FDA Approval for Dasatinib
Brand name(s): Sprycel®
- Approved for Chronic Phase Philadelphia chromosome-positive Chronic Myelogenous Leukemia (CP-CML)
- Approved for Chronic Phase (CP) Chronic Myelogenous Leukemia (CML) with resistance or intolerance to prior therapy
- Approved for Chronic Myelogenous Leukemia (CML) and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (ALL) with resistance or intolerance to prior therapy
- Drug Warning Issued
Chronic Phase Philadelphia chromosome positive Chronic Myelogenous Leukemia (CP-CML)
On October 28, 2010, the Food and Drug Administration (FDA) granted accelerated approval to dasatinib (Sprycel, made by Bristol-Myers Squibb), an orally administered kinase inhibitor, for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase (CP-CML). The recommended dasatinib dose for this indication is 100 mg orally once daily. Sprycel was originally approved in June 2006 for the treatment of adult patients with CP-CML resistant or intolerant to prior therapy that included imatinib.
The efficacy and safety of dasatinib in adults with newly diagnosed CP-CML were demonstrated in a single randomized active-control open-label multinational clinical trial. Five hundred and nineteen patients were randomly assigned to receive either dasatinib 100 mg once a day (n = 259) or imatinib 400 mg once a day (n = 260). The primary objective was to compare the rate of confirmed complete cytogenetic response (CCyR) by 12 months between the two treatment groups. Confirmed CCyR was defined as a CCyR noted on two consecutive occasions at least 28 days apart. The rate of major molecular response (MMR) at any time was a secondary endpoint. MMR was defined as BCR-ABL ratios less than 0.1 percent by RQ-PCR in peripheral blood samples standardized on the International Scale.
The primary efficacy endpoint, rate of confirmed CCyR by 12 months, was achieved in 199 patients treated with dasatinib (76.8 percent) and in 172 patients (66.2 percent) treated with imatinib (p = 0.007). The rate of MMR at any time was also higher in patients treated with dasatinib (52.1 percent) than in patients treated with imatinib (33.8 percent; p < 0.0001).
Seventy-one percent of patients treated with dasatinib, compared with 78 percent of patients treated with imatini,b experienced at least one adverse drug reaction. Overall incidences of grade 3-4 toxicity were 7.8 percent among patients treated with dasatinib compared with 7.0 percent among patients treated with imatinib. Common adverse reactions reported more frequently by patients treated with dasatinib than patients treated with imatinib include anemia, cough, dyspnea, headache, neutropenia, pleural effusion, and thrombocytopenia.
Chronic Phase (CP) Chronic Myelogenous Leukemia (CML) with resistance or intolerance to prior therapy, including imatinib mesylate
On November 8, 2007, the FDA granted accelerated approval of a new dosing regimen of dasatinib for the treatment of adults with chronic phase (CP) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy, including imatinib mesylate.
The new dosing regimen is 100 mg taken orally once daily. The FDA had previously granted accelerated approval to dasatinib in June 2006 for the treatment of adults with CP, accelerated phase, or myelogenous or lymphoid blast phases of CML with resistance to or intolerance to prior therapy, including imatinib mesylate. In June 2006, the FDA also granted regular approval for the treatment of patients with Philadelphia positive acute lymphoblastic leukemia. The recommended dosing regimen in the 2006 approval was 70 mg twice daily.
A randomized, 2x2, open-label study evaluated the safety and efficacy of four dosing regimens of dasatinib in patients with CP CML. Dasatinib was administered at a dose of 100 mg once daily, 140 mg once daily, 50 mg twice daily or 70 mg twice daily. Patients with significant cardiac disease were excluded from the study. A total of 670 patients were randomized. The primary endpoint was major cytogenetic response (MCyR), defined as elimination or substantial diminution (by at least 65 percent) of Ph+ hematopoietic cells.
The primary analysis showed comparable efficacy for the 100 mg once daily schedule (MCyR=53 percent, 95 percent CI: 44 percent-62 percent) and the 70 mg twice daily schedule (MCyR=51 percent, 95 percent CI: 42 percent-60 percent).
Safety analyses revealed a reduction in adverse reactions with the 100 mg once daily dose regimen compared with the previously approved 70 mg twice daily regimen. These adverse events included fluid retention all grades (24 percent vs. 32 percent), pleural effusion all grades (10 percent vs. 18 percent), and grade 3/4 hematologic toxicities, including neutropenia (34 percent vs. 43 percent), thrombocytopenia (22 percent vs. 38 percent), and anemia (10 percent vs. 17 percent).
Submission of further follow-up data from ongoing studies will convert this accelerated approval to regular approval.
Chronic Myelogenous Leukemia (CML) and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (ALL) in patients resistant or intolerant to prior therapy
On June 28, 2006, the U.S. Food and Drug Administration (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 myelogenous or lymphoid blast (MB or LB) phase chronic myelogenous 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.
Drug Warning Issued
On October 11, 2011, the FDA notified healthcare professionals that dasatinib may increase the risk of a rare but serious condition in which there is abnormally high blood pressure in the arteries of the lungs (pulmonary arterial hypertension [PAH]). Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs). In reported cases, patients developed PAH after starting dasatinib, including after more than one year of treatment.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.