Oncology · 2001
Imatinib (STI571, Gleevec) in chronic myeloid leukemia
Imatinib mesylate (signal transduction inhibitor 571)
Chronic myeloid leukemia had been understood at the molecular level for longer than almost any other cancer. The Philadelphia chromosome, a reciprocal translocation between chromosomes 9 and 22, had been identified in CML cells in 1960, and by the 1980s it was known to produce a constitutively active BCR-ABL tyrosine kinase that drove uncontrolled myeloid proliferation. The connection between a single identifiable oncogenic protein and a specific cancer made CML an attractive target for anyone attempting to design a molecule that would block the driver without broadly damaging normal cells. The concept was straightforward; the chemistry was not.
Nicholas Lydon, a medicinal chemist at Ciba-Geigy in Basel, developed STI571 as part of a program to screen compounds for kinase inhibitor activity. The compound showed potent and selective inhibition of BCR-ABL in cell lines but was initially deprioritized by the company for commercial reasons. Brian Druker at Oregon Health and Science University had been collaborating with Ciba-Geigy researchers and recognized the compound's potential; he pushed to bring it into clinical trials despite internal resistance. Phase I trials begun in 1998 showed responses that were historically unusual in their speed and completeness.
Druker and colleagues reported their findings in the New England Journal of Medicine in April 2001. Imatinib produced complete hematologic responses in 53 of 54 chronic-phase CML patients who had failed interferon alfa. Charles Sawyers contributed data from accelerated-phase and blast-crisis patients, where response rates were lower but still substantial. The FDA granted accelerated approval in May 2001, less than three months after publication, one of the fastest approvals in the agency's history at that time.
The survival data that accumulated in subsequent years altered how CML prognosis was discussed. Median survival in chronic-phase CML had been measured in roughly three to five years before the imatinib era; patients maintaining a major molecular response on the drug approached normal life expectancy. Resistance emerged in some patients through BCR-ABL kinase domain mutations, particularly T315I, which prompted second-generation inhibitors: dasatinib and nilotinib were approved in 2006 and 2007 respectively, each active against most imatinib-resistant mutations. The mutation-resistance problem and its solution by the next-generation drug class became the template for how targeted therapy resistance was framed in oncology going forward.
Imatinib's success reoriented pharmaceutical oncology investment toward kinase inhibitors and defined targets. Within a decade, EGFR inhibitors in lung cancer, BRAF inhibitors in melanoma, and HER2-directed therapy in breast cancer all followed the same logic: identify the driver mutation, design a specific inhibitor, select patients by molecular profile. Druker, Lydon, and Sawyers received the Lasker-DeBakey Clinical Medical Research Award in 2009 for their work on imatinib.
Key People
- Brian Druker — Clinical investigator who led the imatinib CML trials at OHSU
- Nicholas Lydon — Medicinal chemist at Ciba-Geigy who developed the STI571 compound
- Charles Sawyers — Co-investigator in accelerated-phase and blast-crisis imatinib trials
- Alex Matter — Oncology program leader at Ciba-Geigy who supported the imatinib program internally
N Engl J Med 2001;344:1031-1037
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