SKI606 is Bosutinib. Findings were presented at the most recent ASCO
conference.
Regards,
Pat Elliott
Phoenix, Arizona
http://www.ascopost.com/articles/september-2010/bosutinib-may-have-a-major-r
ole-in-cml-.aspx
Bosutinib May Have a Major Role in CML
By Alice Goodman September 2010, Volume 1, Issue 4
On the heels of the positive studies of nilotinib (Tasigna) and dasatinib
(Sprycel) as first-line therapy for chronic-phase chronic myeloid leukemia
(CML), promising results for another tyrosine kinase
inhibitor-bosutinib-were presented at the 2010 ASCO Annual Meeting. Two
separate studies reported at the meeting showed that bosutinib was effective
as second- and third-line therapy in patients for whom imatinib and other
therapies have failed.
The first study found that half of the patients who were either
imatinib-resistant or imatinib-intolerant achieved a complete cytogenetic
response (CCyR) with bosutinib.1 The second study suggested that bosutinib
was also effective as third-line therapy in chronic-phase CML, after failure
on first-line imatinib and second-line dasatinib.2
We see very good activity for bosutinib in both second- and third-line
therapy, with high levels of response," said lead author of the first study
and senior author of the second study, Jorge E. Cortes, MD, Chair of the CML
Section, Department of Leukemia at M.D. Anderson Cancer Center in Houston.
Noting that toxicity of bosutinib was acceptable in these studies, he
commented, "Bosutinib is a contender for a major role in the treatment of
CML."
Bosutinib is 30 times more potent than imatinib. This drug inhibits BCR-ABL
signaling in CML cells and is active against all imatinib-resistant
mutations, with the exception of the T315-I clone. Pfizer is sponsoring a
phase III study of bosutinib as first-line therapy for patients with newly
diagnosed chronic-phase CML. The trial is currently accruing patients.
Second-line Therapy
Dr. Cortes presented a multicenter phase I/II study in patients for whom
prior imatinib therapy failed.1 Phase I was a dose-finding study that
included 18 patients treated with bosutinib at 400, 500, or 600 mg/d. The
phase II trial included 276 patients treated with bosutinib at 500 mg/d. The
median age was 52 years, median time from diagnosis was 4 years, and
patients had been on prior imatinib therapy for a median of 2.3 years. About
70% were imatinib-resistant, and 30% were imatinib-intolerant.
At a median follow-up of almost 3 years, median duration of bosutinib
therapy was 13.7 months. Three-quarters of patients had dose interruptions,
and 45% required dose reductions. The dose of bosutinib was escalated to 600
mg in 33 patients (22%).
Of the 109 patients evaluable for best response, an overall response was
seen in 102 (94%), and complete hematologic response was observed in 99
(91%). Of the 214 patients analyzed for cytogenetic response (CyR), a major
CyR was observed in 136 (64%) and complete CyR was seen in 106 (50%). Of the
151 patients evaluated for molecular response, a major molecular response
was seen in 79 patients (51%) and a complete molecular response was seen in
49 (32%).
Response rates were higher in imatinib-intolerant patients than in
imatinib-resistant patients. Time to achieve a major CyR was about 6 months,
but responses continue to improve over time, Dr. Cortes said, and are
continuing well into the second and third years of therapy.
At 2 years, median progression-free survival (PFS) was 77% in
imatinib-resistant patients and 86% in imatinib-intolerant patients. "The
majority of patients are still alive," Dr. Cortes said.
Adverse events on treatment included diarrhea in 84% (grade 3/4, 9%), rash
in 34% (grade 3/4, 9%), nausea in 44% (grade 3/4, 2%), and vomiting in 36%
(grade 3/4, 3%). Fluid retention was uncommon, and pleural effusion occurred
in 3%. The rates of grade 3 or 4 myelosuppression were as follows:
thrombocytopenia, 24%; neutropenia, 16%; and anemia, 12%.
Third-line Therapy
A related poster focused on third-line therapy with bosutinib.2 The poster,
presented by Hanna J. Khoury, MD, Winship Cancer Institute at Emory
University in Atlanta, showed that bosutinib was effective and well
tolerated as third-line therapy in 90 patients with chronic-phase CML in
whom both first-line imatinib and second-line dasatinib had failed. In
imatinib- and dasatinib-resistant patients, a complete CyR was reported in 6
(22%) of 27 evaluable patients, a complete hematologic response was reported
in 18 (86%) of 21 evaluable patients, and a major molecular response was
observed in 6 (27%) of 22 evaluable patients. Cytogenetic and molecular
response rates were higher in the 23 patients who were on study due to
intolerance to imatinib or dasatinib.
The starting dose of bosutinib was 500 mg/d, with escalation to 600 mg if
required. Median duration of treatment was 6.1 months in this ongoing phase
II trial. Thus far, 3 patients have died and 14 have had disease
progression. With a fo
