Ibrutinib, Star in CLL, Subject to Lowly Drug Resistance

Yet Even Bad News Is Good News

Jenni Laidman

June 16, 2014

The targeted agent ibrutinib (Imbruvica, Pharmacyclics) for the treatment of chronic lymphocytic leukemia (CLL) has taken the world of hematologic oncology by storm.

The latest round of praise came at the recent meeting of the American Society of Clinical Oncology, where the drug was called "transformative" and "game changing" in the setting of relapsed disease.

Nevertheless, the drug's investigators now report that ibrutinib is subject to resistance, a problem ubiquitous in cancer drugs.

But they are beginning to identify markers associated with resistance to the drug, according to a study published in the June 12 issue of the New England Journal of Medicine.

Relatively few CLL patients relapse after initially responding successfully to ibrutinib, report the investigators, led by Jennifer A. Woyach, MD, assistant professor of internal medicine at The Ohio State University in Columbus.

In fact, only about 5% of CLL patients have disease progression after an initial successful response, according to an accompanying letter.

Overwhelmingly, the news about ibrutinib has been positive.

In the phase 3 RESONATE trial, which involved 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma, ibrutinib reduced the risk for mortality by 57% (hazard ratio, 0.43; P = .005) and produced a much higher overall response rate than ofatumumab (42.6% vs 4.1%; P < .001).

To understand resistance to ibrutinib, Dr. Woyach and her colleagues performed whole-exome sequencing on samples taken from patients with CLL at baseline and at time of relapse from 6 patients with acquired resistance to ibrutinib.

Ibrutinib is a first-in-class inhibitor of Bruton's tyrosine kinase (BTK), essential for B-cell receptor activities. Ibrutinib irreversibly binds to BTK, rendering it kinase inactive, inducing B-cell apoptosis, halting proliferation, and interrupting B-cell receptor signaling in vitro.

The investigators uncovered 2 mutations associated with resistance.

In 5 of the 6 patients, there was a mutation of the BTK protein that prevents irreversible drug binding. In the sixth patient, a mutation at PLCγ2, which is immediately downstream of BTK, allows B-cell receptor-mediated activation independent of BTK. Neither of these mutations were in evidence prior to treatment.

The researchers also performed Ion Torrent sequencing on samples from 9 patients with prolonged lymphocytosis to determine whether it has similar resistant features; they found no evidence of these mutations.

The results suggest that patients with increased genomic instability, including those with del(17p13.1), del(11q22.3), or complex karyotypes (that is, a genotype possessing 3 or more genetic abnormalities) could be at risk for relapse, the investigators report.

"About 3% of untreated patients and 20% to 30% of treated patients will have a deletion in 17p or a complex karyotype," said John Byrd, D. Warren Brown Designated Chair of Leukemia Research at The Ohio State University.

"We know those patients have more genomic instability; that's probably why they develop these mutations. That's our hypothesis," Dr. Byrd told Medscape Medical News.

"On the basis of available data, patients with del(17p13.1) or a complex karyotype seem to be the most rational choice for combination therapies designed to avoid the development of resistance," the investigators write.

Findings Reinforce Approach

The study confirms that ibrutinib is targeting BTK rather than alternate kinases, which has been a subject of some debate, said Dr. Byrd.

"This pattern of resistance has not been seen with other kinase inhibitors," he explained.

For instance, imatinib (Gleevec) tends to produce multiple mutations in the kinase domain that interfere with drug binding, Dr. Byrd said. "With ibrutinib, you see a single mutation at the site where the drug binds irreversibly, or you see a mutation in a downstream kinase."

Unlike other kinase inhibitors, ibrutinib targets a gene that is not mutated in oncogenesis.

"That's beauty of this drug and the story it tells," Dr. Byrd said. "Ibrutinib takes targeted therapy another step. It is the first time a drug targets a gene that is not recurrently mutated and is effective in treating an entire disease."

Dr. Woyach has disclosed no relevant financial relationships. Many of the study authors report financial relationships with industry, including Pharmacyclics, as detailed in the publication.

N Engl J Med. 2014;370:2286-2294, 2352-2354. Abstract, Letter

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