In the long-term, phase 1b/2 PCYC-1102 clinical trial, single-agent ibrutinib, the first FDA-approved once-daily Bruton’s tyrosine kinase inhibitor, showed efficacy and good tolerability in patients with chronic lymphocytic leukemia (CLL) or with small lymphocytic lymphoma (SLL), including patients with deletion (del)17p.
The study included 132 patients (aged ≥65 years) with treatment-naïve (N = 31) or with relapsed or refractory (N = 101) CLL or SLL to ibrutinib 420 mg or 840 mg daily until disease progression or until unacceptable toxicity. The overall response rate (ORR), including partial response with lymphocytosis, was assessed based on risk group, including lack of IGHV mutation, complex karyotype, and based on hierarchical order for del17p then del11q.
At 5 years of follow-up, the longest study period for single-agent ibrutinib in this patient population, the ORR was 89%, including complete response (CR) of 14%, for all patients. The ORR was 87% in the treatment-naïve arm (CR, 29%), and 89% in the relapsed or refractory arm (CR, 10%).
The median progression-free survival (PFS) was not reached in the treatment-naïve arm compared with 52 months in the relapsed or refractory arm; the estimated 60-month PFS rates were 92% and 43%, respectively. In the relapsed or refractory arm, the median PFS was 55 months in patients with del11q; 26 months for patients with del17p; and the PFS was not reached in patients without del17p, del11q, trisomy 12, or del13q. Furthermore, the median PFS was 33 months in patients with complex karyotype; it was not reached in patients without complex karyotype; it was 43 months in patients without IGHV mutation, and 63 months in patients with IGHV mutation.
The 5-year overall survival (OS) was 92% in treatment-naïve patients and 57% in those with relapsed or refractory disease. The median OS was not reached in treatment-naïve patients; it was 63 months in patients who received 1 to 2 previous treatments, 59 months in patients who received 3 previous treatments, and 39 months in those who received ≥4 previous regimens. The median duration of response was not reached in treatment-naïve patients and was 45 months in patients with relapsed or refractory disease.
In all patients, the onset of treatment-emergent grade ≥3 adverse events (AEs) was highest in year 1 of therapy and was lower in subsequent years. At approximately 5 years of follow-up, the most common grade ≥3 AEs were, in order of frequency, hypertension, pneumonia, neutropenia, and atrial fibrillation; most of these events decreased over time.
Overall, ibrutinib demonstrated durable responses in patients with treatment-naïve or with relapsed or refractory CLL or SLL, including those with del17p, del11q, or without IGHV mutation. Long-term ibrutinib therapy was effective and well-tolerated, with a manageable safety profile, with 65% of treatment-naïve older patients and 30% of patients with relapsed or refractory disease continuing treatment at 5 years of follow-up.