Risk of Progression Significantly Reduced With Upfront Ibrutinib and Obinutuzumab in CLL/SLL

Carol Moreno, MD

A significant reduction in the risk of disease progression or death was observed from treatment with the upfront combination of ibrutinib (Imbruvica) plus obinutuzumab (Gazyva) in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) compared with chlorambucil and obinutuzumab. 

In results from the phase III iLLUMINATE (PCYC-1130) trial presented at the 2018 ASH Annual Meeting, a 77% reduction in risk was noticed for patients with CLL/SLL and an 85% reduction for patients with high-risk CLL.^1,2

“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])/TP53mutations, 11q deletion (del[11q]), and/or unmutatedIGHVdisease—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-na&iuml;ve patients were &ge;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) orTP53mutation. 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 unmutatedIGHVdisease, 12% had del(11q), and 16% had del(17p) and/orTP53mutations. In the chlorambucil/obinutuzumab arm, 53% of patients had unmutatedIGHVdisease, 19% had del(11q), and 20% had del(17p) and/orTP53-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 unmutatedIGHVdisease without del(17p).

&ldquo;While single-agent ibrutinib provides a PFS rate of 74% at 4 years, the combination of ibrutinib/obinutuzumab offers another option to achieve long-term PFS,&rdquo; said Moreno, a senior staff member, Department of Hematology, of the Hospital de Sant Pau i Santa Creu, Autonomous University of Barcelona in Barcelona, Spain.

OS had not yet been reached in either arm (HR, 0.92; 95% CI, 0.48-1.72;P= .81). Forty-six patients (40%) on the chlorambucil arm have crossed over to treatment with single-agent ibrutinib, Moreno added.

Ibrutinib combined with obinutuzumab also led to an improvement in ORR and complete response (CR) or CR with incomplete bone marrow recovery (CRi) rate when assessed by IRC and investigator assessment. In the IRC assessment, the ORR and CR/CRi rates were 88% and 19% with ibrutinib/obinutuzumab versus 73% and 8% with chlorambucil/obinutuzumab, respectively. The ORR and CR/CRi rates via investigator assessment were 91% and 41% versus 81% and 16%, respectively.

In the high-risk population, Moreno noted that the IRC-assessed ORR rates with ibrutinib/obinutuzumab and chlorambucil/obinutuzumab were 90% and 68%, respectively; the CR/Cri rates were 14% and 4%.

A minimal residual disease (MRD) analysis showed that uMRD in the ITT population was achieved in 35% of patients on ibrutinib/obinutuzumab when tested in the bone marrow and/or peripheral blood compared with 25% of those on chlorambucil/obinutuzumab. In the high-risk population, uMRD in the peripheral blood and/or bone marrow was achieved in 27% of those who received ibrutinib/obinutuzumab versus 15% with chlorambucil/obinutuzumab.

Ibrutinib combined with obinutuzumab also showed a prolongation in time to next treatment. The median has not been reached in either arm (HR, 0.06; 95% CI, 0.02-0.18;P<.0001) versus the comparator arm, yet results showed a 94% reduction in the risk for needing second-line therapy with the ibrutinib regimen. Moreover, salvage treatment for patients with relapsed disease was needed in 4% of patients on the ibrutinib arm compared with 44% of those on the chemoimmunotherapy arm.

The median duration of treatment was 29.3 months with ibrutinib and 4.6 months with obinutuzumab compared with 5.1 months and 4.6 months with chlorambucil and obinutuzumab, respectively. Treatment was discontinued in 30% of patients who received ibrutinib; the primary reason for discontinuation was adverse events (AEs; 16%).

The safety profiles were consistent with AEs expected with each agent alone. The most frequent AEs reported in the ibrutinib and chlorambucil arms during the AE period—defined as time from the first dose until 30 days after the last dose of treatment or initiation of subsequent antineoplastic therapy&mdash;were neutropenia (43% with ibrutinib vs 63% with chlorambucil), thrombocytopenia (35% vs 25%), diarrhea (34% vs 10%), cough (27% vs 12%), IRRs (25% vs 58%), arthralgia (22% vs 10%), pyrexia (19% vs 26%), anemia (17% vs 25%), and nausea (12% vs 30%). Obinutuzumab dose was interrupted due to IRRs in 6% of patients on ibrutinib versus 30% of those on chlorambucil.

Grade &ge;3 AEs during the AE period occurred in 77% of patients on ibrutinib/obinutuzumab versus 72% of those on chlorambucil/obinutuzumab. The most frequently reported in both arms were neutropenia (36% with ibrutinib vs 46% with chlorambucil), thrombocytopenia (19% vs 10%), pneumonia (7% vs 4%), febrile neutropenia (4% vs 6%), IRRs (2% vs 8%), and anemia (4% vs 8%).

The FDA approved ibrutinib as a frontline treatment of patients with CLL in March 2016; the agent was previously approved by the FDA for patients with CLL, pretreated mantle cell lymphoma, and Waldenstr&ouml;m&rsquo;s macroglobulinemia.

References:

1. Moreno C, Greil R, Demirkan F, et al. Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE. In: Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 691.
2. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicenter, randomized, open-label, phase 3 trial [published online ahead of print, December 3, 2018].Lancet Oncol. doi: 10.1016/S1470-2045(18)30788-5.