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Phase III Study Strengthens Support of Ibrutinib as Second-line Therapy for CLL and SLL

The results of RESONATE study
10 Jun 2014
Haematologic malignancies;  Anticancer agents & Biologic therapy

In a head-to-head comparison of two drugs for the treatment of relapsed chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL), ibrutinib statistically significantly outperformed ofatumumab as a second-line therapy, according to a multicentre interim study published in the OnLine First edition of the New England Journal of Medicine on 31 May 2014.

Ibrutinib is the first drug designed to target Bruton's tyrosine kinase (BTK), a protein essential for CLL-cell survival and proliferation. In patients with CLL or SLL, a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome.

The RESONATE study

In this phase III trial, patients at risk for a poor outcome were randomised to receive once daily oral ibrutinib or the anti-CD20 antibody ofatumumab, a drug considered part of the current standard of care for CLL. Of the 391 patients enrolled to the study, 195 were randomised to ibrutinib and 196 to ofatumumab.

The primary endpoint was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary endpoints.

Median follow-up was 9.4 months and showed that ibrutinib significantly improved progression-free survival as a second-line therapy. The median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; p < 0.001). The study team observed similar progression-free survival results regardless of age, clinical stage or unique factors such as genetic mutation status.

Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; p = 0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group.

The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, p < 0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues.

The most frequent non-haematologic adverse events were diarrhoea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.

A principal investigator of the study was Dr John Byrd, who is haematology division director at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). In 2013, Dr Byrd and his team reported findings from a phase Ib/II study of 85 patients with relapsed CLL patients on ibrutinib in the New England Journal of Medicine. Based on positive early response rates, the study Data Monitoring Committee recommended patients be given option to switch to the ibrutinib arm of the study. At that time, 29% of patients with confirmed disease progression on ofatumumab crossed over to the ibrutinib arm of the study.

"There is no question that ibrutinib far outperforms existing therapies we have for CLL, and we're excited to see this drug improving the outcome for patients who were once considered incurable," says Dr Byrd in the accompanying press release.

Phase III studies are currently underway at The OSUCCC – James and affiliated cancer centers to determine whether ibrutinib is effective as a first-line therapy in CLL, and in other blood cancer treatment challenges such as reducing graft versus host disease in bone marrow transplant patients.

This research was funded with support from the Four Winds Foundation, D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, Mr. and Mrs. Al Lipkin, Harry T. Mangurian Jr. Foundation, Sullivan CLL Research Foundation, the USA National Institutes of Health (P50 CA140158, RO1 CA177292), Leukemia & Lymphoma Society and Janssen Research and Development. Dr Byrd has no financial interest in Janssen, manufacturer of ibrutinib.

Resistance mechanisms

Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized yet. The team in which dr Byrd was a senior author published results also in NEJM from the study that evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance.

The team performed whole-exome sequencing at baseline and the time of relapse on samples from 6 patients with acquired resistance to ibrutinib therapy. They then performed functional analysis of identified mutations. In addition, they performed Ion Torrent sequencing for identified resistance mutations on samples from 9 patients with prolonged lymphocytosis.

They identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in 5 patients and identified 3 distinct mutations in PLCγ2 in 2 patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell–receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib.

The researchers concluded that resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell–receptor pathway in the mechanism of action of ibrutinib in CLL.


Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. NEJM 2014; OnLine First May 31, DOI: 10.1056/NEJMoa1400376

Woyach JA, Furman RR, Liu T-M, et al. Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib. NEJM 2014; OnLine First May 28. DOI: 10.1056/NEJMoa1400029

Last update: 10 Jun 2014

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