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O'Brien Covers Evolution of Ibrutinib in CLL

Gina Columbus @ginacolumbusonc
Published: Tuesday, Feb 13, 2018

Susan M. O’Brien, MD
Susan M. O'Brien, MD
Ibrutinib (Imbruvica) has played an important role in the development of treatment for patients with chronic lymphocytic leukemia (CLL), and long-term follow-up of the RESONATE and RESONATE-2 studies are evidence of the long-lasting responses with the BTK inhibitor.

The phase III RESONATE trial investigated ibrutinib in the second-line setting compared with ofatumumab (Arzerra) in patients with relapsed/refractory CLL. In the long-term follow-up analysis, ibrutinib demonstrated a superior progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus ofatumumab.

The median PFS was not reached with 74% of patients alive and progression free at 2 years, and second-line ibrutinib PFS outcomes were significantly improved compared with patients receiving it in later lines of therapy (P = .0348). Additionally, the ORR was higher in the ibrutinib arm in all evaluable subgroups compared with ofatumumab (P <.0001). In addition, In addition, the complete response (CR) rate improved with 7% of patients.1

Ibrutinib was investigated in the frontline setting in the phase III RESONATE-2 study for patients with CLL and small lymphocytic leukemia (SLL), which included 269 patients who were 65 years or older. At 29 months of follow-up, frontline ibrutinib reduced the risk of progression or death by 88% versus chlorambucil.2 Additionally, the quality of responses has improved over time with 18% of patients with CLL and SLL achieving a CR or CR with incomplete platelet recovery with single-agent ibrutinib.

Treatment-related adverse events decreased in frequency, allowing 79% of patients to continue treatment with ibrutinib. OS remains significantly improved, resulting in 2-year survival rate estimates of 95% in the ibrutinib arm versus 84% in the chlorambucil arm. Moreover, ORR was 92% versus 36% in the ibrutinib and chlorambucil arms, respectively (P <.0001).

Five-year follow-up data of ibrutinib is also now available. Results of the phase Ib/II PCYC-1102 study, which evaluated 5 years with ibrutinib therapy in both treatment-naïve and relapsed/refractory patients with CLL/SLL, showed that the agent is efficacious and safe with 89% of both patient subgroups experiencing a complete or partial response to the therapy. Additionally, patients lived without disease progression longer when ibrutinib is administered earlier than in the third-line setting or beyond.3

With the PCYC-1102 study follow-up, the most frequent grade 3 or higher AEs with ibrutinib were hypertension (26%), pneumonia (22%), neutropenia (17%), thrombocytopenia (9%), and atrial fibrillation (9%).

At the 2017 ASH Annual Meeting, patient-reported outcomes were investigated for patients treated with frontline ibrutinib on the RESONATE-2 trial. With 3-years of follow-up for these patients, ibrutinib showed greater sustained improvements compared with chlorambucil.4 Additionally, ibrutinib was associated with increased quality-adjusted survival time at the time of primary analysis.

Having shown significant improvements as a single agent, the next step for ibrutinib will be in combination, according to Susan O’Brien, MD.

“It is normal to build on single agents by looking for combination partners based on preclinical data or agents that lack overlapping toxicities,” said O’Brien, a hematologist and oncologist at UC Irvine Health. “The idea of moving forward from a single agent to a combination is logical and we hope to do this further with ibrutinib.”

In an interview with OncLive, O’Brien, discussed the tremendous impact that has been seen with ibrutinib following the long-term follow-up of the RESONATE studies and highlights where this regimen is headed in the future of treatment for patients with CLL.

OncLive: Can you discuss the long-term data that we have seen with the resonate and RESONATE-2 trials?

O’Brien: We now have 4-year follow-up from the original RESONATE study. That was the randomized trial of ibrutinib versus ofatumumab in relapsed patients, which led to the full approval of ibrutinib. We have seen very good data. The important message from this study is that responses can be very durable and that toxicity does not increase over time.

The one toxicity that is seen occurring is hypertension; therefore, we must monitor patients for that. In my experience, it is more likely to occur in patients that already had hypertension and they may just need an adjustment to their medicine. In general, the side effects that impact the patient's day-to-day living such as diarrhea, are diminished over time. We haven't seen any new safety signals.

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