Imatinib (STI571, Gleevec) in chronic myeloid leukemia

Chronic myeloid leukemia had been understood at the molecular level for longer than almost any other cancer. Peter Nowell and David Hungerford had found the small Philadelphia chromosome in CML cells in 1960, Janet Rowley showed in 1973 that it came from an exchange between chromosomes 9 and 22, 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 trying to design a molecule that would block the driver without broadly damaging normal cells. Until then, cancer drugs had worked by killing cells that divided quickly, cancerous or not.

Nicholas Lydon, a biochemist at Ciba-Geigy in Basel, set up the company's tyrosine kinase inhibitor program in 1986, and STI571 came out of its screening work with the chemist Jürg Zimmermann. Brian Druker at Oregon Health and Science University tested compounds Lydon sent him, and in 1996 the two reported that STI571 killed cells that depended on BCR-ABL. The company, which merged with Sandoz to form Novartis, had little enthusiasm: CML was rare, the market looked small, and the drug had caused toxicity in dogs. Druker pressed it to go ahead, and the phase I trial began in June 1998 with Druker, Charles Sawyers and Moshe Talpaz treating patients.

Druker and colleagues reported their findings in the New England Journal of Medicine in April 2001. Of 83 chronic-phase patients who had failed interferon alfa, 54 received 300 mg or more a day, and 53 of them had complete hematologic responses, usually within four weeks. A companion paper, with Sawyers as second author, reported responses in 21 of 38 patients in myeloid blast crisis and 14 of 20 with lymphoid blast crisis or Philadelphia-positive ALL, though nearly all the lymphoid responses relapsed. The FDA granted accelerated approval on May 10, 2001, about ten weeks after Novartis filed its application; FDA reviewers later called it the fastest approval of a cancer drug up to then.

In 2006 the investigators reported that 89 percent of patients treated with imatinib were alive five years after diagnosis. Before imatinib, a patient with CML could expect to live about three to five years; a Swedish registry study in 2016 estimated that patients diagnosed in 2013 would lose, on average, fewer than three years of life to the disease. Resistance emerged in some patients through mutations in the BCR-ABL kinase domain. Dasatinib, which Sawyers developed with Bristol-Myers Squibb scientists, was approved in June 2006 and nilotinib in 2007; both worked against most resistant mutants but not T315I, which remained untreatable by these drugs until ponatinib was approved in December 2012.

By 2009 the Lasker Foundation counted hundreds of cancer drugs aimed at specific molecules in development and dozens approved. EGFR inhibitors in lung cancer (gefitinib was first approved in 2003) and BRAF inhibitors in melanoma (vemurafenib, 2011) followed the same logic: identify the driver, 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.