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Figure 1 Annual Event Rates for Patients Receiving Imatinib in the IRIS Trial 8
7.5
Event: loss of CHR; loss of MCyR; AP/BC; death during treatment AP/BC
Patients with event, %
7 6 4.8
5 4
3.3 2.8
3 2
1.8
1.5
1.7
1.4 0.9
1 0
1
2
3
0.8
4
0.5
0.4
0.3
5
1.3
0
0
6
7
8
Years of receiving imatinib AP indicates advanced phase; BC, blast crisis; CHR, complete hematologic response; IRIS, International Randomised Study of Interferon versus STI571; MCyR, major cytogenetic response. Source: Reference 8.
Figure 2 The ENESTnd Trial: MMR and CCyR, by 12 Months Nilotinib 300 mg bid (n = 282)
Nilotinib 400 mg bid (n = 281)
Imatinib 400 mg/day (n = 283)
100
Patients responding to therapy, %
were rare in patients receiving either nilotinib or imatinib, and there was no clinically relevant prolongation in QT interval or decrease in left-ventricular ejection fraction in patients receiving either study drug. Lipase and amylase elevations, abnormal liver function tests, and hyperglycemia were higher in the nilotinib arms, and some of these events were grade 3/4 (≤1% to 9%). Grade 3 and 4 hematologic events that occurred any time during the study are shown in Figure 3.14 Rates of grade 3/4 anemia and thrombocytopenia in patients receiving nilotinib (4% and 4%, respectively; and 10% and 12%, respectively) were similar to those experienced by patients receiving imatinib (5% and 9%), while the rate of neutropenia was approximately half (12% and 10%, respectively, vs 20%). On June 17, 2010, the US Food and Drug Administration (FDA) granted accelerated approval to nilotinib for the treatment of adult patients with newly diagnosed chronic-phase Ph+ CML. The recommended nilotinib dose for this indication is 300 mg twice daily, orally.16
Pericardial and pleural effusion events were rare in patients receiving either nilotinib or imatinib.
P <.001 P <.001
90 80
80 70
78
P <.001
60
65
P <.001
50
44
43
40 30 22
20 10 0
MMRa
CCyR
a
First-line treatment strategies: dasatinib The Dasatinib versus Imatinib Study in Treatment-NaĂŻve CML Patients (DASISION) is a multinational study that randomized 519 patients with newly diagnosed chronic-phase CML to receive either dasatinib 100 mg/day (n = 259) or imatinib 400 mg/day (n = 260).17,18 Patients were stratified according to the Hasford risk score, with 19% of patients categorized as high risk in each arm.17-19 Note that the Hasford categorization places fewer patients in the high-risk group than does the Sokal risk score. The primary end point was the rate of confirmed CCyR at 12 months, and secondary end points included rate of MMR, time to confirmed CCyR and MMR, and duration of confirmed CCyR.17,18 Median time from diagnosis to study entry was 1 month.18 Results after a minimum followup of 12 months and a median treatment duration of 14 months were reported during an oral abstract session by Hagop Kantarjian, MD, Chair, Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston.17 Of patients receiving dasatinib, 77% had a confirmed CCyR by 12 months compared with 66% of patients receiv-
BCR-ABL transcript level â&#x2030;¤0.1% in peripheral blood on RQ-PCR assay, as expressed on the International Scale. Patients who did not undergo RQ-PCR assessment at 12 months were considered to have had no response. CCyR indicates complete cytogenetic response; MMR, major molecular response; RQ-PCR, real-time quantitative polymerase chain reaction. Source: Reference 14.
Figure 3 The ENESTnd Trial: Grade 3/4 Hematologic Toxicities Nilotinib 300 mg bid (n = 282) 25
Patients with hematologic toxicities, %
MMR at 24 months. Median time from diagnosis to study entry was 31 days. Results after a median follow-up of 18.5 months were reported during an oral abstract session by Richard Larson, MD, Director, Hematologic Malignancies Clinical Research Program, University of Chicago Medical Center, Illinois.13,14 Results for the primary end point, MMR rates at 12 months, are shown in Figure 2.13,14 The rates for nilotinib 300 mg twice daily (44%) and 400 mg twice daily (43%) were significantly higher and twice that for imatinib (22%, P <.001 for both comparisons).13 Rates of MMR at 12 months among patients with a high Sokal risk score were 41%, 32%, and 17%, respectively.14 MMR rates continued to rise, and with a median follow-up of 18.5 months, remain significantly higher for the two nilotinib arms compared with the imatinib arm (66%, 62%, and 40%, respectively; P <.001 for both comparisons).13 For patients who have had a real-time quantitative polymerase chain reaction assessment after receiving 24 months of study drug (N = 145), 86% (n = 49), 88% (n = 48), and 48% (n = 48) achieved MMR, respectively. As reported by Saglio and colleagues, after a median follow-up of 13.8 months, 50% of the intent-to-treat population had achieved MMR 8.6 (nilotinib 300 mg) and 11.0 (nilotinib 400 mg) months after randomization (median not yet achieved for patients receiving imatinib).14 As seen in Figure 2, CCyR rates by 12 months were 80%, 78%, and 65% (P <.001 for both comparisons).13,14 Also, significantly fewer patients receiving nilotinib have progressed to advanced phase or blast crisis compared with those receiving imatinib (0.7%, 0.4%, and 4.2%; P = .006 and P = .003, respectively).13 No patient who had progressed to advanced phase or blast crisis had achieved an MMR. Nilotinib and imatinib both had good safety and adverse event profiles. Overall, grade 3 or grade 4 nonhematologic adverse events were uncommon in the safety population (patients who received at least one dose of the study drug; N = 836).13,14 Rates of any grade nausea (33%), muscle spasms (26%), diarrhea (24%), and vomiting (16%) were higher for patients in the imatinib arm than for those in either nilotinib arm (12%, 7%, 8%, and 5%, 300 mg twice daily; and 20%, 6%, 6%, and 9%, 400 mg twice daily).13 Rash (32% and 37%, respectively), headache (14% and 22%, respectively), pruritus (15% and 13%, respectively), and alopecia (8% and 13%, respectively) were more common in the nilotinib arms (vs 12%, 8%, 5%, and 4%, respectively, for patients receiving imatinib).13 Fluid retention events of any grade were more common in the imatinib arm. Pericardial and pleural effusion events
Nilotinib 400 mg bid (n = 281)
Imatinib 400 mg/day (n = 283)
20
20
15 12
12 10
10
5
4
4
10
9
5
0
Anemia
Neutropenia
Thrombocytopenia
Source: Reference 14.
ing imatinib (P = .067; Figure 4).17 The MMR rate at 12 months was also significantly higher for the dasatinib arm compared with the imatinib arm (46% vs 28%, P <.001), as was the rate of an MMR at any time (52% vs 34%, P <.001). Patients receiving dasatinib also
achieved MMR earlier than did patients receiving imatinib. Considering only the patients who achieved MMR, the median time to MMR for patients receiving dasatinib was 6.3 months (vs 9.2 months for patients who achieved Continued on page 14
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