Ibrutinib Triples PFS, Doubles OS in Phase III CLL Trial

John C. Byrd, MD

Treatment with single-agent ibrutinib (Imbruvica) dramatically increased progression-free survival (PFS) by nearly 80% and significantly extended overall survival (OS) by 57% compared with ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to phase III findings presented at the 2014 ASCO Annual Meeting.

In February 2014, the first-in-class oral BTK inhibitor ibrutinib was granted an accelerated approval for the treatment of patients with CLL following at least one prior therapy, based on a single-arm clinical trial demonstrating a durable improvement in overall response rates (ORR). The impressive findings from the phase III RESONATE study are meant to support a full approval for the drug, which was approved just 5 years after initially entering phase I trials.

"Ibrutinib shows in CLL that a single drug that doesn't target a recurrent mutation can produce durable remissions in essentially all of the patients with the disease," lead study author John C. Byrd, MD, a professor of Medicine at The Ohio State University Comprehensive Cancer Center in Columbus, Ohio, said in an interview with OncLive. "It sort of opens that avenue potentially to other blood cancers, assuming that we find a similar good target and good drug. I think that's the reason ibrutinib has been so successful in CLL, and some of the other diseases like mantle cell, because it is a good target and ibrutinib very potently inhibits the target."

The clear advantage for ibrutinib over ofatumumab was discovered at a 9.4-month interim analysis of the study. Based on phase II results and very promising early results, the study was unblinded 4 months after the enrollment of the last patient. At the first analysis, 57 patients in the ofatumumab group had crossed over to receive ibrutinib following progression.

Prior to crossover, the phase III study randomized 391 patients with CLL in a 1:1 ratio to either ibrutinib at 420 mg once daily (n = 195) or ofatumumab for up to 24 weeks at an initial dose of 300 mg at week 1, followed by a dose of 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks (n = 196). The median age of patients in each arm was 67 years. Patients in the ibrutinib arm received a median of 3 prior therapies, whereas those in the ofatumumab arm had received a median of 2 prior therapies.

For the primary endpoint of PFS, the median in the ibrutinib arm was not reached compared with an 8.1-month median with ofatumumab (hazard ratio [HR] = 0.22, 95% CI, 0.15—0.32, P < .0001). At 6 months, 88% of patients treated with ibrutinib were progression-free compared with 65% in the ofatumumab group. Additionally, a similar benefit was observed in patients with high-risk characteristics and those treated with a purine analog. In patients with the 17p13.1 deletion, the HR was 0.25 (95% CI, 0.14-0.45).

For the secondary endpoint of OS, ibrutinib also demonstrated superior efficacy. At 12 months, the OS rate was 90% for patients treated with ibrutinib compared with 81% in the ofatumumab group. The median OS was not reached for patients treated with ibrutinib (HR = 0.43; 95% CI, 0.24-0.79; P = .005).

By traditional response criteria, the ORR with ibrutinib was 43% (all partial responses [PR]) compared with 4% for ofatumumab (odds ratio = 17.4; 95% CI, 8.1-37.3; P < .001). Lymphocytosis, which was observed in 69% of patients in the ibrutinib arm, does not generally indicate progression in patients treated with BTK inhibitors. Once including patients with a lymphocytosis who had a PR, the ORR was 63% with ibrutinib.

"Patients with a PR with lymphocytosis actually do the same as patients who have PR. It's something you expect with this drug, it's not something that you would call a patient regressing as long as they're benefiting in other areas," Byrd explained. "If you look at the investigator assessed response, it was even higher than 63, it was 85 percent."

Richter's transformation was found to be equivalent in both groups, with 2 patients developing the complication in each arm. The most frequently observed adverse events of any grade for ibrutinib and ofatumumab, respectively, were diarrhea (47.7% vs 17.8%), fatigue (27.7% vs 29.8%), and nausea (26.2% vs 18.3%). The most common grade 3/4 adverse events with ibrutinib and ofatumumab were neutropenia (16% vs 14%), pneumonia (7% vs 5%), and thrombocytopenia (6% vs 4%).

Atrial fibrillation was more frequent with ibrutinib (5.1% vs 0.5%) and major hemorrhages were reported in 1.0% versus 1.6%, for ibrutinib and ofatumumab. Treatment discontinuation due to adverse events was similar between both arms, with 86% of patients remaining on ibrutinib treatment at the time of the analysis.

"There were some side effects that came out that were more apparent with ibrutinib, mild infections, mild bruising, some ocular side effects such as mild blurred vision, and there was a higher frequency of atrial fibrillation and diarrhea," Byrd said. "In the ofatumumab arm there were more infusion events—obviously&mdash;and peripheral neuropathy came as something that had not been previously associated with ofatumumab."

Ibrutinib, which is an irreversible small-molecule inhibitor of BTK, works by blocking B-cell activation and signaling, preventing the growth of malignant B cells that overexpress BTK.

In November 2013, ibrutinib was approved as a treatment for patients with mantle cell lymphoma (MCL). This initial approval followed multiple breakthrough therapy designations from the FDA in early 2013 as a treatment for CLL/SLL, MCL, and Waldenström's macroglobulinemia. The drug continues to be explored extensively as a monotherapy and in combination across a variety of B cell malignancies.

"The most exciting thing about the RESONATE study—and this ASCO meeting&mdash;is that we have a bunch of exciting new therapies coming forward, and it's a real bright future for patients with CLL," Byrd remarked.

Byrd JC, Brown JR, O'Brien SM, et al. Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial. J Clin Oncol. 2014;32:5s (suppl; abstr LBA7008).

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