Nilotinib – ASH December 11, 2007
Live from Pearson Airport in Toronto, en route to Montreal…. Here is the presentation this
morning regarding Nilotinib.
This was an interesting open label study designed to test the efficacy of Nilotinib in patients who
never achieved a response to IM. The median age group was 58 years, which is a fairly close
representation of this patient population. The median time since diagnosis with CML was 58
mos, which represents a population that had had the disease for quite some time. The targeted
dose on this study was 800 mg daily and to this extent the median dose was successful and
achieved a median dose of 790mg. 170 patients had their dose interrupted and median dose
interruption was about 19 days. The results are for 320 patients who received at least 6 months of
therapy. Of the 320 patients who started the trial, 188 remain on the trial, 132 patients
discontinued the treatment. 15.9% for disease progression (consider avg length of disease
duration), 15.9% for adverse effects. 56.3% of the patients achieved a major cyto response. And
40% achieved CCR. There were 6 cardiac failure deaths on this study and at the question period,
Dr. Shah asked for clarification on why those events may have occurred. Dr. Kantarjian reported
that they are doing a “baseline” with the patients versus the “normal” population with this disease
and they will be able to report on that at another time. There have been reports of this drug being
impacted by diet and high fat content could significantly (by 80%) increase the level of the drug
in patients that could cause problems so, fasting and some diet restrictions are necessary. I am
just guessing and I could be wrong, but this may make adherent/compliant issues for patients
difficult.
Hagop M. Kantarjian, Andreas Hochhaus, Jorge Cortes, Giovanni Martinelli, Kapil N. Bhalla,
Francis J. Giles, Gert Ossenkoppele, Norbert Gattermann, Ariful Haque, Neil Gallagher, Michele
Baccarani, Phillip le Coutre. Leukemia, University of Texas M.D. Anderson Cancer Center,
Houston, TX, USA; Med. Fakultaet Mannheim, University of Heidelberg, Mannheim, Germany;
MD Anderson Cancer Center, Houston, TX, USA; Molecular Biology Unit, Institute of
Hematology and Medical Oncology, Bologna, Italy; Cancer Biology, H. Lee Moffitt Cancer
Center, University of South Florida, Tampa, FL, USA; Hematology and Medical Oncology,
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Pathology,
Free University, Amsterdam, Netherlands; Hematology, University of Dusseldorf, Dusseldorf,
Germany; Novartis, East Hanover, NJ, USA; Novartis, East Hanover, NJ, USA; Istituto di
Ematologia e Oncologia Medica "Seragnoli", University of Bologna, Bologna, Italy; Campus
Virchow Klinikum, Charite, Humboldt-Universitat, Berlin, Germany
Background: Nilotinib is a novel, selective BCR-ABL inhibitor, designed to bind the ATPbinding site of BCR-ABL protein with higher affinity than imatinib. It is more potent than
imatinib (IC50 <30 nM) against wild-type BCR-ABL and active against 32/33 imatinib-resistant
BCR-ABL mutants. Methods: This open-label study was designed to evaluate the safety and
efficacy of nilotinib in patients (pts) with Philadelphia (Ph+) imatinib-resistant or -intolerant
CML-CP. Planned nilotinib dose was 400 mg twice daily (BID) with escalation to 600 mg BID
for inadequate responses. The primary endpoint was the rate of major cytogenetic response
(MCyR) determined on the conventional intent-to-treat patient population. Cytogenetic response
(CyR) was assessed by bone marrow karyotyping ; peripheral blood FISH was used if a marrow
sample cannot be obtained. Results: This analysis includes data from 320 pts who received at
least 6 months of nilotinib therapy (70.6% imatinib-resistant; 29.4% imatinib-intolerant). The
median age was 58 years, the median duration of CML was 57.3 months, and 50.3% were males.
Treatment with nilotinib is ongoing in 188 pts (58.8%) and 132 pts (41.3%) discontinued the
treatment [51 (15.9%) for disease progression, 51 (15.9%) for adverse events (AE)]. The median
duration of nilotinib exposure was 341 (1–624) days and the median average dose intensity was
792.1 mg/d (47.9–1111.6 mg/d). The dose was escalated to 600 mg BID in only 51 pts (15.9%).
Complete hematological remission (CHR) at baseline was reported in 114 pts. Of the remaining
206 pts, 157 (76.2%) achieved CHR in 1 month. MCyR was observed in 180 pts (56.3%):
128/320 pts (40.0%) had complete cytogenetic response (CCyR). The median time to CHR and to
first MCyR was 1.0 and 2.8 months, respectively. The median duration of MCyR has not been
reached. Minor and Minimal CyR was seen in 22 (6.9%) and 42 (13.1%) patients respectively.
The most frequent Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia
(27%), neutropenia (30%), anemia (9%), and asymptomatic serum lipase elevation (15%).
Conclusion: The present study confirms nilotinib is an effective therapeutic option in CML-CP
pts with imatinib-resistance or -intolerance, with an acceptable safety and tolerability profile.
With longer follow up, cytogenetic response continues to increase and no change in safety profile
has been observed on nilotinib therapy.
Abstract #735 appears in Blood, Volume 110, issue 11, November 16, 2007
Keywords: Chronic Myeloid Leukemia|Tyrosine Kinase Inhibitor|Clinical Data