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).
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 Imbruvixa 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 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.
In the ibrutinib cohort, 62% of patients had unmutated IGHVdisease, 12% had del(11q), and 16% had del(17p) and/or TP53mutations. 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.