 2 is suggested. However, Millennium Pharmaceuticals, Inc. and the principal investigator have verified the MTD as shown here.

4 511 Velcade Approved for Multiple Myeloma Phase II Results Two phase II multicenter studies (Table 1), with a total of 256 patients with multiple myeloma, comprised the efficacy population for the FDA analysis. All patients had received at least one prior treatment and were considered to have progressed on their most recent regimen. Each study used the same schedule of twice-weekly i.v. bolus dosing of bortezomib for 2 weeks (days 1, 4, 8, and 11) each 21 days for up to eight cycles, with an extension study for continuing responders. In the smaller study reported by Jagannath et al. [17], 54 patients were prospectively randomized to receive either 1.0-mg/m 2 or 1.3-mg/m 2 doses following relapse from front-line therapies. Responses occurred at both dose levels (23% versus 35%, p not significant) with overlapping confidence intervals; one CR occurred at each dose level. The larger phase II study [18] enrolled 202 myeloma patients on a single-arm schedule of bortezomib 1.3 mg/m 2. All had been heavily pretreated (median number of Table 2. Summary of patient population and disease characteristics from the phase II study of 202 patients [17] Patient characteristics Median age in years (range) 59 (34-84) Gender: male/female 60%/40% Race: Caucasian/African American/other 81%/10%/8% Karnofsky performance status score 70 20% Hemoglobin <100 g/l 44% Platelet count < /l 21% Disease characteristics Type of myeloma (%): IgG/IgA/light chain 60%/24%/14% Median β-2 microglobulin (mg/l) 3.5 Median creatinine clearance (ml/minute) 73.9 Abnormal cytogenetics35% Chromosome 13 deletion 15% Median duration of multiple myeloma since diagnosis in years 4.0 Previous therapy Any prior steroids, e.g., dexamethasone, VAD 99% Any prior alkylating agents, e.g., MP, VBMCP 92% Any prior anthracyclines, e.g., VAD, mitoxantrone 81% Any prior thalidomide therapy 83% Received at least two of the above 98% Received at least three of the above 92% Received all four of the above 66% Prior stem cell transplant/other high-dose therapy 64% Prior experimental or other types of therapy 44% Abbreviations: MP = melphalan and prednisone; VBMCP = vincristine, carmustine, melphalan, cyclophosphamide, prednisone. Table 3. FDA response analysis for bortezomib monotherapy from the phase II study of 202 patients [17] Response analysis (n = 188 evaluable) n (%) (95% CI) Blade criteria overall response rate (CR + PR) 52 (27.7) (21-35) CR 5 (2.7) (1-6) PR 47 (25) (19-32) SWOG clinical remission criteria 33 (17.6) (12-24) Median duration of response (Kaplan-Meier) 365 days (224-E) Abbreviations: CI = confidence interval; E = not evaluable. prior therapies was six, including high-dose/stem cell transplant therapy in almost two-thirds), and all were considered to have progressed on their most recent treatment (Table 2). The median age was 59 years, 35% had abnormal cytogenetics, and 15% had chromosome 13 deletions. The monoclonal protein class was IgG in 60%, light chain disease in 14%, and 9% were nonsecretory. In our independent review, we determined that 188 patients were eligible and evaluable for response per protocol criteria. Among those, CRs occurred in five patients (3%) and PRs occurred in 47 (25%), using the Blade criteria for an overall response rate (CR + PR) of 28%. Using the SWOG criteria independently, we confirmed clinical remissions in 17.6% (Table 3). The median time to response was 38 days (range, days) and the median response duration (CR + PR) was 365 days (range, days). The median survival time of all patients enrolled was 16 months. The response rate to bortezomib was independent of the number and type of prior therapies. There was a lower likelihood of response in patients with either greater than 50% plasma cells (20% versus 35%, p = 0.03 Fisher s exact test) or abnormal marrow cytogenetics (19% versus 35%, p = 0.047). However, the response rate in patients with chromosome 13 abnormalities (24%) did not differ from the response rate in patients without chromosome 13 abnormalities (28%). Some