'Imatinib Changed Everything': The Future Is Now More Hopeful

Kristin Jenkins

March 09, 2017

The enduring impact that imatinib (Gleevec, Novartis Pharmaceuticals) has made on the treatment of chronic myelogenous leukemia (CML), as well as on the whole field of oncology, has been highlighted once again.

"Imatinib changed everything," declares the headline of an editorial in the March 9 issue of the New England Journal of Medicine.

Imatinib "pointed oncology in a new direction," writes editorialist Dan L. Longo, MD, professor of medicine at Harvard Medical School in Boston, Massachusetts, who is also deputy editor of the NEJM.

"The analysis of cancer at the genetic level and the development of (mainly) oral agents that can inhibit driver mutations constitute a conceptual departure from the medical oncology of the 1990s," he says. "The future of oncology is more hopeful now."

The editorial accompanies an article that reports long-term outcomes from one of the first large studies of the drug, the International Randomized Study of Interferon and STI571 (IRIS). IRIS compared imatinib to the standard therapy used for CML at the time, interferon alpha plus cytarabine.

The results of the study, which had a median follow-up period of 10.9 years, show a significant improvement in survival with imatinib.

A direct comparison of overall survival (OS) cannot be made, because of crossover, the researchers note. But they estimate that the 10-year survival rate was 83.5% for patients who received imatinib as their initial therapy. This is comparable to the rate seen in other imatinib-based trials, such as the CML-IV study, which reported a 10-year overall survival rate of 84%, notes lead author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II, Abteilung Hämatologie-Onkologie, Universitätsklinikum Jena, Germany, and colleagues.

In contrast, 50% of patients in the IRIS trial who were randomly allocated to the comparator arm had died after 5 to 6 years, Dr Hochhaus told Medscape Medical News. "This was a major breakthrough," he noted, adding that the trial provides "proof of concept for inhibition of driver mutations."

Trial Fundamentally Changed Therapy

These latest results confirm earlier findings that the use of imatinib as initial therapy significantly improves survival, with few serious drug-related adverse events or late toxic effects, the researchers comment.

Of the 553 patients who received imatinib as initial therapy, 6.9% discontinued therapy because of adverse events, most of which took place in the first year of treatment. Discontinuance then declined in frequency.

Serious cardiac adverse events of any cause were reported in 39 patients (7.1%) in the imatinib group, and serious adverse events of a second neoplasm, either benign or malignant, were reported in 62 (11.3%) patients. In 51 patients who experienced an adverse event thought to be related to imatinib, abdominal pain was the most frequently seen; it occurred in four patients.

The analysis also shows that 48.3% of patients randomly assigned to receive imatinib as initial therapy completed treatment, and 82.8% had a complete cytogenetic response.

"With more than 10 years of follow-up in IRIS, the long-term outcomes in imatinib-treated patients that we describe here confirm and extend earlier findings," the researchers say. "No new safety signals [since the 5-year analysis] and few drug-related serious adverse events were observed during the later years of follow-up, and molecular and cytogenetic response rates were high among the patients who could be evaluated."

In patients who experienced a major molecular response to therapy, an analysis of CML-related deaths alone shows that the estimated survival rate at 10 years was 97.8%, compared to 89.4% in patients without a major molecular response. Similar trends in 10-year survival rates were seen at 18 months in patients with and those without a major molecular response.

These results highlight how much targeted therapies have improved outcomes for patients with CML, the authors comment. The annual age-adjusted mortality rate dropped from 0.9 deaths per 100,000 persons in 1966 to 0.4 deaths per 100,000 persons in 2006, they add.

This trial fundamentally changed CML treatment and led to marked improvements in prognosis for patients. Dr Dan Longo and colleagues

"This trial fundamentally changed CML treatment and led to marked improvements in prognosis for patients," the researchers say. "The ability of imatinib to reduce rates of disease progression and CML-related death (and the resulting increase in the rate of overall survival) has made it a model for targeted cancer. Survival is now considered to be driven by coexisting conditions rather than by CML."

Because CML patients can now be expected to live for decades, it is important to monitor and manage age-related health problems as well as any other conditions coexisting during the chronic phase of disease, the researchers emphasize.

Issues related to poor adherence to the oral-drug regimens — which became apparent during IRIS, particularly in routine clinical practice — were resolved when clinicians "learned to conduct more specific consultations with patients to ensure that they were taking their medication as prescribed," they say.

Imatinib has been joined by several more tyrosine kinase inhibitors, including the second-generation agents nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol-Myers Squibb). Both of these agents produce a higher rate of deep molecular response and give better early control of disease than imatinib, the researchers note. In addition, rates of progression to the accelerated phase and blast crisis of CML, as well as rates of disease-related death, are lower with nilotinib than with imatinib, they say.

Both nilotinib and dasatinib are approved as first-line therapies for patients with CML in the chronic phase. However, the benefits and risks of imatinib compared to these newer tyrosine kinase inhibitors, as well as the role of second-line inhibitor therapy, still need to be determined, Dr Hochhaus and colleagues emphasize.

The researchers also say "it remains to be seen" how the long-term safety profiles of these next-generation targeted therapies will stack up against imatinib. "Given the long-term safety and efficacy results with imatinib and the increasing availability of generic imatinib, comparative analyses evaluating the available tyrosine kinase inhibitors for first-line therapy are likely to be forthcoming," they predict.

The researchers also emphasize the durability of the response seen with imatinib in CML, which has not been reproduced to date. Although high response rates have been seen with other targeted agents in other cancer types, for example BRAF-driven melanoma and EGFR-mutated lung cancer, the durability of these responses "is much less impressive" than the durability of responses to targeted therapy in the chronic phase of CML, when BCR-ABL1 drives disease progression. This "further underscores the importance of initiating treatment early in the course of the disease," they say.

Even with an improved prognosis for patients with common cancers, "none of the new tools appears to cure a majority of patients," Dr Longo points out in his editorial.

"We still need to learn how to combine therapies that have different targets, to identify patients who are likely to have a response, and to define mechanisms of resistance," he adds.

The IRIS study was funded by Novartis Pharmaceuticals. Dr Hochhaus has financial relationships with Novartis, Bristol-Myers Squibb, Pfizer, Ariad Pharmaceuticals, and Merck Sharp & Dohme; coauthors also report financial relationships, as detailed in the article. Dr Longo is the deputy editor of the NEJM.

N Engl J Med. 2017;376:10.


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