Phase III Data Showcase PFS Benefit With Frontline Ibrutinib/Obinutuzumab Combo in High-Risk CLL

Gina Columbus @ginacolumbusonc
Published: Monday, Dec 03, 2018

Carol Moreno, MD

Carol Moreno, MD

The first-line combination of ibrutinib (Imbruvica) and obinutuzumab (Gazyva) was associated with a 77% reduction in the risk for disease progression or death compared with chemoimmunotherapy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to data from the phase III iLLUMINATE (PCYC-1130) trial that were presented at the 2018 ASH Annual Meeting.1,2

Results also showed that there was an 85% reduction in the risk for disease progression or death in patients with high-risk CLL who were treated with the BTK inhibitor regimen.

“Ibrutinib [plus] obinutuzumab represents an effective chemotherapy-free treatment regimen for (treatment-naïve) patients with CLL—including importantly, for patients with high-risk features,” said lead study author Carol Moreno, MD, who presented the findings during the meeting. “iLLUMINATE is the first study to prospectively evaluate a chemotherapy-free regimen against chemoimmunotherapy, including a genomically defined high-risk CLL population.”

In October 2018, the FDA granted a priority review designation to a supplemental new drug application for the frontline regimen of ibrutinib plus obinutuzumab in this patient population based on the iLLUMINATE findings. If approved, ibrutinib plus obinutuzumab could become the first chemotherapy-free, anti-CD20 combination available in the United States for the first-line treatment of patients with CLL/SLL.

The international, open-label, randomized, phase III iLLUMINATE trial randomized 229 patients 1:1 to receive 420 mg of continuous ibrutinib daily plus 1000 mg of obinutuzumab split on days 1-2, and on days 8 and 15 of cycle 1, and day 1 of the subsequent 28-day cycles for 6 cycles; or 0.5 mg/kg of chlorambucil on days 1 and 15 of each 28-day cycle for 6 cycles plus the obinutuzumab regimen.

The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee (IRC); secondary endpoints were PFS in a high-risk patient population—those with 17p deletion [del(17p)]/TP53 mutations, 11q deletion [del(11q)], and/or unmutated IGHV disease—rate of undetectable minimal residual disease (uMRD), overall response rate (ORR), overall survival (OS), infusion-related reactions (IRRs), and safety. Patients who progressed on chlorambucil/obinutuzumab, determined by IRC, were permitted to cross over to second-line therapy with ibrutinib monotherapy.

To be eligible for enrollment, treatment-naïve patients were ≥65 or <65 years of age with a Cumulative Illness Rating Scale (CIRS) score >6, creatinine clearance (CrCI) <70 mL/min, and/or del(17p) or TP53 mutation. The median age was 71 years (range, 40-87) and 65% of patients had high-risk genomic features. Fifty-two percent of patients overall had either Rai III or IV disease, while bulky disease was in 27% of ibrutinib-treated patients and 38% of patients who received chlorambucil therapy.

In the ibrutinib cohort, 62% of patients had unmutated IGHV disease, 12% had del(11q), and 16% had del(17p) and/or TP53 mutations. In the chlorambucil/obinutuzumab arm, 53% of patients had unmutated IGHV disease, 19% had del(11q), and 20% had del(17p) and/or TP53-mutant disease. Thirty-three percent of patients in the ibrutinib cohort had a CIRS score >6 versus 31% of those treated with chemoimmunotherapy; 23% in the ibrutinib arm had CrCI <60 mL/min compared with 33% of those who received chlorambucil.

At a median follow-up of 31.3 months (range, 0.2-36.9), the median PFS with ibrutinib and obinutuzumab was not reached by IRC compared with 19.0 months with standard chemoimmunotherapy (HR, 0.23; 95% CI, 0.15-0.37; P <.0001). By investigator assessment, the median PFS was again not reached with the ibrutinib regimen versus 21.9 months for the chlorambucil arm (HR, 0.26; 95% CI, 0.16-0.42; P <.0001). The estimated median PFS at 30 months was 79% with ibrutinib and obinutuzumab and 31% with chlorambucil/obinutuzumab.

The PFS benefit with ibrutinib and obinutuzumab was consistent across subgroups. For patients with bulky disease, the median PFS was not reached with the ibrutinib regimen versus 14.7 months with chlorambucil/obinutuzumab. Additionally, for those with unmutated IGHV who received ibrutinib/obinutuzumab, the median PFS was not reached and was 14.6 months for chemoimmunotherapy. In patients with del(11q) and del(17p), the median PFS was not reached with ibrutinib and was 15.2 months and 11.3 month, respectively, with chemoimmunotherapy.

Additionally, by IRC assessment, ibrutinib/obinutuzumab demonstrated an 85% reduction in the risk of progression or death in high-risk patients, an 84% reduction among high-risk patients with del(17p), and an 85% reduction in the risk of progression or death among patients with unmutated IGHV disease without del(17p).

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