2001: Imatinib: Targeted Therapy Revolution (2001)

The FDA approval of imatinib (Gleevec/Glivec) for chronic myeloid leukaemia (CML) in May 2001—
granted after only 72 days of review, the fastest approval in FDA history at that point—is widely
regarded as the founding moment of modern targeted cancer therapy. CML is driven in over 95 % of
cases by the Philadelphia chromosome, a reciprocal translocation between chromosomes 9 and 22 that
fuses the BCR gene with the ABL1 kinase gene. The resulting BCR-ABL1 oncoprotein is a constitutively
active tyrosine kinase that drives malignant proliferation of myeloid progenitor cells.

Brian Druker at Oregon Health & Science University had collaborated throughout the 1990s with
Nicholas Lydon and colleagues at Ciba-Geigy (later Novartis) to develop a small-molecule inhibitor
selective for the ABL kinase. The compound CGP57148B—later named STI571 and then imatinib—was
shown to potently inhibit BCR-ABL1 in vitro and to produce complete haematological remissions in
CML cell lines and mouse models. Phase I clinical trials in 1998 produced results that shocked
haematologists: virtually every patient in the early stages of CML achieved a complete haematologic
response, with minimal toxicity.

The Phase II and III results confirmed a complete cytogenetic response rate exceeding 70 % in
chronic-phase CML—an outcome previously achievable only with allogeneic stem-cell transplantation.
Five-year survival in imatinib-treated patients exceeded 89 %, compared with historical rates of
roughly 40 % with interferon-alpha. The drug transformed CML from a disease with a median survival
of three to five years into one where most patients can expect a near-normal lifespan.

Imatinib's molecular precision—occupying the ATP-binding pocket of BCR-ABL1 with high selectivity—
also exemplified the power of structure-based drug design. Its success triggered a wave of kinase
inhibitor programmes across oncology and opened the rational design era of small-molecule targeted
therapy.