A Solution to Ibrutinib Resistance in MCL?

Nick Mulcahy

August 07, 2014

In May, researchers at 2 major American cancer centers began recruiting patients for a phase 1 clinical trial with a lofty goal: to remedy the significant problem of primary resistance to ibrutinib (Imbruvica, Pharmacyclics and Janssen Biotech) in the treatment of mantle cell lymphoma (MCL).

The trial employs the combination of ibrutinib and the investigational agent palbociclib (Pfizer) in previously treated MCL.

Palbociclib is an oral therapy that selectively inhibits the cyclin-dependent kinases CDK4 and CDK6 to regain cell cycle control and block tumor cell proliferation. CDK4 and CDK6 are overactivated in numerous cancers.

The rationale for the addition of palbociclib can be found in a report published online July 31 in Cancer Discovery, the flagship journal of the American Association of Cancer Research.

The report details the genomic analysis and subsequent in vivo experiments that scientists undertook in a relatively short period of time in an effort to gain insight into ibrutinib, a drug that is both a landscape changer and flawed.

The phase 1 trial comes only a year after ibrutinib was described as a "breakthrough" in MCL. That is when a phase 3 clinical trial of patients with recurrent MCL demonstrated a response rate at 15 months that was approximately double that of standard therapies, and a dramatically better median progression-free survival.

The US Food and Drug Administration approval of ibrutinib for recurrent MCL followed quickly, in late 2013, and the drug was granted breakthrough status for this indication.

However, as impressive as ibrutinib is, the drug only works initially in about two-thirds of patients. Furthermore, even responders eventually develop acquired resistance.

Dr. Selina Chen-Kiang

"The drug doesn't work for about 32% of patients; their lymphomas are said to have primary resistance to ibrutinib. We are also learning that most patients whose lymphomas respond to ibrutinib eventually relapse because their tumors acquire resistance to the drug," said study lead author Selina Chen-Kiang, PhD, in a press statement. She is professor of pathology and laboratory medicine and of microbiology and immunology at Weill Cornell Medical College in New York City.

The authors conducted a longitudinal study using RNA and genomic sequencing to investigate molecular events that occur during treatment with ibrutinib.

To identify possible molecular reasons for acquired resistance to ibrutinib, the team used 5 serial biopsies from a patient with MCL who initially responded to ibrutinib but then progressed. They found, for the first time, a mutation in BTK, which is the target of ibrutinib. The mutation is known as C481S and appears at relapse.

Further analyses revealed the consequences of the relapse-specific BTK C481S mutation, including activation of the PI3K and CDK4 signaling pathways, which promote cell survival and proliferation.

Lab experiments indicated that blocking CDK4 with palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C481S mutation sensitive to investigational drugs that inhibit PI3K. Also, palbociclib made ibrutinib-resistant lymphoma cells sensitive to both ibrutinib and investigational drugs that inhibit PI3K.

"These data identify a genomic basis for acquired ibrutinib resistance in MCL and suggest a strategy to override both primary and acquired ibrutinib resistance," the authors summarize.

Targeting CDK4 with palbociclib plus a BTK inhibitor is one of the possible drug combinations that makes sense in this environment, they note.

A combination of a CDK4 inhibitor such as palbociclib and a PI3K inhibitor might be also effective for treating patients who do not respond to ibrutinib, they say.

This study was supported by funds from the Lymphoma Research Foundation, the Lymphoma Foundation, the Cancer Research and Treatment Fund, the Leukemia and Lymphoma Society, and the National Cancer Institute. Dr. Chen-Kiang has disclosed no relevant financial relationships. A number of coauthors report financial ties, including employment, to either Janssen or Pharmacyclics, as detailed in the publication.

Cancer Discov. Published online July 31, 2014. Abstract

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