responders became transfusion independent, and in some, there was preliminary evidence of recovery of normal immunoglobulin synthesis. The median number of treatment cycles was six; 28% of patients received the planned dose throughout the study, while doses were reduced in 33% of patients and one or more doses were omitted in 63%. For all patients whose intended dose level was 1.3 mg/m 2, the mean actual administered dose was 1.1 mg/m 2. Adverse Events In the FDA safety review, all 228 patients in the two phase II studies who received the 1.3 mg/m 2 dose were combined for analysis (Table 4). The most commonly reported

5 Kane, Bross, Farrell et al. 512 Table 4. Most commonly reported ( 20% overall) adverse events among the 228 patients receiving the 1.3 mg/m 2 bortezomib dose (both phase II studies) Adverse event All events Grade 3 events Grade 4 events n (%) n (%) n (%) Asthenic conditions 149 (65) 42 (18) 1 (<1) ausea 145 (64) 13 (6) 0 ( Diarrhea 116 (51) 16 (7) 2 (<1) Appetite decreased 99 (43) 6 (3) 0 ( Constipation 97 (43) 5 (2) 0 ( Thrombocytopenia 97 (43) 61 (27) 7 (3) Peripheral neuropathy 84 (37) 31 (14) 0 ( Pyrexia 82 (36) 9 (4) 0 ( Vomiting 82 (36) 16 (7) 1 (<1) Anemia 74 (32) 21 (9) 0 ( Headache 63 (28) 8 (4) 0 ( Insomnia 62 (27) 3 (1) 0 ( Arthralgia 60 (26) 11 (5) 0 ( Pain in limb 59 (26) 16 (7) 0 ( Edema 58 (25) 3 (1) 0 ( eutropenia 55 (24) 30 (13) 6 (3) Paresthesia and dysesthesia 53 (23) 6 (3) 0 ( Dyspnea 50 (22) 7 (3) 1 (<1) Dizziness (excluding vertigo) 48 (21) 3 (1) 0 ( Rash 47 (21) 1 (<1) 0 ( adverse events (AEs) were: asthenic (malaise-fatigue) conditions (65%), nausea (64%), diarrhea (51%), anorexia (43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%), pyrexia (36%), vomiting (36%), and anemia (32%). Severe AEs ( grade 3 severity) included thrombocytopenia (29%), peripheral neuropathy (14%), neutropenia (15%), asthenia (11%), and anemia (9%); diarrhea, nausea, and vomiting each were 7%. The frequency and severity of diarrhea were dose dependent. erve conduction studies were performed in a small number of patients and were consistent with axonal degeneration. While improvement in neuropathy occurred after stopping bortezomib, the time course and completeness of neurologic recovery are uncertain. There was no apparent difference in the reported incidence of serious events or study discontinuation due to AEs for those patients between the ages of 51 and 65 years and those aged > 65 years. Physicians should be alert for progressive neuropathic signs and symptoms. Gastrointestinal reactions should be expected and may warrant premedication. Assuring adequate hydration also is important to reduce consequences of hypotension. Warnings, precautions, dosing, and dose adjustments for AEs are detailed in the label [19] (package insert) and should be reviewed before administration. ACCELERATED APPROVAL Bortezomib has been granted accelerated approval on the basis of evidence of an adequate rate and duration of response in a heavily pretreated patient group, albeit in a small number of patients. The FDA may grant accelerated approval [20] on the basis of a surrogate end point reasonably likely to predict clinical benefit, whereas regular or full approval requires direct confirmation of clinical benefit. Accelerated approval also requires demonstration of a meaningful therapeutic benefit to patients over existing treatments for serious or life-threatening illnesses. Where no other therapy has demonstrated efficacy in a particular disease setting, some single-arm studies have been judged sufficiently credible to allow accelerated approval. Judging the results of single-arm studies in advanced disease settings can be problematic if treatment results are modest; the FDA review process may also include presenting such findings to qualified independent consultants for outside expert opinion as to the credibility and relevance of the assertions. A recent report details the relationships among various study end points, trial designs, and FDA approval actions since 1990 [21]. Response rate and time to tumor progression are frequently utilized as surrogates for clinical