Carfilzomib (Kyprolis, Onyx Pharmaceuticals, Inc, South San Francisco, CA) is a selective proteasome inhibitor that irreversibly binds to active sites within the proteolytic core of the 26S proteasome, resulting in inhibition of proteasome activity. Preclinical studies have shown carfilzomib inhibits tumor growth and promotes tumor cell death, with sustained proteasome inhibition for more than 48 hours when using a consecutive-day dosing regimen.1-4
A series of phase 2 studies have demonstrated the clinical efficacy and safety of single-agent carfilzomib as a salvage therapy for patients with multiple myeloma (MM).5-8 An open-label, multicenter, single-arm phase 2 pilot study (PX-171-003-A0) of single-agent carfilzomib was conducted in 46 patients with relapsed and refractory multiple myeloma (RRMM) at a dose of 20 mg/m2 administered IV twice weekly for 3 weeks followed by 1 week of rest in each 28-day treatment cycle.5 In this pilot study, 7 of 42 response-evaluable patients achieved a partial response for an overall response rate (ORR) of 16.7%. The treatment was well tolerated with manageable toxicities.
Based on these findings, the study was amended (PX-171-003-A1; Clinicaltrials.gov NCT00511238) to include an expanded dosing cohort of 266 patients with RRMM employing the same dosing schedule but escalating the dose from 20 to 27 mg/m2 in the second treatment cycle.6 Results from the 003-A1 study supported the accelerated approval of carfilzomib for select patients with RRMM by the FDA in July 2012. This synopsis provides an overview of the 003-A1 study, including the design, efficacy and safety results, and briefly, its implications to the treatment of MM.
Patients and Methods
Patients with RRMM could enroll in the 003-A1 study provided they met the following eligibility criteria:
- ≥18 years old
- Measurable progressive MM, responsive to ≥1 prior regimens – at least a partial response by International Myeloma Working Group (IMWG) Uniform Response Criteria,9 or at least a minimal response by the European Group for Blood and Marrow Transplantation (EBMT) criteria10
- Refractory to their most recent therapy (ie, ≤25% response or progression either during therapy or ≤60 days after completion of therapy)
- Received ≥2 prior regimens for relapsed disease, including bortezomib, thalidomide, or lenalidomide; an alkylating agent; or an anthracycline alone or in combination
- Eastern Cooperative Oncology Group performance status 0-2
- Adequate bone marrow, liver, and kidney function
Carfilzomib was administered IV over 2 to 10 minutes on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle, for up to 12 cycles. The dose for cycle 1 was 20 mg/m2, which was escalated to 27 mg/m2 for all cycles thereafter. Oral or IV dexamethasone (4 mg) was administered prior to each carfilzomib dose during cycle 1 and during subsequent cycles as indicated.
The primary efficacy end point in the response-evaluable population (patients with both baseline and postbaseline disease assessments) was ORR (stringent complete response, complete response, very good partial response, or partial response). Secondary end points included clinical benefit response (CBR) rate (minimal response or better), duration of response (DOR), progression-free survival, overall survival (OS), and safety. Response was assessed using the IMWG criteria9 amended to include minimal response from the EBMT criteria,10 and safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) version 3.0.
From July 2008 through October 2009, 266 patients with RRMM enrolled at 30 sites in the United States and Canada. This was a heavily pretreated, high-risk population with 82% of patients having received at least 4 prior lines of therapy (Table 1). Nearly all patients (99.6%) had received prior bortezomib treatment, and all had received an immunomodulatory drug (IMiD). Bortezomib-refractory disease was common (73%), with 64% of patients refractory to both bortezomib and lenalidomide. At baseline, 38% of patients had International Staging System (ISS) stage II disease and 31% had stage III disease, and 28% had unfavorable cytogenetic or fluorescence in situ hybridization (FISH) markers. Patient age ranged from 37 to 87 years, with a median of 63 years. Renal insufficiency was prevalent, with a median creatinine clearance of 70 mL/min (range, 16-203 mL/min).
All patients received at least 1 dose of carfilzomib. Sixty-nine patients (26%) did not have their dose escalated from 20 to 27 mg/m2 after cycle 1 as planned primarily due to treatment discontinuation during cycle 1 (n=51). Thirty-one patients (12%) completed 12 treatment cycles and continued on to an extended treatment protocol (PX-171-010; ClinicalTrials.gov NCT00884312). Overall, the mean duration of treatment was 3.0 months (range, 0.03-16.9 months).
In response-evaluable patients (n=257), the ORR was 23.7% and CBR 37.0% (Table 2). The median time to best response was 1.9 months, and the median DOR was 7.8 months. Generally, there were no differences in the ORR by demographic and baseline disease characteristics, but these comparisons are subject to the limitations of subgroup analyses. The ORR was 29.6% in the subgroup with unfavorable cytogenetics/FISH (n=71) and 22.8% in the subgroup with normal/favorable cytogenetics/ FISH (n=158). The ORR was moderately lower in the subgroup with ≥2 prior lines of bortezomib-based therapy compared with the subgroup with <2 prior lines (18.5% vs 29.5%). In patients refractory to both bortezomib and lenalidomide (n=169), the ORR was 15.4%, with a median DOR of 7.8 months (95% CI, 6.7-10.1). The median OS was 15.6 months (95% CI, 13.0-19.2) in the response-evaluable population and 15.4 months (95% CI, 12.5-19.0) in the intent-to-treat population (N=266).
The safety-evaluable population comprised all 266 patients. Table 3 summarizes AEs that occurred at a rate of ≥25% for any grade or were of clinical interest. The most common hematologic AEs were anemia, thrombocytopenia, and lymphopenia with rates of 24%, 29%, and 20%, respectively, for grade 3/4 events. Generally, most hematologic events were deemed possibly or probably related to treatment.
Some nonhematologic AEs were more common than others, such as fatigue (49%) and nausea (45%), but nonhematologic AEs were usually grade 1/2 in severity and effectively managed with supportive care.
Other events of particular clinical concern in patients with RRMM were generally infrequent. The incidence of cardiac AEs was low (3.8% for congestive heart failure, 1.5% for cardiac arrest, and <1% for myocardial infarction), as was the rate of acute renal failure (5% of patients). Febrile neutropenia occurred in <1% of patients.
Despite more than three-quarters of patients (77%) having active grade 1/2 peripheral neuropathy at study entry, only 33 (12.4%) experienced new-onset or worsening of preexisting peripheral neuropathy, and only 3 (1.1%) experienced events of grade 3 in severity. There were no grade 4 events.
To manage AEs, 21.4% of patients required dose delays, 17.7% required dose reductions, and 12% discontinued treatment. AEs leading to treatment discontinuation included hypercalcemia associated with progressive disease (n=5), congestive heart failure, cardiac arrest, dyspnea, pneumonia, spinal cord compression (n=4 each), and increased serum creatinine (n=3).
Twenty-four patients (9%) died on study or within 30 days of their last dose, with 12 deaths due to disease progression, 6 deaths due to an AE deemed by investigators as unrelated to treatment, and 5 deaths due to an AE considered possibly or probably related to treatment, which included cardiac arrest (n=2), dyspnea, hepatic failure, and unknown cause (n=1 each).
Single-agent carfilzomib provided clinically meaningful and durable responses in this heavily pretreated study population with RRMM. Responses to carfilzomib were not significantly affected by most high-risk disease factors, including unfavorable cytogenetic status, older age, and higher ISS stage where rapid relapses and aggressive disease are hallmarks.11 Importantly, carfilzomib was active in patients with disease resistant to bortezomib and IMiDs, and the OS results compare favorably with historical data.12
Carfilzomib was generally well tolerated with manageable toxicities, particularly considering the treatment history and associated comorbidities of these patients. Dose reductions and discontinuations were generally limited, and no cumulative toxicities were observed in up to 12 cycles, indicating that carfilzomib administration can be extended for long-term control of MM. Thirty-one patients extended carfilzomib treatment in the PX-171-010 study, with 10 patients still on study as of July 12, 2012.
These results suggest that carfilzomib could be used in a broad range of patient populations in the relapsed and refractory disease setting, including in patients with renal impairment, unfavorable cytogenetic abnormalities, or advanced age.
Additional studies are under way to better understand the benefit of carfilzomib in RRMM, its potential role in other treatment settings (eg, frontline), and in combination with standard chemotherapy and/or targeted agents. Three phase 3 trials have been initiated, including the FOCUS study (Clini calTrials.gov NCT01302392),13 which will provide definitive efficacy and safety data on single-agent carfilzomib compared with best supportive care (corticosteroid with or without cyclophosphamide) in RRMM; the ASPIRE study, which will assess the efficacy and safety of combining carfilzomib with lenalidomide and low-dose dexamethasone in patients with relapsed MM (ClinicalTrials.gov NCT01080391); and the ENDEAVOR study (ClinicalTrials.gov NCT01568866), a head-to-head comparison of carfilzomib versus bortezomib in combination with low-dose dexamethasone in patients with relapsed MM.
Implications for Oncologists
Despite recent advances in MM therapies, patients with RRMM have a poor prognosis with a median OS of approximately 9 months.12 As bortezomib, lenalidomide, and thalidomide are now used more frequently in the frontline setting in combination with other MM therapies, there is a significant need for novel salvage therapies in patients with RRMM.14-16
Single-agent carfilzomib is a treatment option that should be considered for patients with RRMM who have received ≥2 prior lines of therapy that included bortezomib and an IMiD as single-agent regimens or in combination with other MM therapies.
- O’Connor OA, Stewart AK, Vallone M, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009;15:7085-7091.
- Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67:6383-6391.
- Alsina M, Trudel S, Furman RR, et al. A phase 1 single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res. 2012;18:4830-4840.
- McCormack PL. Carfilzomib: in relapsed, or relapsed and refractory, multiple myeloma. Drugs. 2012;72:2023-2032.
- Jagannath S, Vij R, Stewart AK, et al. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012;12:310-318.
- Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012; 120:2817-2825.
- Vij R, Siegel DS, Jagannath S, et al. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012;158:739-748.
- Vij R, Wang M, Kaufman JL, et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012;119:5661-5670.
- Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467-1473.
- Bladé 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;102:1115-1123.
- Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3-9.
- Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26:149-157.
- Hajek R, Bryce R, Ro S, et al. Design and rationale of FOCUS (PX-171-011): a randomized, open-label, phase 3 study of carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM). BMC Cancer. 2012; 12:415.
- Richards T, Weber D. Advances in treatment for relapses and refractory multiple myeloma. Med Oncol. 2010;27(suppl 1):S25-S42.
- van de Donk NW, Lokhorst HM, Dimopoulos M, et al. Treatment of relapsed and refractory multiple myeloma in the era of novel agents. Cancer Treat Rev. 2011;37:266-283.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Multiple Myeloma. Version 1.2013. www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed October 10, 2012.