Nilotinib Abstracts from the ASCO 2008 Meeting!
Nilotinib in patients with imatinib-resistant or -intolerant chronic myelogenous leukemia in chronic phase
(CML-CP): Updated phase II results.
Sub-category: Leukemia
Category: Leukemia, Myelodysplasia, and Transplantation
Meeting: 2008 ASCO Annual Meeting
Abstract No: 7010
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 7010)
Author(s): H. M. Kantarjian, F. J. Giles, A. Hochhaus, K. N. Bhalla, G. J. Ossenkoppele, N. Gattermann, A.
Haque, N. Gallagher, F. Castagnetti, P. le Coutre
Abstract: Background: Nilotinib, a potent and highly selective BCR-ABL inhibitor, has been approved in both the
US and Europe for the treatment of patients (pts) with CML-CP and accelerated phase CML (CML-AP) who are
resistant or intolerant to prior therapy, including imatinib. Methods: This phase 2, open-label study was designed to
evaluate the efficacy and safety of nilotinib in pts with Philadelphia chromosome-positive (Ph+) imatinib-resistant or -
intolerant CML-CP. Nilotinib was administered at 400 mg twice daily (BID), with the possibility to dose escalate to
600 mg BID for inadequate responses. The primary endpoint was the rate of major cytogenetic response (MCyR).
Results: Included in this analysis were 321 pts (71% imatinib-resistant; 29% imatinib-intolerant). 72% of pts received
prior imatinib doses > 600 mg. Of the 206 pts who did not have complete hematological remission (CHR) at baseline,
158 (77%) achieved CHR during nilotinib therapy. Overall, MCyR was observed in 184 pts (57%); 41% had
complete CyR. MCyR was observed in 125 (55%) of the 227 imatinib-resistant pts and in 59 (63%) of the 94
imatinib-intolerant pts. The median time to CHR and MCyR was 1.0 and 2.8 months, respectively. The majority of pts
(84%) maintained MCyR for at least 18 months. At 18 months, the estimated overall survival rate was 91%.
Treatment with nilotinib is ongoing in more than half of pts enrolled. The most frequent grade 3/4 laboratory
abnormalities were thrombocytopenia (28%), neutropenia (30%), and asymptomatic serum lipase elevation (15%).
Grade 3/4 non-hematologic AEs were rare and included rash, headache, and diarrhea. A low incidence of QT
prolongation (QTcF > 500 msec, < 1%) was observed overall. The safety profile of nilotinib has not changed with
increased follow up. There was minimal cross-intolerance between nilotinib and imatinib in pts intolerant to prior
imatinib treatment. Conclusions: The present study confirms that nilotinib induces significant and durable responses in
CML- CP pts with imatinib-resistance or -intolerance. Nilotinib is well tolerated, with minimal occurrence of grade 3/4
AEs and minimal cross-intolerance to imatinib, and is a valuable new treatment option for this pt population.
Efficacy of nilotinib (AMN107) in patients (Pts) with newly diagnosed, previously untreated philadelphia
chromosome (Ph)- positive chronic myelogenous leukemia in early chronic phase (CML-CP).
Sub-category: Leukemia
Category: Leukemia, Myelodysplasia, and Transplantation
Meeting: 2008 ASCO Annual Meeting
Abstract No: 7016
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 7016)
Author(s): J. E. Cortes, S. M. O'Brien, A. Ferrajoli, G. Borthakur, J. Burger, W. Wierda, G. Garcia-Manero, L.
Letvak, H. M. Kantarjian
Abstract: Background: Nilotinib is an oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl
approximately 30-fold more potent than imatinib effective in CML after imatinib failure. We initiated a phase II study
to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Methods: The primary
objective was to estimate the proportion of pts attaining major molecular response at 12 months (mo). Pts with
untreated CML-CP were eligible and received nilotinib 400mg twice daily. Results: Thirty-five pts have been treated
for a median of 6.5 months (mo). The median age was 47 years (yrs). The rate of complete cytogenetic response
[CCyR] at 3, 6 and 12 mo compares favorably to those observed in historical controls treated with imatinib 400mg or
800 mg daily: Major molecular response (MMR) was observed in 13% at 3 mo, 45% at 6 mo, and 45% at 12 mo.
Grade 3-4 thrombocytopenia was observed in 6% and neutropenia in 3%. Other grade 3-4 adverse events included
elevation of lipase in 9% and bilirubin in 9%. Fifteen (43%) pts had transient treatment interruptions (median 11 days)
and 14 had dose reductions. The actual median dose is 800mg daily. Thirty-two patients continue on study.
Conclusion: Nilotinib 400 mg twice induces a CCyR in nearly all patients as early as 3 months after the start of therapy
with a favorable toxicity profile. Accrual is ongoing.
Months on therapy Percent with CCyR (No. evaluable) P value
Nilotinib Imatinib 400mg Imatinib 800mg
3mo 96 (31) 37 (49) 62 (202) < 0.0001
6mo 100 (20) 54 (48) 82 (199) < 0.0001
12mo 100 (11) 65 (48) 86 (197) 0.0007
Response to nilotinib in chronic myelogenous leukemia patients in chronic phase (CML-CP) according to
BCR-ABL mutations at baseline.
