Cancer Medications : Nexavar, Oncaspar

by National Cancer Institute

(Page 11 of 18)

Nexavar

On December 20, 2005, the FDA granted approval for sorafenib (Nexavar® tablets, made by Bayer Pharmaceuticals Corp.), a small molecule Raf kinase and VEGF receptor kinase inhibitor, for the treatment of patients with advanced renal cell carcinoma (RCC).

This indication is based on the demonstration of improved progression-free survival (PFS) in a large, multinational, randomized double-blind, placebo-controlled phase III study and a supportive phase II study. Overall survival results from the phase III study are preliminary at this time.

The sorafenib phase III study was conducted in patients with advanced (unresectable or metastatic) renal cell carcinoma who had received one prior systemic treatment. Eligibility also included ECOG performance status (PS) 0 or 1, and MSKCC (Memorial Sloan Kettering Cancer Center) RCC prognostic risk category of low or intermediate.

Patients with brain metastases, MSKCC high risk score, or advanced cardiac conditions were not eligible. Study endpoints included overall survival, progression-free survival, and response rate.

Among 769 patients randomized, the median age was 59 years and 70 percent were male; there were approximately equal patient numbers in each arm for each category of PS and MSKCC prognostic risk category. Baseline patient and disease characteristics were well balanced. Regarding prior therapies, 93 percent had prior nephrectomies; 99 percent had received prior systemic therapies, including interleukin-2 (44 percent) and an interferon (68 percent).

PFS (time from randomization to progression or death from any cause), progression and response rate were determined by independent blinded radiologic review. The median PFS was 167 days in the sorafenib group versus 84 days in the placebo control group (HR 0.44, 95 percent CI for HR: 0.35 - 0.55), logrank p < 0.000001). Results were similar regardless of MSKCC prognostic risk category, ECOG PS, age, or prior therapy.

Time-to-progression was similarly improved. Tumor response was determined by independent radiological review according to RECIST criteria. Overall, of 672 patients who were evaluable for response, seven (2 percent) sorafenib patients and no (0 percent) placebo patients had confirmed partial responses.

Sorafenib toxicities (based on an updated phase III study database of 902 patients) included reversible skin rashes in 40 percent and hand-foot skin reaction in 30 percent. Diarrhea was reported in 43 percent, treatment-emergent hypertension in 17 percent, and sensory neuropathic changes in 13 percent.

Alopecia, oral mucositis, and hemorrhage also were reported more commonly on the sorafenib arm. The incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib group (2.9 percent) compared with the placebo group (0.4 percent). Grade 3 and 4 adverse events were unusual; only hand-foot skin reaction occurred at 5 percent or greater frequency in the sorafenib arm.

Laboratory findings included asymptomatic hypophosphatemia in 45 percent versus 12 percent and serum lipase elevations in 41 percent versus 30 percent of sorafenib versus placebo patients, respectively. Grade 4 pancreatitis was reported in two sorafenib patients, although both patients subsequently resumed sorafenib, one at full dose.

Physicians should be aware of the importance of frequent blood pressure monitoring and management, especially during the first six weeks after starting sorafenib, and the unusual laboratory alterations on sorafenib therapy.

The recommended dose is 400 mg (two 200 mg tablets) twice daily taken either one hour before or two hours after meals. Adverse events were accommodated by temporary dose interruptions or reductions to 400 mg once daily or 400 mg every other day.

Sorafenib metabolism is principally hepatic via CYP3A4 and UGT1A9 pathways. Sorafenib is an inhibitor of UGT1A1.

Oncaspar

On July 24, 2006, the FDA granted approval to pegaspargase (Oncaspar®, made by Enzon Pharmaceuticals, Inc.) for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multi-agent chemotherapy regimen. Pegaspargase was previously approved in February 1994 for the treatment of patients with ALL who were hypersensitive to native forms of L-asparaginase.

Asparaginase exerts selective antileukemia activity by depletion of serum asparagine. The current approval is based on similar sustained reductions of serum asparagine concentrations in patients receiving an pegaspargase-containing regimen compared to patients receiving a native E. coli L-asparaginase-containing regimen. Due to the longer half-life of pegaspargase, similar antileukemic activity was achieved with a single pegaspargase dose compared to six to nine doses of native E. coli asparaginase

The trial (Children's Oncology Group Study 1962) supporting this new indication was an open label, randomized, multicenter clinical trial that enrolled 118 children (ages 1-9 years) with previously untreated, standard-risk ALL. Treatment consisted of a four-week induction phase (IP) and two eight-week delayed intensification (DI) phases.

All patients received multi-agent chemotherapy regimen consisting of intrathecal cytosine arabinoside and systemic therapy with vincristine, prednisone, and methotrexate with either native E. coli asparaginase or pegaspargase during IP and intrathecal methotrexate and systemic therapy with mercaptopurine and either native E. coli asparaginase or pegaspargase during both DI phases.

Pegaspargase was administered intramuscularly at 2,500 IU/m2 on day 3 of the four-week induction phase and on day 3 of each of two eight-week DI phases. Native E. coli L-asparaginase was administered intramuscularly at 6,000 IU/m2 three times weekly for nine doses during induction and for six doses during each DI phase.

The two study arms were balanced for most major prognostic factors; however, patients allocated to receive the native E. coli asparaginase-containing chemotherapy had a higher percentage of children ages 1-2 years (34 percent vs. 19 percent), with platelet counts <50,000 cells/µl (51 percent vs. 34 percent), and with equivocal central nervous system involvement (15 percent vs. 7 percent).

The study demonstrated similar mean asparagine concentrations between the two study arms at multiple time-points during all treatment phases. Event-free survival (time from randomization to either death, induction failure, relapse at any site, or start of new cancer treatment) was assessed in all patients. With a median follow-up of 3.2 years, the three-year event-free survival rates were approximately 80 percent in both arms.

The most serious, sometimes fatal, pegaspargase toxicities were anaphylaxis, other serious allergic reactions, thrombosis (including sagittal sinus thrombosis), pancreatitis, glucose intolerance, and coagulopathy.

The most common adverse events were allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases.

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