FDA Approves Ibrutinib Plus Obinutuzumab in Frontline CLL/SLL

The FDA has approved the combination of ibrutinib (Imbruvica) and obinutuzumab (Gazyva) for the first-line treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The decision is based on results from the phase III iLLUMINATE (PCYC-1130) trial, in which the combination demonstrated a 77% reduction in the risk of progression or death compared with chlorambucil plus obinutuzumab. Moreover, at a median follow-up of 31 months, the median progression-free survival (PFS), as assessed by an independent review committee (IRC), was not reached compared with 19 months for chlorambucil and obinutuzumab (HR, 0.23; 95% CI, 0.15-0.37; P <.0001).

"In just a few years, Imbruvica has become an important treatment for chronic lymphocytic leukemia,” said lead iLLUMINATE study author Carol Moreno, MD, PhD, consultant hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain. “Imbruvica as a single agent—and now as a combination with obinutuzumab—provides patients with CLL with an alternative to frontline treatment with chemoimmunotherapy.”

The agency also updated the ibrutinib label to include additional long-term efficacy data supporting its use as a monotherapy in CLL/SLL, with approximately 5-year follow-up data from the phase III RESONATE and RESONATE-2 trials.

"This label update builds upon the established efficacy and safety of Imbruvica in the frontline treatment of patients with CLL/SLL, as a monotherapy or in combination with other treatments," said Craig Tendler, MD, vice president, Clinical Development and Global Medical Affairs, Janssen Research & Development, LLC. "This milestone represents our continued commitment to develop Imbruvica-based, non-chemotherapy regimens to address the clinical needs of patients living 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 PFS as assessed by an 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.

Additional results shoed that patients with high-risk disease—which includes those with 17p deletion/TP53 mutation, 11q deletion, or unmutated IGHV—who were treated with the ibrutinib combination experienced an 85% reduction in the risk of progression or death (HR, 0.15; 95% CI, 0.09-0.27). The IRC-evaluated overall response rate was 89% in ibrutinib/obinutuzumab arm versus 73% in the chlorambucil/obinutuzumab arm.

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—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 ≥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%).

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.