Adding the targeted drug Imbruvica to a standard combination treatment reduced the risk of disease progression by 80 percent compared with the standard combination alone in patients with pretreated CLL or SLL.
Adding the targeted drug Imbruvica (ibrutinib) to a standard combination treatment reduced the risk of disease progression by 80 percent compared with the standard combination alone in patients with pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to results from the phase 3 HELIOS study.
Imbruvica prevents new cancer cells from growing by inhibiting the activity of the enzyme Bruton’s tyrosine kinase (BTK). In the study, it was added to the standard pairing of the chemotherapy Treanda (bendamustine) and Rituxan (rituximab), which recognizes the protein CD20 on the outsides of cancerous B cells and helps the immune system to kill them.
The significant progression-free survival (PFS) benefit of the triplet combination was determined during an interim analysis in March 2015, at which point the study was unblinded and patients receiving placebo were allowed to cross over to the Imbruvica arm.
The results were announced May 30 during the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.
“This becomes one of the most important changing points in the history of CLL, where the treatment of CLL patients will no longer be BR (bendamustine/rituximab), but BR with ibrutinib,” lead study author Asher Chanan-Khan, a professor of Medicine at Mayo Clinic, said when presenting the HELIOS data during a press briefing during the ASCO meeting.
The double-blind, phase 3 HELIOS trial randomized 578 previously treated patients with measurable relapsed/refractory CLL/SLL to BR for a maximum of six cycles plus either placebo (n = 289) or 420 mg/day of Imbruvica (n = 289). The full six cycles of BR were completed by 83 percent and 78 percent of patients in the Imbruvica and placebo arms, respectively.
The median patient age was 64 years, and patients had received an average of two prior therapies. Patients with 17p deletions, a chromosomal glitch, affecting more than 20 percent of cells were not included in the study.
The study was powered to detect a hazard ratio (HR) of 0.70 with a P value of .025 for significance. PFS was the primary outcome measure, with secondary endpoints focused on overall survival (OS) and objective response rate (ORR).
The interim analysis was conducted following 50 percent of events. At the time of the review, 31 percent (n = 90) of patients had progressed on placebo and crossed over to the Imbruvica arm, as allowed by the study design.
At a median follow-up of 17.2 months, PFS with Imbruvica was not yet reached, as compared with 13.3 months for patients receiving BR alone (HR = 0.203; 95% confidence interval [CI], 0.150-0.276; P <.0001). The PFS benefit held up across subgroups of high-risk patients.
Commenting on the PFS data, Chanan-Khan said, “You cannot get a better hazard ratio than this. It brings a lot of joy to see such an impactful therapy altering the course of the disease so early…The [PFS] curves started to differentiate four months into analysis, and that is a great testament of how soon the impact of this regimen was.”
ORR was 82.7 percent in the Imbruvica arm versus 67.8 percent in the control group (P <.0001). Complete response (CR) rates (including CR with incomplete blood count recovery) were 10.4 percent versus 2.8 percent with Imbruvica versus placebo, respectively.
The OS analysis showed a nonsignificant 37 percent reduction in the risk of death (P = .0598). Chanan-Khan said the crossover to the Imbruvica arm that was allowed when the trial was unblinded confounded the OS data.
The toxicity profile was similar between the two study arms, and the side effects in the triplet arm were consistent with previously reported safety outcomes for Imbruvica and BR. “The side effect profile was very tolerable and expected for each of the individual drugs that was in this regimen,” said Chanan-Khan.
The most frequently reported all-grade side effects in the Imbruvica versus the placebo arm were neutropenia (58.2 percent vs 54.7 percent), nausea (36.9 percent vs 35.2 percent), diarrhea (35.5 percent vs 23.7 percent), thrombocytopenia (30.7 percent vs. 24.4 percent), fever (24.7 percent vs 22 percent), anemia (22.6 percent vs 28.9 percent), and fatigue (21.6 percent vs 22.6 percent). The most commonly reported graded ¾ side effects werhe hematologic: neutropenia (53.7 percent vs 50.5 percent) and thrombocytopenia (15.0 percent in each arm).
Rates of grade 1/2 bleeding were higher in the triplet versus the BR-alone arm, including hematoma (8 percent vs 1 percent), contusion (7.7 percent vs 3.1 percent), nosebleeds (5.9 percent vs 3.1 percent), ecchymosis — bleeding into the skin (3.1 percent vs 0.7 percent), and the petechiae, or spots on the skin, that can occur as a result of that bleeding (2.8 percent vs 0.3 percent).
Grade ≥3 hemorrhage occurred in 3.8 percent of patients receiving the triplet, compared with 1.7 percent of those receiving BR alone. Grade 3/4 major hemorrhage and atrial fibrillation rates were 2.1 percent versus 1.7 percent and 2.8 percent versus 0.7 percent in the Imbruvica versus placebo arms, respectively. Side effects led to treatment discontinuation in 14.2 percent and 11.8 percent of patients in the triplet and control arms, respectively.
Imbruvica is an irreversible small-molecule inhibitor of BTK and works by blocking B-cell activation and signaling, preventing the growth of malignant B cells that overexpress BTK.
The FDA initially approved Imbruvica in November 2013 for patients with mantle cell lymphoma (MCL) following at least one prior therapy. In February 2014, the FDA approved Imbruvica for patients with previously treated CLL, which was then followed by a full FDA approval and a new indication for high-risk patients with 17p deletions in July 2014.
The full approval and expanded indication were based on data from the phase 3 RESONATE study, in which Imbruvica lowered the risk of progression by 75 percent in patients with CLL who harbored a 17p deletion and by 78 percent in the full population of the study when compared with the anti-CD20 drug Arzerra (ofatumumab). At 12 months, the OS rate was 90 percent for patients treated with Imbruvica compared with 81 percent in the Arzerra group. The median OS was not reached for patients treated with Imbruvica (HR = 0.43; 95% CI, 0.24-0.79; P = .005).
Imbruvica was also granted an indication for Waldenström’s macroglobulinemia in January 2015.
Janssen Research & Development, a subsidiary of Johnson & Johnson, funded the HELIOS trial. Janssen developed Imbruvica in collaboration with Pharmacyclics, which recently became a wholly-owned subsidiary of AbbVie in a multibillion-dollar acquisition.
Pharmacyclics announced in a press release that the full HELIOS data would be submitted to regulatory authorities for future Imbruvica labeling considerations.
“We knew ibrutinib was an effective single-agent treatment option with an established safety profile, and we now have additional evidence suggesting that ibrutinib improves outcomes when combined with existing treatment regimens," HELIOS investigator Simon Rule, consultant hematologist in the Department of Hematology, and Head of the Lymphoma Service, at Derriford Hospital in the United Kingdom, said in the press release. “The results from the HELIOS trial are very encouraging for previously treated patients with CLL or SLL, and suggest that the ibrutinib combination may be an option for these patients moving forward.”
Chanan-Khan AAA, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): first results from a randomized, double-blind, placebo-controlled, phase III study. J Clin Oncol. 2015;33 (suppl; abstr LBA7005).