Sub-category: Leukemia
Category: Leukemia, Myelodysplasia, and Transplantation
Meeting: 2008 ASCO Annual Meeting
Abstract No: 7060
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 7060)
Author(s): G. Saglio, J. Radich, D. Kim, G. Martinelli, S. Branford, M. Mueller, S. Soverini, Y. Shou, A.
Hochhaus, T. Hughes
Abstract: Background: Nilotinib is a potent and highly-selective BCR-ABL inhibitor approved in the US and
Europe for the treatment of patients (pts) with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia
(CML) in chronic phase (CP) and accelerated phase (AP) who are resistant or intolerant to prior therapy including
imatinib. Methods: This subanalysis of a phase 2 study of nilotinib in imatinib-resistant or-intolerant CML-CP pts
assessed the occurrence of baseline BCR-ABL mutations and their impact on treatment outcome following 12 months
of therapy. The BCR-ABL kinase domain (amino acid 230-490) was amplified and mutations identified by direct
sequencing that allowed for detection of > 20% minor alleles. Results: Of the 275 pts with mutation data available, 113
(41%) had BCR-ABL mutations at initiation of nilotinib therapy. Amongst imatinib-resistant patients, the frequency of
mutations at initiation was 56%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in
60%, complete cytogenetic response (CCyR) in 42%, and major molecular response (MMR) in 25% of pts without
baseline mutations, versus 50%, 32%, and 21% of pts with mutations, respectively, among the imatinib-resistant pts.
Response rates in pts with mutations of < =150 nM cellular IC50 (M244V, L248V, G250E, Q252H, E275K,
D276G, F317L, M351T, E355A, E355G, L387F, F486S) and with mutations of unknown IC50 values had
comparable response rates to those for pts without baseline mutations: MCyR were 62% and 58%, respectively, and
CCyR were 40% and 42%, respectively. For patients (n=26) with less sensitive BCR-ABL mutations (in vitro cellular
IC50 > 150 nM), MCyR was achieved in 1 of 8 pts (13%) with Y253H, 3 of 8 pts (38%) with E255K/V, and 1 of
10 pts (10%) with F359C/V. None of these patients achieved CCyR. Conclusions: A significant proportion of
imatinib-resistant pts with BCR-ABL mutations at baseline respond to imatinib. Pts with sensitive BCR-ABL
mutations exhibited response rates on nilotinib therapy comparable to those for patients with no baseline mutations.
Less sensitive mutations represented <15% of the cohort and may be associated with less favorable responses. Larger
cohort and longer follow up are required to validate these findings.
Pharmacokinetic analysis of nilotinib in Chinese chronic myelogenous leukemia (CML) patients (pts) with
imatinib-resistant or-intolerant disease in blast crisis (BC), accelerated phase (AP) or chronic phase (CP).
Sub-category: Leukemia
Category: Leukemia, Myelodysplasia, and Transplantation
Meeting: 2008 ASCO Annual Meeting
Abstract No: 18020
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 18020)
Author(s): L. Zhou, P. Hu, F. Meng, J. Wang, C. Wang, Z. Hu, Z. Shen
Abstract: Background: Nilotinib, a potent and highly selective inhibitor of BCR-ABL, has been approved in both
the US and EU for the treatment of patients with CML-CP and -AP resistant or intolerant to prior therapy including
imatinib. It has previously been suggested that Asian patients may require different dosing regimens for TKIs than that
normally recommended in Caucasian patients. We report here a pharmacokinetic (PK) analysis of nilotinib in 21
Chinese imatinib resistant or intolerant CML pts. Methods: The Expanding Nilotinib Access in Clinical Trials
(ENACT) is an ongoing global study initiated to provide expanded access to nilotinib and to obtain additional safety
information in pts with imatinib-resistant or -intolerant CML-CP, -AP, or blast crisis (-BC). In this study, nilotinib was
administered at 400 mg twice daily (BID). Pharmacokinetic parameters of nilotinib, including area under the
concentration-time curve (AUC), maximum concentration (Cmax), time to reach Cmax (Tmax), trough concentration
(Cmin), and ratio of accumulation (RA), were obtained on days 1 and 15. Results: 21 Chinese CML patients were
included in this analysis. 76% were male; mean age was 40 y (range, 19-67 y); mean body weight was 68.3 kg
(range, 48-90 kg). Cmax of nilotinib occurred between 1-12.05 h after drug administration. Mean Cmax of the first
dose of nilotinib was 638 ng/mL and occurred a median of 3h after first administration. After repeat dose of 400mg
BID for 15 days, mean Cmax was 2161 ng/mL and a Cmin of 1743 ng/mL was reached. Mean AUC was 5076.32
ng•hr/mL on day 1 and 17751.30 ng•hr/mL on day 15. Thus, the steady-state serum level of nilotinib was more than 3
times the level measured after the first dose. The steady-state mean Cmax and AUC values observed in this study
were comparable to those observed in previous studies with CML patients from other ethnic groups (Cmax=2260
ng/mL and AUC=18000 ng•hr/mL). The adverse event profile in this cohort was similar to that reported for the pivotal
phase I/II registration study. Conclusions: The recommended nilotinib dosing of 400 mg BID is appropriate and well
tolerated for Chinese patients with CML.