Chemotherapy is a blunt instrument designed to indiscriminately kill rapidly dividing cells in the hope that the cancer cells die more and grow back less than healthy cells. That normal cells are routinely damaged in this destructive procedure accounts for the side effects and toxicity of traditional chemotherapy.
The old paradigm of testing chemotherapy drugs and hoping that they worked was displaced at the turn of this century when a drug was designed based on the known biology of cancer to interfere with the cellular processes causing a particular cancer, without damage to normal cells. That agent was imatinib, also known as Gleevec. Imatinib showed that if you can identify the biologic process contributing to a cancer, then drugs could be designed to interfere with that process, not only effectively treating the cancer, but also minimizing side effects.
In the ensuing years, cancer research has shifted to this new paradigm, resulting in many new therapies targeted to the cancer and not to normal cells. The improvements in survival, however, have been modest compared to what was seen with imatinib.
The B-cell receptor pathway tightly controls the growth of the infection-fighting cells we call B-cells. When B-cells become cancerous, this pathway becomes unregulated and contributes to the malignant nature of the cells. However, this overactive pathway can be inhibited by novel drugs. In the last year, the results of clinical trials in humans conclusively showed that these new drugs are extremely effective at treating low-grade B-cell lymphomas and leukemias for a long time and with very few side effects.
Ibrutinib targets Bruton’s tyrosine kinase (BTK), a protein essential for B-cell survival and proliferation. While it kills malignant B cells, ibrutinib has little effect on healthy T cells—unlike other lymphoma therapies. This leaves an important arm of the immune system largely intact, enabling patients to remain healthier during treatment.
Many patients respond well to this novel B-cell receptor pathway inhibitor, which lacks many of the side effects of chemotherapy, and it frequently produces long-lasting remissions even in patients with high-risk genetic lesions. Results from a study published in the The New England Journal of Medicine in 2013 reported an overall response rate of 71% for patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib tablets. At 26 months, the estimated progression-free survival rate was 75% and overall survival was 83%. Ibrutinib has also shown very promising results in the treatment of patients with other B-cell malignancies, including mantle cell lymphoma (MCL), a rare and aggressive B-cell subtype of non-Hodgkin lymphoma.
With approval from the U.S. Food and Drug Administration (FDA) expected at the end of 2013, ibrutinib would be the first in a class of oral BTK inhibitors and one of the first medicines to file for FDA approval via the new Breakthrough Therapy Designation pathway, which is intended to expedite the development and review of drugs for serious or life- threatening conditions.
To follow soon after will be other much anticipated B-cell pathway inhibitors for leukemia, including syk (spleen tyrosine kinase) inhibitors, like fostamatinib, and phosphoinositide-3 kinase (PI3K) inhibitors, like idelalisib.
The B-cell receptor pathway inhibitors are innovative because they help fulfill the initial promise of imatinib. They will help patients who are no longer responsive to chemotherapy live longer, provide an alternative to chemotherapy in the future, and will stimulate additional research to find similar advances for other cancers.