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‘Imatinib changed everything’ about curing cancer

March 18, 2017

More than 80% of patients with chronic myelogenous leukemia (CML) remained alive after 11 years of follow-up in the randomized trial of imatinib (Gleevec) that forever changed the field of oncology.

Patients assigned to imatinib had a 10-year survival of 83.3%. Of patients initially allocated to imatinib, 82.8% had a complete cytogenetic response. Treatment with imatinib did not result in unacceptable cumulative or late toxicity.

The analysis focused solely on patients treated with imatinib because patients assigned to the interferon alfa-cytarabine comparator arm had a median duration of treatment of less than a year before crossover to imatinib, Andreas Hochhaus, MD, of University Clinic Jena in Germany, and co-authors reported online in the New England Journal of Medicine (NEJM).

“The ability of imatinib to reduce rates of disease progression and CML-related death … has made it a model for targeted cancer therapy,” the authors said in their discussion of the findings. “Although high rates of response have now also been observed with targeted therapies in patients who have other cancers with well-characterized molecular abnormalities … the durability of responses observed with targeted therapies for these cancers is much less impressive (and similar to the results with imatinib in patients with CML in blast crisis).”

The title of an accompanying editorial captured the impact of the drug and the trial results in three words: “Imatinib Changed Everything.”

“The development of imatinib fundamentally altered the field of oncology,” wrote NEJM deputy editor Dan L. Longo, MD. “Priorities shifted from agents that were active on dividing cells to understanding the biology of individual types of cancer. Once genetic analysis of tumors began, nearly all the cancer types had more complex genetic abnormalities than did CML, but the complexity gave rise to a revolution in cancer nosology.

“We now recognize that the grouping of tumors on the basis of the appearance of a hematoxylin and eosin-stained tissue fragment examined under a light microscope lumps together entities that are distinct both genetically and clinically.”

Lessons learned in the aftermath of the groundbreaking trial of imatinib made the future of oncology “more hopeful now,” Longo added.

Development of imatinib followed a scientific trail that revealed that CML is driven by the BCR-ABL1 tyrosine kinase product of the Philadelphia chromosome. Imatinib was developed as a BCR-ABL1 tyrosine kinase inhibitor and received FDA approval in mid-2001. The agency granted accelerated approval to imatinib on the basis of phase II trials that demonstrated high-level activity in CML.

To corroborate the phase II data, drug maker Novartis (Ciba-Geigy when imatinib development began) organized an international phase III trial (IRIS, International Randomized Study of Interferon and STI571). The trial compared imatinib (known as STI571 when the study was planned) against the then-standard of care, interferon-alfa plus cytarabine, in patients with newly diagnosed CML.

After 18 months of follow-up, initial results showed estimated rates of complete cytogenetic response of 76.2 with imatinib and 14.5% with interferon-cytarabine (P<0.001). Rates of event-free survival (EFS, defined as freedom from progression to accelerated phase or blast crisis) were 96.7% with imatinib and 91.5% with the comparator (P<0.001).

Hochhaus and co-authors reported long-term follow-up from the IRIS trial. Investigators at 177 centers in 16 countries enrolled 1,106 patients, beginning in June 2000, and the last visit of the last patient enrolled occurred in January 2012.

The data showed that 48.3% of patients assigned to imatinib completed the planned course of treatment, compared with 1.3% of patients assigned to interferon-cytarabine. The safety analysis showed that 9.3% of imatinib-treated patients had treatment-related serious adverse events, 7.1% had cardiac serious adverse events of any cause, and 11.3% had a second neoplasm of any cause. No new safety signals occurred during 5 years of follow-up.

Imatinib-treated patients had an estimated 10-year freedom from progression to accelerated phase or blast crisis of 92.1%. The estimated 10-year EFS was 79.6% with imatinib and 56.6% with interferon-cytarabine. Individual patient status included 260 patients who were alive and still on treatment at 10 years, 96 patients who were alive and no longer on treatment, 86 patients who had died, and 111 patients who had unknown survival status.

Among 304 patients who could be evaluated for molecular response at 12 months, the estimated overall survival at 10 years was 91.1% among those with a major molecular response and 85.3% among those without a major molecular response at 12 months. CML-specific survival was 97.8% in patients who had major molecular response and 89.4% among those who did not.

Development of imatinib was “spectacularly important” because it established legitimacy for the concept of personalized medicine, said Richard Silver, MD, of New York Presbyterian Medical Center and Weill Cornell Medicine in New York City.

“The molecular abnormality was found, then the genetic abnormality was found, and then a drug was designed to take advantage of that knowledge,” said Silver, who was involved in the phase III trial. “Imatinib blocked the tyrosine kinase that was involved in the production of leukemia and effectively changed the natural history of the disease.”

Other drugs subsequently developed to treat imatinib-unresponsive disease took advantage of the knowledge acquired from development of imatinib, as did targeted therapies developed for other cancers.

“It changed the way cancer research developed over the next 10 years,” said Silver. “People began looking for the molecular abnormalities that caused cancer, which has become routine today.”

The IRIS trial was supported by Novartis.

Hochhaus disclosed relationships with Novartis, Bristol-Myers Squibb, Pfizer, Ariad Pharmaceuticals, and Merck Sharp & Dohme. One or more coauthors disclosed relationships with Novartis, Celgene, Bristol-Myers Squibb, Ariad Pharmaceuticals, CTI BioPharma, Incyte, Pfizer, Gilead Sciences, Amgen, and MolecularMD, as well as patent and royalty interests.

Primary Source

New England Journal of Medicine

Source Reference: Hochhaus A, et al. “Long-term outcomes of imatinib tratment for chronic myeloid leukemia.” N Engl J Med. 2017;376:917-927.


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