Results of extended treatment with 420mg ibrutinib daily in ND and R/R CLL

In January 2017, Steven E. Coutré from the Stanford Cancer Center, Stanford University School of Medicine, Stanford, California, and colleagues reported the results of up to 44 months continued follow-up from the phase Ib/II study PCYC-1102, and its extension study PCYC-1103. The trials were evaluating the efficacy and safety of daily ibrutinib monotherapy at 420mg in the treatment of Treatment Naïve (TN) or Relapsed/Refractory (R/R) CLL, administered until disease progression or discontinuation.

Key Highlights:

• 94 CLL pts, TN = 27pts, R/R = 67 (two or more prior therapies, median 4)
  • TN group = ≥65 years old, average = 71 yrs
  • R/R group: average age = 66 yrs, del17p = 34% (23pts), del11q = 33% (18pts)
• TN group ORR = 85%, CR = 26%, PR = 52%
• R/R CLL group ORR = 94%, CR = 9%, PR = 82%
• Estimated 30-month PFS: TN = 96% (95% CI, 74–99), R/R = 76% (95% CI, 63–85­)
• Median PFS was not reached in both groups
• Estimated 30-month OS: TN = 96% (95% CI, 76–99), R/R = 87% (95% CI, 76–93­)
• Within R/R group:
  • 30-month OS: del17p = 81% (95% CI, 58–93), del11q = 88% (95% CI, 61–97), no del = 90% (95% CI, 66–98)
  • 30-month PFS: del17p = 60% (95% CI, 34–78), del11q = 82% (95% CI, 55–94), no del = 85% (95% CI, 60–95)
• Adverse events (AEs):
  • 13% discontinued due to progressive disease (4% of TN pts, 16% of R/R pts)
  • 13% discontinued due to AEs (11% of TN pts, 13% of R/R pts)
  • Most common ≥ Grade 3 AEs in TN: hypertension = 26%, pneumonia = 4%, neutropenia = 4%, and thrombocytopenia = 4%
  • Most common ≥ Grade 3 AEs in R/R: hypertension = 22%, pneumonia = 19%, neutropenia = 16%, thrombocytopenia = 7%, and anemia = 1%
  • Infectious events ≥ Grade 3 higher in R/R than TN group
  • Treatment-related AEs ≥ Grade 3: TN = 22%, R/R = 37%

In conclusion, the authors state that 66% pts remained on ibrutinib in the extension study at the 420mg dose, and that this resulted in durable responses that were tolerated well in both TN and R/R CLL settings. Future trials are investigating possible advantages of combination therapy in the treatment of CLL.

Abstract:

Purpose: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL. Experimental Design: We report data with 44 months of follow-up on 94 patients with TN and R/R CLL/SLL receiving ibrutinib 420 mg once-daily in PCYC-1102 and the long-term extension study PCYC-1103. Results: Ninety-four CLL/SLL patients (27 TN, 67 R/R) were treated with ibrutinib (420 mg/day). Patients with R/R disease had received a median of four prior therapies (range, 1–12). Responses were rapid and durable and median duration of response was not reached. Best overall response was 91% [85% TN (complete response, CR 26%) and 94% R/R (9% CR)]. Median progression-free survival (PFS) was not reached in either group. The 30-month PFS rate was 96% and 76% for TN and R/R patients, respectively. Ibrutinib was well tolerated with extended follow-up; rates of grade ≥3 cytopenias and fatigue, as well as discontinuations due to toxicities decreased over time. Conclusions: Single-agent ibrutinib at 420 mg once-daily resulted in durable responses and was well tolerated with up to 44 months follow-up in patients with TN and R/R CLL/SLL. Currently, 66% of patients continue on ibrutinib.