The results showed a two-year overall survival rate of 98 percent with Imbruvica.
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Imbruvica (ibrutinib) reduced the risk of death by 84 percent versus the chemotherapy chlorambucil in treatment-naïve elderly patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). These results from the phase 3 RESONATE-2 study were presented at the 2015 meeting of the American Society of Hematology, a gathering of more than 25,000 hematologists and other hematology/oncology professionals.1
The results, which were simultaneously published online in The New England Journal of Medicine
, also showed a two-year overall survival (OS) rate of 98 percent with Imbruvica.2
“The [Imbruvica] 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, 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 [Imbruvica] in this setting and the value it may bring as an appropriate treatment option for these patients."
RESONATE-2 included 269 treatment-naïve patients who were at least 65 years old with CLL or SLL. The median age was 73 years. Investigators studied Imbruvica 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, Azienda Ospedaliera Niguarda Cà Granda, Milan, Italy, said when presenting the data.
Patients were randomized one-to-one to receive either 420 mg of Imbruvica 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 Imbruvica if such treatment was indicated, and 43 patients did so.
The median duration of treatment was 17.4 months with Imbruvica and 7.1 months with chlorambucil. At the time of study completion, 87 percent of patients in the Imbruvica 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, Imbruvica led to an 84 percent reduction in the risk of progression or death; investigators calculated that risk reduction as 91 percent. At a median follow-up of 18.4 months, the median PFS was not yet reached with Imbruvica versus 19 months with chlorambucil .The median 18-month PFS rates were 94 percent and 45 percent, respectively, and the results were consistent across subgroups. The 24-month OS rates were 98 percent versus 85 percent, respectively.
As per IRC review, ORR was 86 percent with Imbruvica, with 4.4 percent of those being complete responses, versus 35.3 percent with chlorambucil, 1.5 percent of them complete responses. Investigator-assessed ORR was 90.4 percent, with 9.6 percent of those being complete responses, versus 35.3 percent, with 4.5 percent of those being complete responses, respectively.
Imbruvica 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 percent versus 36.8 percent of patients who took Imbruvica and chlorambucil, respectively, and a reduction in spleen enlargement was seen in 75.7 percent versus 39.1 percent of patients. Rates of sustained hematologic improvements were 84 percent with Imbruvica versus 45 percent with chlorambucil in patients with baseline anemia, and were, respectively, 77 percent versus 43 percent in patients with thrombocytopenia.
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 Imbruvica, 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 percent with Imbruvica and in 2 percent with chlorambucil. There were three deaths in the Imbruvica arm and 17 in the chlorambucil arm.
Based on the RESONATE-2 data, the codevelopers of Imbruvica, 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. Imbruvica 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 3 head-to-head trial to evaluate the efficacy and safety of [Imbruvica] monotherapy versus traditional chemotherapy in patients with treatment-naive CLL," Craig Tendler, 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 [Imbruvica] that have not been seen before and this suggests that long-term benefits of [Imbruvica] in the frontline setting may be quite impactful.
- Tedeschi A, Barr PM, Robak T, et al. Results from the international, randomized phase 3 study of ibrutinib versus chlorambucil in patients 65 years and older with treatment-naïve CLL/SLL (RESONATE-2). Presented at: the 57th Annual Meeting of the American Society of Hematology; Orlando, Florida; December 5-8, 2015. Abstract 495.
- Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia [published online December 6, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1509388.