1098 Efficacy and Safety of Bosutinib (SKI-606) in Patients with Chronic Phase (CP) Ph+ Chronic
Myelogenous Leukemia (CML) with Resistance or Intolerance to Imatinib
Saturday, December 6, 2008
Hall A (Moscone Center)
Poster Board I-203
Jorge Cortes, MD1, Hagop M Kantarjian2, Dong-Wook Kim, MD, PhD3, H. Jean Khoury, MD, FACP4, Anna G.
Turkina, MD5*, Zhi-Xiang Shen, MD6*, Tim H Brummendorf, MD7*, Mammen Chandy, MD8*, Steven Arkin, MD9
and Carlo Gambacorti-Passerini, MD10*
1M.D. Anderson Cancer Center, Houston, TX
2The University of Texas M. D. Anderson Cancer Center, Houston, TX
3Hematology, St. Mary's Hospital, Seoul, South Korea
4Emory University, Atlanta, GA
5Hematology Research Center, Russia
6Rui Jin Hospital, China
7Universitäts-Klinikum Hamburg-Eppendorf, Hamburg, Germany
8Christian Medical College Hospital, India
9Wyeth Research, Cambridge, MA
10University Milano Bicocca, Monza, Italy
Bosutinib (SKI-606) is an orally bioavailable dual Src/Abl inhibitor demonstrating inhibitory activity against BCR-
Abl phosphorylation, and is 200 times more potent than imatinib but with minimal inhibition of platelet-derived
growth factor receptor (PDGFR) or c-kit. The phase I portion of this study identified a treatment dose of 500 mg
daily and showed evidence of clinical efficacy. The phase II portion of the study to investigate the efficacy and
safety of bosutinib in patients (pts) with CP Ph+ CML who have failed imatinib therapy is ongoing. Preliminary
data for 283 treated pts, median age 54 yrs (range 18 – 91 yrs) and 52% male are reported. A subset of pts
received treatment in addition to imatinib, including interferon (91 pts), dasatinib (71 pts), nilotinib (7 pts) and
stem cell transplant (13 pts). Among pts who failed imatinib (and received no other tyrosine kinase inhibitor
treatment), 137 were imatinib-resistant (all received imatinib ≥600mg) and 64 pts were imatinib-intolerant;
median duration of bosutinib treatment to date is 7.7 mos (range 0.2 – 28.2 mos) and 4.5 mos (range 0.5 –
21.5 mos), respectively. Among 67 imatinib-resistant pts evaluable for hematological response, 53 (79%) had
complete hematological response (CHR). Of 84 imatinib-resistant pts evaluable for cytogenetic response, 34
(40%), achieved a major cytogenetic response (MCyR), including 24 (29%) with a complete cytogenetic
response (CCyR). Of 34 pts with MCyR, 31 have maintained their response to date. Of 60 evaluable imatinib-
resistant pts, 20 (33%) achieved major molecular response, 10 (17%) of which were complete. Among imatinib-
intolerant pts, 22 of 29 evaluable (76%) achieved CHR, and 13 of 22 evaluable (59%) achieved MCyR,
including 11 (50%) with CCyR. Of 25 evaluable imatinib-intolerant pts, 7 (28%) achieved major molecular
response, 5 (20%) of which were complete. Of 105 pts with baseline samples tested for mutations, 17 different
mutations were found in 45 pts (43%). CHR occurred in 5/6 pts (83%) with P-loop mutations and 13/17 (76%)
with non-P-loop mutations; MCyR occurred in 3/6 pts (50%) and 11/24 pts (46%), with P-loop and non-P-loop
mutations, respectively. Treatment was generally well tolerated. The most common adverse events among
treated pts (n=283) were gastrointestinal (nausea, vomiting, diarrhea), these were usually grade 1 – 2,
manageable and transient, diminishing in frequency and severity after the first 3 – 4 weeks of treatment. Grade
3 – 4 non-hematologic toxicity occurring in ≥5% of pts were diarrhea (8%), rash (8%) and increased ALT (5%).
