Use of imatinib in CML has pointed oncology in a new direction

Conceptual shift in medical oncology field

After nearly 11 years of follow-up, long-term treatment with imatinib is associated with prolonged control of chronic myeloid leukaemia (CML) with no cumulative or late toxic effects. Commenting on the results from the IRIS study published on 9 March 2017 in the New England Journal of Medicine (NEJM), Dan Longo wrote that “although the journey to cancer cure has just begun, the use of imatinib to treat CML has pointed oncology in a new direction”.

The editorial article features successes of medical treatment for different cancer types. For example, paediatric acute leukaemia, several forms of lymphoma and testicular cancer became in many cases curable. Adjuvant chemotherapy led to longer survival among patients with early breast cancer. The fundamental principle of chemotherapy is to target dividing cells. However, efforts to use chemotherapy in patients with other types of cancer resulted in rare success and toxic effects. Breast cancer and prostate cancer, are furthermore susceptible to hormonal manipulation.

Research efforts in CML led to a number of agents able to inhibit protein tyrosine kinases. Imatinib interfered with the viral oncogene v-abl and platelet-derived growth factor receptor activity in vitro and in mice. It also inhibited the growth of BCR-ABL–positive cells. Subsequently, Druker et al. reported data from phase I study in CML patients treated with imatinib; complete haematologic responses were seen in 53 of the 54 patients, and in 7 patients, the Philadelphia chromosome was no longer detectable. No other drug in oncology had achieved such results.

A decade later, the IRIS study investigators report survival rate of 83% among patients in the imatinib group. In the course of the trial, 83% of the patients in the imatinib group had a complete cytogenetic response. Approximately one patient in five had a stable deep molecular response for 1 year or longer. Approximately 40% of the patients who stopped therapy remained in remission for 3 years or longer, with the rest having a relapse. Thus, imatinib is highly successful at controlling the disease in the long term, but few, if any, patients would be considered as cured.

In the editorial article, Dan Longo wrote: “The development of imatinib fundamentally altered the field of oncology. 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, … the complexity gave rise to a revolution in cancer nosology.”

Indeed, the analysis of cancers at the molecular level and the development of oral anticancer agents that can inhibit driver mutations represent a conceptual shift in medical oncology field. Tumour heterogeneity and mechanisms of resistance still limit therapeutic advances, but liquid biopsy may help to detect and anticipate the adaptation of the tumour to therapy and to select secondary treatments. On top of the genetic guidance of therapeutic decisions is the remarkable recent progress in immunotherapy for different cancer types.

The prognosis in common cancers is improving, but none of the new tools appears to cure a majority of patients. However, the imatinib story suggested that the understanding of the pathogenesis of the tumour can lead to a less toxic and more effective treatment approaches and how it is crucial to identify targets, elucidate molecular mechanisms of resistance, design new generation of anticancer agents, combine treatments with different targets and identify patients who will likely respond to treatment.

Reference

Longo DL. Imatinib Changed Everything. N Engl J Med 2017; 376:982-983.