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 follow-up of 23 months, median
overall survival was not reached in either resistant or intolerant
patients. Responses were seen in patients with common BCR-ABL
mutations, but not in those with T315I mutations. ■
References
1. Cortes JE, Kantarjian H, Brummendorf T, et al: Safety and
efficacy or bosutinib (SKI-606) in patients with chronic phase
chronic myeloid leukemia following resistance or intolerance to
imatinib. 2010 ASCO Annual Meeting. Abstract 6502. Presented June 7, 2010.
2. Khoury HJ, Kim D, Zaritskey A, et al: Safety and efficacy of
third-line bosutinib in imatinib and dasatinib resistant or
intolerant chronic phase chronic myeloid leukemia. 2010 ASCO Annual
Meeting. Abstract 6514. Presented June 7, 2010
