Already approved for use in patients with pretreated chronic lymphocytic leukemia (CLL), new results show that ibrutinib (Imbruvica, Pharmacyclics/AbbVie) also works when used up front.
The new results on first-line use, from the RESONATE-2 study, also show that it is superior to chlorambucil (Leukeran, Aspen Global Inc) used alone in a subset of frail and elderly patients. For other CLL patients, more agreesive treatment would be used, says an expert not involved in the trial.
CLL primarily affects older patients who often have comorbidities as well as disease-related immunosuppression and myelosuppression. Fludarabine‐based regimens are generally unsuitable for frail or older patients. Instead, chlorambucil has been used as a standard first‐line therapy in this population of patients.
The new results show that ibrutinib was superior to chlorambucil among older treatment-naive patients with CLL or small lymphocytic lymphoma (SLL). The results come from the RESONATE-2 study, presented here at the American Society of Hematology (ASH) 57th Annual Meeting and simultaneously published online in the New England Journal of Medicine.
"There was a 91% reduction in risk of progression (by investigator) and 84% reduction in risk of death with ibrutinib as compared with chlorambucil," said lead author Alessandra Tedeschi, MD, of Azienda Ospedaliera Niguarda Cà Granda, Milano, Italy.
Treatment with ibrutinib also significantly improved bone marrow function, as reflected by sustained increase in hemoglobin and platelets, she said.
"Ibrutinib showed favorable benefit‐risk profile as first-line treatment of patients with CLL/SLL vs traditional chemotherapy," Dr Tedeschi said during a press briefing.
"Turning Point"
Ibrutinib is a first-in-class oral, covalent inhibitor of Bruton's tyrosine kinase. It has already been approved for patients with CLL who have received one or more prior therapies and for patients with CLL and the del17p mutation (including first-line). As previously reportedby Medscape Medical News, ibrutinib has stirred up considerable excitement in hematology circles, with experts describing it as a "turning point" in the treatment of CLL.
No Changes in Practice Yet
Although the data are impressive, the drug is not practice changing, according to Tait D. Shanafelt, MD, professor of medicine at the Mayo Clinic, in Rochester, Minnesota, who was approached to comment on the new results.
However, it may begin to change the standard of care for certain patients, he told Medscape Medical News. "We know that ibrutinib is a very active drug that has really transformed the care of CLL since its FDA approval for relapsed disease and 17p about 22 months ago. This study tried to take it into the first-line setting."
One of the really important points of this study was that the researchers recruited primarily elderly patients who were felt to be unsuited to receive more aggressive treatments, which would be the standard regimen for most CLL patients, he emphasized.
"It showed impressive improvements in progression-free and overall survival," said Dr Shanafelt. "So I think if the FDA broadens the label, and for patients who fit that eligibility criteria of not being able to tolerate more aggressive treatments, it could have practice-changing implications."
But that would only be for that narrow subset of patients, he reiterated, because the new trial did not compare ibrutinib with what would be considered standard-of-care therapy for any fit patient in 2015.
Even for this narrow subpopulation, other data now show that there are therapies that are more effective in improving survival compared with chlorambucil alone. "Chlorambucil alone would not be considered to be an acceptable comparator if the trial were designed today," he said.
Dr Shanafelt pointed to a German study published in the New England Journal of Medicine early last year that compared treatment with chlorambucil alone to treatment with combination obinutuzumab-chlorambucil or rituximab-chlorambucil in an untreated patient population similar to the one in the current study (N Engl J Med. 2015;370:1101-10).
"The German CLL study was conducted in a population of elderly patients with comorbidities and reduced organ function," he said. "They found that adding monoclonal antibodies in two different arms improved survival over chlorambucil alone."
That is where the challenge is with this new ibrutinib study, he commented. It is showing superiority for a treatment (chlorambucil alone) for which other studies have already shown superiority in terms of overall survival in this elderly population with comorbidities, Dr Shanafelt said. "So we have to interpret the data in the context of the changes that have occurred across the field in the past few years."
Although these results cannot be applied to the majority of CLL patients who are fit enough to receive other therapies, there are currently pivotal trials ongoing in the United States and Europe that are comparing ibrutinib with the more active therapies in the broader CLL population. "Those trials should give us an answer in a year or two."
Details of RESONATE-2 Results
The trial compared ibrutinib with chlorambucil, with both drugs used as single agents in treatment-naive older patients with CLL/SLL.
The cohort included 269 patients. The median age was 73 years; 70% of the patients were older than 70 years, Dr Tedeschi pointed out. Of this group, 45% had advanced Rai stage disease, 20% had del11q, and 69% had comorbidities at baseline, including CIRS score >6, reduced creatinine clearance, or an ECOG status of 2. Patients with del17p were excluded.
Participants were randomly assigned in a ratio of 1:1 to receive either 420 mg ibrutinib daily until progression or chlorambucil 0.5 mg/kg (up to maximum of 0.8 mg/kg) on days 1 and 15 of a 28 -day cycle for up to 12 cycles.
At a median follow-up of 18.4 months, patients receiving ibrutinib had significantly longer (investigator assessed) progression-free survival (median not reached [NR] vs 15 months for chlorambucil; hazard ratio [HR], 0.09; P < .0001).
The 18-month progression-free survival was 93.9% vs 44.8% in favor of ibrutinib. Patients receiving ibrutinib also had significantly prolonged overall survival (median NR for either arm; HR, 0.16; P = .0010); at 24 months, overall survival was 97.8% vs 85.3%, respectively.
Three deaths occurred in the ibrutinib arm; 17 deaths occurred among patients receiving chlorambucil.
The overall response rate (ORR) was 86.0% with ibrutinib (4.4% complete response [CR] or complete remission with incomplete blood count recovery [Cri]) vs 35.3% with chlorambucil (1.5% CR/CRi), and it was higher with ibrutinib at all evaluated time points.
The investigator-assessed ORR was 90.4% (9.6% CR/CRi) vs 35.3% (4.5% CR/CRi), respectively.
Median event-free survival (EFS) was also prolonged with ibrutinib treatment (NR vs 12 months; HR, 0.17, P < .0001). A reduction in lymph node burden of ≥50% was observed in 91.2% patients receiving ibrutinib, compared with 36.8% in the chlorambucil arm (P < .0001).
Finally, the rates of sustained hematologic improvements were significantly higher in the ibrutinib arm, including those patients with baseline anemia (84% vs 45%; P < .0001) or thrombocytopenia (77% vs 43%; P = .0054).
The most common adverse events in the ibrutinib arm were of grade 1 and did not result in treatment discontinuation. They included diarrhea, fatigue, cough, and nausea. The most common events with chlorambucil were nausea, fatigue, neutropenia, anemia, and vomiting.
Grade 3 maculopapular rash occurred in 3% of patients receiving ibrutinib vs 2% for chlorambucil. No cases of grade 4 maculopapular rashes occurred among patients receiving ibrutinib. Adverse events leading to treatment discontinuation were less frequent with ibrutinib (9% vs 23%).
The study was supported by Pharmacyclics, by grants from the National Institutes of Health, and by the MD Anderson Moon Shot Program in CLL. Several coauthors report relationships with industry, and several coauthors were employees of Pharmacyclics/AbbVie.
American Academy of Addiction Psychiatry (AAAP) 26th Annual Meeting. Abstract 495. Presented December 6, 2015.
N Engl J Med. Published online Dec 6, 2015. Abstract
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