27 pts (10%) reported grade 1/2 fluid retention adverse events, including 21 pts with edema, and 6 pts with
effusions: 4 pleural, 1 pericardial, and 1 pleural and pericardial. A single patient experienced grade 3 pleural
effusion possibly related to bosutinib with concomitant pneumonia and a pre-treatment history of recurrent
pleural effusions. Grade 3 – 4 hematologic laboratory abnormalities included thrombocytopenia in 65 pts
(23%), neutropenia in 37 pts (13%) and anemia in 17 pts (6%). 124 pts (44%) had at least 1 temporary
treatment interruption and 85 pts (30%) had at least 1 dose reduction due to toxicity. 37 pts (13%) have
permanently discontinued treatment due to adverse event. Bosutinib is effective in pts with CP CML with
resistance or intolerance to imatinib across a range of mutations. Unlike other tyrosine kinase inhibitors,
bosutinib does not significantly inhibit PDGFR or c-kit, and this may be responsible for the relatively favorable
toxicity profile with few pts experiencing hematologic toxicity or fluid retention.
3220 Determination of the Activity Profile of Bosutinib, Dasatinib and Nilotinib against 18 Imatinib
Resistant Bcr/Abl Mutants
Monday, December 8, 2008
Hall A (Moscone Center)
Poster Board III-302
Sara Redaelli, MS1*, Rocco Piazza, MD1*, Roberta Rostagno1*, Marianna Sassone, MD1*, Vera Magistroni,
PhD1*, Pietro Perini, MS1*, Manuela Marega, MS1*, Frank Boschelli, PhD2* and Carlo Gambacorti, MD3
1Dept.Clinical Medicine and Prevention, University Milano Bicocca S.Gerardo Hospital, Monza, Italy
2Oncology, Wyeth, Pearl River, NY
3Dept.Clinical Medicine and Prevention, University Milano Bicocca S.Gerardo Hospital, Monza, Italy
The treatment of Chronic Myeloid Leukemia (CML) has been radically modified by the discovery of imatinib (IM),
a selective inhibitor of the fusion protein Bcr-Abl, the cause of the disease. A variable portion of CML patients
experience resistance to IM therapy. Resistance can arise from different mechanisms but in the vast majority of
cases is due to point mutations into the protein sequence that alter directly or indirectly the drug-protein
binding. Mutation sites can be schematically clustered in four region: the P loop, the IM binding site, the
catalytic domain and the activation loop (A loop). At present more than 70 mutations conferring different levels
of resistance have been found in CML patients. Recently, several new inhibitors have been developed in order
to obtain an increased potency and a broad range of activity against IM resistant mutants. Nilotinib (NIL) is an
IM derivative about 30-fold more potent than IM. Dasatinib (DAS) is a dual-specific Src/Abl inhibitor, structurally
unrelated to IM and characterized by an activity 100 to 300-fold higher than IM. Bosutinib (BOS) is a dual
Src/Abl inhibitor that shows an activity 10 to 30-fold higher than IM. It is known that resistance to second
generation TKIs can also arise and the analysis of mutation profiles reveals substantial differences among
different TKIs. Presently the choice of a TKI to treat a patient resistant to IM is mostly based on an empirical
basis, e.g. the fact that a certain patient has not been previously exposed to that particular TKI. The possibility
to directly compare the different activities of TKIs against a given mutation is of remarkable importance in
clinical practice. Such a tool could be used similarly to an antibiogram for bacterial diseases, guiding the choice
of the most appropriate inhibitor for each patient.
In our study, we investigated the activity of BOS, DAS, IM and NIL against a panel of 18 mutated forms of
BCR/ABL chosen to cover the most common mutations found in patients. Stable Ba/F3 transfectant cell lines
were generated and the TKIs antiproliferative activity was determined by tritiated thymidine incorporation assay.
The relative IC50 increase over wild type BCR/ABL (Relative Resistance RR) was calculated. We classified the
RR values in three categories: sensitive (RR 2), resistant (between 2.01 and 10) or highly resistant (>10) as
presented in the table.