Cancer Medications : Rituxan, Sprycel

by National Cancer Institute

(Page 13 of 18)

Rituxan

On February 10, 2006, the FDA granted approval to rituximab (Rituxan, made by Genentech and Biogen-Idec) for use in the first-line treatment of patients with diffuse large B-cell, CD20-positive, non-Hodgkin's lymphoma in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

Safety and efficacy were demonstrated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1,854 patients. These trials enrolled primarily patients with diffuse large B-cell lymphoma who had not received prior therapy.

Two of the three studies (E4494 and LNH 98-5/GELA) were restricted to patients 60 years of age or greater, while the third (M39045/MiNT) enrolled patients between ages 18 and 60 years. In E4494 and LNH98-5, the majority of patients had stage III-IV disease, while the majority had stage I-II disease in M39045. Patients received rituximab 375 mg/m2 by differing schedules in combination with CHOP or other anthracycline-based chemotherapy regimens (R-CHEMO).

Each study utilized composite time-to-event endpoints, incorporating disease progression events as the main outcome measure and included overall survival among secondary analyses. Determination of the primary endpoint was based upon investigator-assessment.

In each study, hazard ratios for the main outcome measures favored the rituximab-containing arms. In addition, each study showed an overall survival benefit among patients receiving rituximab. With two years of follow-up, more patients were alive by Kaplan-Meier estimates in the rituximab-containing versus control arms for each study as follows: 74 percent vs. 63 percent, 69 percent vs. 58 percent, and 95 percent vs. 86 percent.

In one of the studies, five-year data were available and demonstrated that the survival advantage persisted with estimated five-year survival rates of 58 percent vs. 46 percent for R-CHOP and CHOP, respectively. Results were generally consistent across subgroups, including age, gender and disease prognostic variables.

There was neither additional improvement in progression-free survival nor overall survival for patients in E4494 receiving R-CHOP who were subsequently randomized to additional rituximab after achieving a complete or partial response as compared to those who received R-CHOP alone.

In all three studies, the dose intensity for rituximab in the R-CHOP and R-CHEMO induction arms was high and rituximab treatment was not associated with a reduction in the dose intensities of individual chemotherapy components.

Adverse events associated with rituximab were generally consistent with the labeled adverse reactions described for single-agent rituximab. Grade 3/ 4 adverse events occurring with ≥ 2 percent excess in the rituximab arm in at least one study included infection, thrombocytopenia, and lung toxicity/dyspnea.

The following serious adverse reactions, some with fatal outcomes, have been reported in patients receiving rituximab: severe or fatal infusion reactions, tumor lysis syndrome, severe mucocutaneous reactions, hepatitis B reactivation with fulminant hepatitis, other viral infections, hypersensitivity reactions, cardiac arrhythmias, renal (kidney) toxicity, and bowel obstruction and perforation.

Sprycel

On June 28, 2006, the FDA granted accelerated approval to dasatinib (Sprycel™, made by Bristol-Myers Squibb) for use in the treatment of adults with chronic phase (CP), accelerated phase (AP), or myeloid or lymphoid blast (MB or LB) phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy, including imatinib mesylate (Gleevec®). Submission of further follow-up data from ongoing studies will convert this accelerated approval to regular approval.

In addition, the FDA granted regular approval to dasatinib for use in the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

Efficacy was demonstrated in four single-arm studies. A total of 445 patients were treated with dasatinib at a starting dose of 70 mg twice daily. Median times from initial diagnosis were 64, 91, and 49 months in CP, AP, and MB patients, respectively, and 28 and 20 months in LB and Ph+ ALL patients, respectively.

The patient population was extensively pre-treated. Prior treatment included imatinib, chemotherapy, interferon, hydroxyurea and/or anagrelide, and bone marrow transplantation. Imatinib was discontinued in 82 percent of patients because of resistance; 18 percent discontinued imatinib because of drug intolerance. The maximum imatinib dose was 400 - 600 mg/day in approximately 50 percent of patients and > 600 mg/day in the remaining patients.

The primary efficacy endpoint in CP studies was major cytogenetic response, defined as elimination or substantial diminution (by at least 65 percent) of Ph+ hematopoietic cells. The major cytogenetic response rate in CP patients was 45 percent (95 percent CI: 37 percent, 52 percent).

Primary endpoints in AP, MB, and LB /Ph+ ALL studies were hematologic responses. Major hematologic response was defined as either a complete hematologic response or no evidence of leukemia. Major hematological response rates were 59 percent (95 percent CI: 49 percent, 68 percent) in AP, 32 percent (95 percent CI: 22 percent, 44 percent) in MB, 31 percent (95 percent CI: 18 percent, 47 percent) in LB, and 42 percent (95 percent CI: 26 percent, 59 percent) in Ph+ ALL.

At the time of data cutoff, the median response duration for CP, AP, or MB phase patients could not be determined since most responding patients had remained in response. The median response duration was 3.7 months (95 percent CI: 2.79, upper limit not reached) for LB patients and 4.8 months (95 percent CI: 2.89, upper limit not reached) for Ph+ ALL patients.

The safety population included 911 patients with CML and Ph+ ALL. Gastrointestinal (diarrhea, nausea, abdominal pain, and vomiting) and constitutional (pyrexia, headache, fatigue, asthenia, and anorexia) events were the most common adverse events. Fluid retention occurred in 50 percent of patients; the most common events included superficial edema (36 percent) and pleural effusion (22 percent). Bleeding occurred in 40 percent of all patients; 14 percent of patients experienced gastrointestinal bleeding.

Hematological toxicities were the most common grade 3/4 adverse events. Neutropenia and thrombocytopenia occurred in approximately 48-83 percent of patients and anemia in 18-70 percent. These events were less common in CP patients than in advanced-stage CML or Ph+ ALL patients.

Other common grade 3/4 events included bleeding (10 percent), fluid retention (9 percent), febrile neutropenia (8 percent), dyspnea (6 percent), pyrexia (5 percent), pleural effusion (5 percent), and diarrhea (5 percent). Grade 3/4 CNS hemorrhage occurred in 1 percent of patients. Fatal CNS hemorrhage was observed in six patients.

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