Ibrutinib reduced the risk of death by 84% versus chlorambucil in treatment-naÃ¯ve elderly patients with chronic lymphocytic leukemia.
Jan Burger, MD, PhD
Ibrutinib (Imbruvica) reduced the risk of death by 84% versus chlorambucil in treatment-naïve elderly patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to results from the phase III RESONATE-2 study presented at the 2015 ASH Annual Meeting.1
The results, which were simultaneously published online in The New England Journal of Medicine, also showed a 2-year overall survival (OS) rate of 98% with ibrutinib.2
“The ibrutinib data represent some of the most compelling results I've seen during my career. These data may change how we clinicians treat patients with CLL or SLL in the frontline setting," lead study investigator Jan Burger, MD, PhD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, said in a statement. “The results showcase the clinical utility of ibrutinib in this setting and the value it may bring as an appropriate treatment option for these patients."
RESONATE-2 included 269 treatment-naïve patients aged ≥65 years with CLL or SLL. The median age was 73 years. Investigators studied ibrutinib in this population because they thought it “should be highly effective, easy to deliver and safe, and could be a promising treatment for these elderly patients,” one of the study’s authors, Alessandra Tedeschi, MD, Azienda Ospedaliera Niguarda Cà Granda, Milan, Italy, said when presenting the data at ASH.
Patients were randomized 1:1 to receive either 420 mg of ibrutinib daily until progression or 0.5 to 0.8 mg/kg of chlorambucil on days 1 and 15 of each 28-day cycle, for a total of 12 cycles. Patients with the 17p deletion were excluded from the study. Patients in the chlorambucil arm were allowed to switch over to an extension study that offered ibrutinib if such treatment was indicated, and 43 patients did so.
The median duration of treatment was 17.4 months with ibrutinib and 7.1 months with chlorambucil. At the time of study completion, 87% of patients in the ibrutinib arm remained on therapy.
The study’s primary endpoint was progression-free survival (PFS) as evaluated by an independent review committee (IRC). Overall survival and overall response rate (ORR) were secondary outcome measures.
The IRC found that, compared with chlorambucil, ibrutinib led to an 84% reduction in the risk of progression or death (HR, 0.16; 95% CI, 0.09-0.28); investigators calculated that risk reduction as 91%. At a median follow-up of 18.4 months, the median PFS was not yet reached with ibrutinib versus 19 months with chlorambucil (P <.0001) .The median 18-month PFS rates were 94% and 45%, respectively, and the results were consistent across subgroups.
The hazard ratio for OS was 0.16 with ibrutinib versus chlorambucil (P = .0010). The 24-month OS rates were 98% versus 85%, respectively.
As per IRC review, ORR was 86% with ibrutinib, with 4.4% of those being complete responses, versus 35.3% with chlorambucil, 1.5% of them complete responses. Investigator-assessed ORR was 90.4%, with 9.6% of those being complete responses, versus 35.3%, with 4.5% of those being complete responses, respectively.
Ibrutinib significantly improved bone marrow function, as reflected by a sustained increase in hemoglobin and platelets. This is important because, in the elderly, bone marrow failure is a common cause of morbidity, Tedeschi said.
A reduction of 50% or more in lymph node burden was observed in 91.2% versus 36.8% of patients (P <.0001) who took ibrutinib and chlorambucil, respectively, and a reduction in spleen enlargement was seen in 75.7% versus 39.1% of patients (P <.0001). Rates of sustained hematologic improvements were 84% with ibrutinib versus 45% with chlorambucil in patients with baseline anemia (P <.0001), and were, respectively, 77% versus 43% in patients with thrombocytopenia (P = .0054).
Adverse events, most of which were grade 1 and did not result in treatment discontinuation, included diarrhea, fatigue, cough, nausea, peripheral edema, dry eye, arthralgia and vomiting. Neutropenia also occurred in both arms, and was typically more severe than grade 1.
Fatigue, nausea, vomiting and cytopenias were more frequent with chlorambucil, as were side effects that led to treatment discontinuation. Hypertension was noted more frequently on ibrutinib, but was limited to grades 1 through 3 and managed without dose modification or discontinuation. Over a median follow-up of approximately 1.5 years, major hemorrhage occurred in 4% with ibrutinib and in 2% with chlorambucil. There were 3 deaths in the ibrutinib arm and 17 in the chlorambucil arm.
Based on the RESONATE-2 data, the codevelopers of ibrutinib, Janssen Biotech (Johnson & Johnson) and Pharmacyclics (AbbVie), have submitted a supplemental new drug application to the FDA for the BTK inhibitor as a therapy for treatment-naïve, elderly patients with CLL. Ibrutinib is currently approved by the FDA for previously treated CLL, previously treated mantle cell lymphoma, and Waldenström's macroglobulinemia.
"RESONATE-2 is the first phase III head-to-head trial to evaluate the efficacy and safety of ibrutinib monotherapy versus traditional chemotherapy in patients with treatment-naive CLL," Craig Tendler, MD, vice president, Late-Stage Development and Global Medical Affairs for Oncology at Janssen, said in a statement. "We continue to see clinically meaningful improvements in progression-free and overall survival in CLL patients with single-agent ibrutinib that have not been seen before and this suggests that long-term benefits of ibrutinib in the frontline setting may be quite impactful.