MZL

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.

References:
  1. Noy A. et al. Targeting BTK with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017 Feb 6. DOI: 1182/blood-2016-10-747345. [Epub ahead of print: 2017 Feb 6]

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.

Expert Opinion

MZL is ready for “Prime time”

Marginal Zone Lymphoma (MZL) represents 4–8% of B-cell malignant lymphomas and has rarely been studied as a separate entity from the other indolent B-cell lymphomas. As a result, clinical research has never been able to identify standard treatments for MZL, either for the untreated or for the Relapsed/Refractory (R/R) patients, and no drug has ever received specific approval for MZL by the national drug agencies.

Several agents have been studied so far in MZL, mainly in the R/R setting, including rituximab, lenalidomide, bortezomib, and idelalisib; however, most of the available data comes from sub-group analysis of larger studies including other lymphoma subtypes and only allows identification of signals of activity. With their phase II study of ibrutinib used as single agent for the treatment of R/R MZL, Noy et al. should be congratulated because they were able to move MZL to “prime time”, providing convincing activity and safety data to identify ibrutinib as a new standard treatment in this rare lymphoma subtype. These data have relevant consequences that go beyond clinical data. The first one is for the patient as, based on published data, for the first time in MZL ibrutinib has been granted accelerated approval by the FDA for the treatment of R/R cases. Also, and equally important, we now have for the first time in MZL clearer data that can be used as reference for clinical research development. From now on, the road for clinical research in MZL is open to new development and it will be easier to design clinical trials in MZL.

Finally, as also highlighted by the same authors, the confirmed activity of ibrutinib in MZL confirms that BCR signaling is an essential pathway in this lymphoma subtype and opens new research questions to improve our understanding of the biology of this rare lymphoma subtype, building the basis for further improvement in the management of the disease.