benefit, but they are not synonymous with clinical benefit. Accelerated approval is a mechanism to accelerate patients access to drugs; it also carries the requirement that the applicant study the drug further, to verify and describe its clinical benefit with the expectation that the accelerated approval can be converted to full approval. These requirements may be addressed in the form of phase IV commitments agreed to by the company at the time of the accelerated approval. Thus, concurrent with accelerated approval, a clear development plan for the product should be under way. For bortezomib, the sponsor will characterize the pharmacokinetics as a single agent in O H O H Figure 1. Chemical structure of bortezomib. OH B OH

6 513 Velcade Approved for Multiple Myeloma patients with myeloma and in patients with hepatic and renal impairments. Drug-drug cytochrome interactions will be examined further, and follow-up to characterize the frequency, severity, and reversibility of the peripheral neuropathy will be undertaken. Also, new studies will compare bortezomib with dexamethasone in relapsed and in previously untreated myeloma patients. The approval letter issued by the FDA, which includes these phase IV commitments, the final product label, and the actual FDA review are available online [19]. REFERECES 1 Salmon SE, Haut A, Bonnet JD et al. Alternating combination chemotherapy and levamisole improves survival in multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol 1983;1: Blade J, Samson D, Reece D et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998;102: Durie BG. Is magnitude of initial response predictive for survival in multiple myeloma? Ann Oncol 1991;2: Samson D, Gaminara E, ewland A et al. Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma. Lancet 1989;2: Palmer M, Belch A, Hanson J et al. Reassessment of the relationship between M-protein decrement and survival in multiple myeloma. Br J Cancer 1989;59: Durie BG, Russell DH, Salmon SE. Reappraisal of plateau phase in multiple myeloma. Lancet 1980;2: Lahuerta JJ, Martinez-Lopez J, Serna JD et al. Remission status defined by immunofixation vs. electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients. Br J Haematol 2000;109: Gerard CJ, Olsson K, Ramanathan R et al. Improved quantitation of minimal residual disease in multiple myeloma using real-time polymerase chain reaction and plasmid-da complementarity determining region III standards. Cancer Res 1998;58: Alexanian R, Bonnet J, Gehan E et al. Combination chemotherapy for multiple myeloma. Cancer 1972;30: Anderson JR, Cain KC, Gelber RD. Analysis of survival by tumor response. J Clin Oncol 1983;1: Simon R, Makuch RW. A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non-responder bias. Stat Med 1984;3: Attal M, Harousseau JL, Stoppa AM et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francaise du Myelome. Engl J Med 1996;335: Levy V, Katsahian S, Fermand JP et al. High dose therapy followed by autologous stem cell transplantation or conventional chemotherapy as a first line treatment in multiple myeloma: a meta-analysis on individual patient data of randomized clinical trials with long-term follow-up [abstract]. Blood 2002;100:1556a. 14 Papandreou C, Pagliaro C, Millikan R et al. Phase I study of PS- 431, a novel proteasome inhibitor, in patients with advanced malignancies [abstract]. Proc Am Soc Clin Oncol 2000;19:738a. 15 Aghajanian C, Soignet S, Dizon DS et al. A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 2002;8: Orlowski RZ, Stinchcombe TE, Mitchell BS et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002;20: Jagannath S, Barlogie B, Berenson J et al. A phase II multicenter randomized study of the proteasome inhibitor bortezomib (VELCADE, formerly PS-341) in multiple myeloma patients relapsed after front-line therapy [abstract]. Blood 2002;100:3027a. 18 Richardson PG, Barlogie B, Berenson J et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. Engl J Med 2003;348: Velcade label [U.S. package insert]. Available online at CFR Available online at guidance/append4.pdf 21 Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 2003;21: