Carfilzomib is an oral second-generation proteasome inhibitor with a mechanism of action that may increase efficacy and reduce adverse effects currently associated with proteasome inhibitor therapy. It is being investigated for use in multiple myeloma and select solid tumors, and the FDA has granted the agent Fast Track status for an indication in relapsed or refractory multiple myeloma. A decision on approval is expected by the end of July 2012.
Ubiquitin–Proteasome Pathway
Proteasomes are large protein complexes in nucleated cells that are responsible for degrading intracellular proteins. Protein degradation is necessary to provide amino acids for new protein synthesis and to remove excess enzymes and transcription factors (proteins that bind sequences of DNA to mediate transfer of genetic information from DNA to mRNA) from the cell.
For proteins to be recognized by the proteasome, they must first be attached to the polypeptide ubiquitin—a process performed by a series of enzymes. Inside the 20S core particle of the 26S proteasome, a target for inhibitors like carfilzomib and bortezomib (Velcade), the proteins are broken down by proteases at three enzymatic sites with chymotrypsin-like (β5), trypsin-like, and caspase-like activities; the chymotrypsin-like activity of the proteasome is most sensitive to deactivation.
This ubiquitin-proteasome pathway is a major mechanism (along with the lysosomal pathway) for maintaining protein homeostasis through protein degradation, and cancer cells appear to be highly dependent on this pathway. Inhibition of the proteasome’s activities can result in buildup of ubiquitinated proteins and disruption of signaling pathways; proteasome inhibitors have been shown to thereby inhibit cell-cycle progression, increase stress response (eg, incorrect formation of proteins), and induce apoptosis.
Comparison with Bortezomib
The proteasome inhibitor bortezomib is approved for treatment of multiple myeloma, as well as treatment of mantle cell lymphoma in patients who have received at least one prior treatment. Resistance to bortezomib has been encountered and—although the precise mechanisms have yet to be elucidated—may be related to the characteristics of this drug as a slowly reversible inhibitor of proteasome activity.
Unlike bortezomib, carfilzomib exhibits mechanistically irreversible inhibition, with new protein synthesis being required for recovery of proteasome activity. Although carfilzomib and bortezomib have similar onset of inhibitory effect, that of carfilzomib is more sustained.
In addition to targeting the chymotrypsin-like β5 protease in the 20S proteasome, these agents target the correlated LMP7 (or β5i) protease in the immunoproteasome 20Si—a specialized proteasome that appears to be preferentially expressed in multiple myeloma. Carfilzomib is more specific than bortezomib, exhibiting little off-target activity, whereas bortezomib is known to interact with proteases other than target proteases.
Carfilzomib appears to be associated with less peripheral neuropathy than bortezomib, the use of which is limited in many patients due to this adverse effect. It is speculated that the lesser frequency of peripheral neuropathy with carfilzomib may be related to its greater specificity, as well as its irreversible binding. The amount of proteasomal inhibition with either carfilzomib or bortezomib does not appear to be correlated with neuropathic effect, suggesting that neuropathy may not be a class effect of proteasome inhibitors.
Prolonged Treatment Tolerated
The largest experience to date with carfilzomib is an open-label phase IIb trial conducted by the Multiple Myeloma Research Consortium (MMRC), which showed that single-agent carfilzomib can induce durable responses in heavily pretreated patients for whom multiple chemotherapy regimens—including those containing bortezomib and immunomodulatory agents—have failed.1 Carfilzomib was given at 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 every 28 days in cycle 1, and then escalated to 27 mg/m2 on the same schedule thereafter for up to 12 cycles. An important finding was that even patients with baseline neuropathy tolerated prolonged treatment with carfilzomib with minimal risk of worsening.
The trial included 266 patients with refractory multiple myeloma who had received at least two prior therapies including bortezomib, either thalidomide (Thalomid) or lenalidomide (Revlimid), and an alkylating agent. Patients had undergone a median of five prior lines of therapy, and at least two bortezomib-containing regimens had failed in most.
Patients had an overall response rate of 24%, with a median duration of response of 7.4 months; responses included complete response in 0.4% of patients, very good partial response in 4.7%, partial response in 19%, and minimal response in 12%, with stable disease for at least 6 weeks being achieved in an additional 32%. The most common adverse events of grade 3 or higher were thrombocytopenia in 22% of patients, anemia in 20%, lymphopenia in 10%, pneumonia in 8%, fatigue in 7%, and hyponatremia and hypercalcemia in 5% each. Analysis in the 77% of patients who had grade 1 or 2 peripheral neuropathy at baseline showed that preexisting neuropathy did not affect tolerability of or response to carfilzomib. Neuropathy of higher than grade 3 occurred in less than 1% of patients.
A parallel MMRC study evaluated carfilzomib at doses of 20 mg/m2 (n = 54) and 27 mg/m2 (n = 19) in patients with relapsed multiple myeloma who were bortezomib-naive.2-4 Overall response rates were 46% and 53%, respectively, in the lower and higher dose groups; overall, median duration of response was 8.8 months. The most common grade 3 or higher adverse events were thrombocytopenia (9%), fatigue (9%), neutropenia (7%), lymphopenia (7%), anemia (5%), pneumonia (5%), and hyperglycemia (5%). Increased creatinine occurred in five patients (16%), with treatment discontinued in one patient due to this adverse event.
Favorable Side-effect Profile
An analysis in 136 patients in these two phase II studies indicated that peripheral neuropathy occurred in 15% of patients and was attributed to carfilzomib in 9%.5 Grade 3 or higher peripheral neuropathy occurred in 2%, and grade 1 or 2 paresthesias and dysesthesias occurred in 7%. None of the patients required discontinuation or dose adjustments due to neurotoxicity. These data appear to establish a favorable side-effect profile of carfilzomib with regard to neuropathy, with no major dosing modifications appearing to be required even in patients with preexisting neuropathy.
It is of interest that an analysis of the two phase II trials in multiple myeloma indicate that an increase in alkaline phosphatase from baseline, most evident during the second cycle of carfilzomib treatment, appears to be associated with response to treatment.6 It is thus possible that this widely available test could be used to predict response to carfilzomib treatment.
Recent Data
At the 2011 Annual Meeting of the American Society of Hematology (ASH), more recent data were presented on carfilzomib. The final results of a phase I/II study of front-line therapy with carfilzomib, lenalidomide, and low-dose dexamethasone in multiple myeloma showed the combination to be highly active and well tolerated in patients with newly diagnosed multiple myeloma.7 Responses were rapid and improved over time, achieving a 100% very good partial response rate. The investigators noted that their results compared favorably to the best front-line regimens in multiple myeloma.
Another study reported at the recent ASH meeting assessed the combination of carfilzomib with thalidomide and dexamethasone as induction therapy prior to high-dose melphalan in newly diagnosed multiple myeloma patients.8 The regimen achieved an 84% response rate in this phase II trial. The investigators called the therapy “feasible and effective,” but noted that longer follow-up is required for major conclusions.
Ongoing Trials
Carfilzomib is currently being evaluated in two phase III clinical trials. The ASPIRE trial is an international trial evaluating the safety and efficacy of carfilzomib in combination with lenalidomide and low-dose dexamethasone vs lenalidomide and low-dose dexamethasone alone in patients with relapsed multiple myeloma. The FOCUS trial is a study of single-agent carfilzomib in relapsed and refractory multiple myeloma designed to support a regulatory filing in Europe. In addition to ongoing studies in patients with multiple myeloma, carfilzomib is being evaluated in a phase Ib/II study in patients with advanced solid tumors. ■
References
1. Siegel D, Martin T, Wang M, et al: Results of PX-171-003-A1, an open-label, single-arm, phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma. Blood 116:Abstract 985, 2010.
2. Wang L, Siegel D, Kaufman JL, et al: Updated results of bortezomib-naïve patients in PX-171-004, an ongoing open label, phase II study of single agent carfilzomib in patients with relapsed or refractory MM. Blood 114:Abstract 302, 2009.
3. Siegel D, Wang L, Orlowski RZ, et al: PX-171-004, an ongoing open label phase II study of single agent carfilzomib in patients with relapsed or refractory MM; updated results from the bortezomib treated cohort. Blood 114:Abstract 303, 2009.
4. Vij R, Siegel DS, Kaufman JL, et al: Results of an ongoing open label, phase II study of carfilzomib in patients with relapsed and/or refractory MM. J Clin Oncol 28(15 suppl):Abstract 8000, 2010.
5. Vij R, Wang L, Orlowski, et al: Carfilzomib, a novel proteasome inhibitor for relapsed or refractory multiple myeloma, is associated with minimal peripheral neuropathic effects. Blood 114:Abstract 430, 2009.
6. Zangari M, Polavaram L, Zhan F, et al: Alkaline phosphatase variation during carfilzomib treatment is associated to best response in multiple myeloma. Blood 114:Abstract 2865, 2009.
7. Jakubowiak AJ, Dytfeld D, Vesole DH, et al: Final results of a frontline phase 1/2 study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in multiple myeloma (MM). 53rd American Society of Hematology Annual Meeting. Abstract 631. Presented December 11, 2011.
8. Sonneveld P, Hacker E, Zweegman S, et al: Carfilzomib combined with thalidomide and dexamethasone (CARTHADEX) as induction treatment prior to high-dose melphalan in newly diagnosed patients with multiple myeloma. A trial of the European Myeloma Network. 53rd American Society of Hematology Annual Meeting. Abstract 633. Presented December 12, 2011.
