Venetoclax and obinutuzumab combination for R/R or naïve CLL patients

On 12 March 2019, Ian Flinn from the Sarah Cannon Research Institute & Tennessee Oncology, Nashville, TN, USA, and colleagues, published in Blood the results of a phase Ib trial investigating the safety and maximum tolerable dose (MTD) for venetoclax when combined with obinutuzumab in chronic lymphocytic leukemia (CLL) patients.

In this multicenter, single-arm, open label, phase Ib trial (NCT01685892) the MTD of venetoclax in combination with obinutuzumab, as well as the safety and preliminary efficacy of this combination treatment was tested in relapsed or refractory (R/R) and in previously-untreated CLL patients.

Study design

• N = 78 CLL patients, aged ≥ 18 years with Eastern Cooperative Oncology Group (ECOG) performance status 0−1 who were either naïve (1L; n = 32) or R/R (n = 45)
  • R/R CLL patients must have received 1−3 prior chemotherapy-containing lines (patients with 17p deletion and/or TP53 mutation could have received at least one prior line with alemtuzumab-based treatment or ibrutinib or idelalisib)
• Two study phases for each patient population (R/R and 1L):
  • Dose establishing phase
    • R/R patients enrolled: n = 23
    • 1L patients enrolled: n = 12
    • Six 28-day treatment cycles with multiple venetoclax doses ranging from 100−400 mg combined with standard-dose obinutuzumab (cycle 1: 100 mg Day 1, 900 mg Day 2, 1000 mg Days 8 and 15; cycles 2−6: 100 mg Day 1)
      • Schedule A (n = 22): venetoclax ramp-up, followed by obinutuzumab
      • Schedule B (n = 13): obinutuzumab loading dose over 21 days followed by venetoclax
    • Venetoclax monotherapy was administered at the end of the sixth treatment cycle until disease progression (PD), unacceptable toxicity or death in the R/R population or until the completion of one-year fixed treatment duration in 1L patients
    • Standard 3 + 3 dose escalation design
    • For TLS prophylaxis hydration, allopurinol, rasburicase, and hospitalisation for the first venetoclax dose were considered
  • Safety expansion phase
    • R/R patients enrolled: n = 22
    • 1L patients enrolled: n = 20
    • Following review of the dose-establishing data and program-wide data from an internal monitoring committee (IMC) and an external scientific overview committee (SOC, composed of CLL experts) the recommended dosing schedules for this phase were established
  • In the R/R cohort:
    • Median number of prior lines (range): 2 (1−6)

Key results

• No dose limiting toxicities were observed with either Schedule A or B during the dose-establishing phase
• The venetoclax MTD was not reached
• The IMC and SOC recommended Schedule B for obinutuzumab administration followed by venetoclax, and a venetoclax dose of 400 mg for the safety-expansion phase
• Patients who received 400 mg of daily venetoclax:
  • R/R patients: 80% (n = 36/45)
  • 1L patients: 100% (n = 32/32)
• Patients completing six venetoclax-obinutuzumab cycles:
  • R/R patients: 93% (n = 42/45)
  • 1L patients: 100% (n = 32/32)
• Median venetoclax treatment duration (range):
  • R/R patients: 789 (8−1516) days
  • 1L patients: 371 (314−883) days
• Median venetoclax dose intensity (range):
  • R/R patients: 100% (31−100)
  • 1L patients: 100% (53−100)
    • Twelve 1L patients received venetoclax beyond one year
  • Two patients discontinued treatment due the following adverse events (AEs) prior to completion of two cycles of combination treatment:
    • Grade 2 respiratory infection (n = 1)
    • Grade 2 ulcerative colitis (n= 1)
  • No differences in safety or the rate of TLS was observed between Schedule A and B cohorts
  • At least one AE mainly of Grade 1−2 (87%) was observed in all evaluable patients (N = 77)
  • The most common AEs were:
    • Infections
    • Diarrhea
    • Infusion-related reactions (all were Grade 1−2 except for two Grade 3 events in the R/R cohort that led to obinutuzumab discontinuation)
    • Neutropenia
  • Grade 3−4 AEs after combination treatment were reported in:
    • R/R patients: 76% of patients
    • 1L patients: 66% of patients
  • The most common Grade 3−4 AEs after combination treatment were:
    • Neutropenia (R/R, 49%; 1L, 47%)
    • Infections (R/R, 18%; 1L, 6%)
  • No clinical TLS was reported
    • During the safety-expansion phase of the study, one laboratory TLS occurred in a 1L patient after obinutuzumab and before initiation of venetoclax
  • Venetoclax was discontinued due to AEs in:
    • R/R patients: 16% (n = 7/45)
    • 1L patients: 3% (n = 1/32)
  • Obinutuzumab was discontinued due to AEs in:
    • R/R patients: 4% (n = 2/45)
    • 1L patients: 0%
  • Deaths were reported in:
    • R/R patients: 7% (n = 3/45)
      • Acute respiratory failure (n = 1)
      • Pneumonia (n = 2)
    • 1L patients: 0%

Efficacy

• Overall response rate (ORR):
  • R/R patients: 95% (95% CI, 84−99)
  • 1L patients: 100% (95% CI, 89−100)
• Patients achieving complete response (CR) or CR with incomplete recovery (CRi):
  • R/R patients: 37% (95% CI, 23−53)
  • 1L patients: 78% (95% CI, 60−91)
• Patients with PD:
  • R/R patients: n = 12
    • Seven of the twelve R/R patients had a 17p deletion/TP53 mutation
  • 1L patients: n = 4
    • Three of the four 1L patients had a 17p deletion/TP53 mutation
  • Undetectable peripheral blood minimal residual disease (PB uMRD) rate ≥ 3 months after last obinutuzumab dose:
    • R/R patients: 64% (n = 27/42)
    • 1L patients: 91% (n = 29/32)
  • Estimated two-year progression-free survival (PFS):
    • R/R patients (median follow-up, 29.3 months): 85.4% (95% CI, 74.5−2)
    • 1L patients (median follow-up, 26.7 months): 90.6% (95% CI, 80.5−100)
  • Median duration of response (range):
    • R/R patients: 40.9 (39.9−8) months
    • 1L patients: not reached

Conclusions

• In this study, the established venetoclax dose in combination with obinutuzumab for R/R or naïve CLL patients was 400 mg daily
• Combination therapy with venetoclax and obinutuzumab had an acceptable safety profile and led to durable responses and high rates of PB uMRD
• Further validation of these preliminary results is needed to confirm the efficacy and safety of venetoclax and obinutuzumab combination in R/R or naïve CLL patients