DLBCL|FL|MCL|MZL|WM

Results from first venetoclax phase I human trial in R/R NHL

This month in the Journal of Clinical Oncology, Matthew S. Davids, from the Dana-Farber Cancer Institute, Boston, MA, and colleagues published the results of the first phase I human trial using venetoclax in R/R NHL subtypes including DLBCL, MCL, FL, WM, and MZL. Their aim was to understand the safety profile and efficacy of venetoclax at different doses using dose escalation after a three week ramp up. Venetoclax inhibits the protein called B-Cell Leukemia/Lymphoma-2 (BCL-2) which is known to be overexpressed in NHL subtypes. BCL-2 itself is an anti-apoptotic protein which when overexpressed prevents programmed cell death.

Key Highlights:

  • Total of 106 pts recruited with R/R NHL: 34 DLBCL, 29 FL, 28 MCL, 4 WM, 3 MZL, 7 Richter transformation (DLBCL occurring from CLL)
  • Venetoclax dose escalation ranged from 200–1,200mg/day using cohorts of three or more patients in a 3 + 3 design
    • Seventy pts in dose-escalation group, 36 pts in safety expansion group (target 1,200mg)
    • Dose escalation was ramped up only if there was no evidence of TLS, increased once per week
    • Treatment continued until unacceptable toxicity, disease progression, or withdrawal
  • All NHL: ORR = 44%, CR = 13%, PR = 31% (OS = 70%, mPFS = 6 months)
    • MCL: ORR = 75%, CR = 21% (OS = 82%, mPFS = 14 months)
    • FL: ORR = 38%, CR = 14% (OS = 100%, mPFS = 11 months)
    • DLBCL: ORR = 18%, CR = 12% (OS = 32%, mPFS = 1 month)
    • DLBCL-RT: ORR = 43%, CR = 0%
    • WM: ORR = 100%, CR = 0%
    • MZL: ORR = 67%, CR = 0%
  • Adverse events:
    • Grade 3 or 4 AEs seen in 56% pts regardless of dose received (15% anemia, 11% neutropenia, 9% thrombocytopenia)
    • Two DLTs in 600mg dose-escalation group – both resolved
    • Dose reduction in 15 pts
    • Ten deaths within 30 days of treatment end due to disease progression
    • Twenty-eight deaths 30 days after treatment end, 24 due to disease progression

The authors stated in the discussion that a dosing strategy beginning at 400mg for a week, before increasing weekly to 800mg, then 1,200mg with monitoring for TLS in NHL other than MCL is suggested for further study. Given the authors data they stated that the maximum cleared dose was found to be 1,200mg for FL and DLBCL, 800mg for MCL, and 600mg for DLBCL-RT. The authors concluded by stating that while venetoclax was shown to be an active single agent treatment option with favorable toxicity profile, combination with other therapies may result in greater efficacy. Further trials into venetoclax use are ongoing.

Reference:
  1. Davids M.S. et al. Phase I First-in-Human Study of Venetoclax in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma. Journal of Clinical Oncology. 2017 Jan 17. DOI: 10.1200/JCO.2016.70.4320 [Epub ahead of print 2017 Jan 17].

Abstract: Purpose. B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods. A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results. NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenstrom macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment- emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion. Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.