Targeting BTK with ibrutinib shown to be effective in R/R MZL

In February 2017, Ariela Noy from the Memorial Sloan Kettering Cancer Center, Weill Cornell Medical School, New York, and colleagues reported in Blood the results of an international, multicenter, open-label, phase II trial into the efficacy and safety of using the BTK inhibitor ibrutinib in the treatment of Relapsed or Refractory (R/R) MZL. The study recruited 63 patients with R/R MZL across all subtypes who received daily ibrutinib at 560mg until disease progression, intolerable toxicity, or until three years had passed. In total, 60 patients were in the evaluable population after exclusions due to non-measurable baseline disease. Investigator (Inv.) and independent (Ind.) assessments were conducted and each set of results reported.

Key Highlights:

• Enrolled 63 pts, 32 pts with extranodal MZL, 17 pts with nodal MZL, 14 pts with splenic MZL
• Median number of prior therapies = 2; 63% previously received anti-CD20 chemoimmunotherapy, 27% previously received rituximab monotherapy alone
• ORR = 53% (95% CI, 40–66), CR = 7% (n=4)
• ORR = 48% (95% CI, 35–62), CR = 4% (n=2)
• Median follow-up of 19.4 months:
  • Median Inv. PFS = 15.0 months (95% CI, 12–NE)
  • Median Ind. PFS = 14.2 months (95% CI, 8.3–NE)
  • Median PFS by subtype:
    • Extranodal = 13.8 months (95% CI, 8.3–NE)
    • Nodal = 8.3 months (95% CI, 2.8–NE)
    • Splenic = 19.4 months (95% CI, 8.2–NE)
  • Estimated 18-month OS = 81% (95% CI, 68–89)
  • Safety:
    • TEAEs ≥Grade 3 = 67% pts
    • Infections ≥Grade 3 = 19% pts
    • Serious TEAEs = 44% pts
    • AE leading to dose reductions = 10% pts
    • Treatment-related deaths: n=3 (PD, cerebral hemorrhage, multiple system organ failure)
  • Twenty-four pts (38%) continue ibrutinib after median follow-up of 19.4 months
  • In total, 39 pts (62%) discontinued treatment due to: PD = 20 pts (32%), AEs = 11 pts (17%), investigator decision = 4 pts (6%), or withdrawal of consent = 4 pts (6%)

In conclusion, the authors state that single-agent ibrutinib was “well tolerated” in this study, and had a safety profile consistent with other ibrutinib studies in NHL and CLL. The results of this study also indicate that BCR signaling via BTK is a pivotal pathway contributing to the tumorigenesis of MZL. Furthermore, ibrutinib showed a high durable ORR across R/R MZL subtypes and could be a new treatment option with a positive risk-benefit profile.

Abstract:

Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically-confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody-containing regimen were treated with ibrutinib 560 mg orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed overall response rate (ORR) by 2007 IWG criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ≥1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% CI, 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7-NE), and median progression-free survival was 14.2 months (95% CI, 8.3-NE). Grade ≥3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit-risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. Given the lack of approved therapies, ibrutinib may provide a treatment option without chemotherapy for MZL.