ASH 2018 | Results from the phase III iLLUMINATE trial on chemotherapy-free first-line treatment for CLL/SLL

On Monday 3 December 2018, Oral Session 642 took place at the 60^th American Society of Hematology (ASH) Annual Meeting, San Diego, CA. During that session, results from the phase III iLLUMINATE (PCYC-1130) trial (Abstract #691) were presented by Carol Moreno from the Autonomous University of Barcelona, Barcelona, SP.

In this international, multicenter, randomized, phase III trial two combination regimens were investigated as first-line treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Ibrutinib and obinutuzumab combination was compared to chlorambucil and obinutuzumab for their efficacy and safety. This study is one of the first to compare a chemotherapy-free regimen to chemo-immunotherapy for CLL/SLL patients. The primary endpoint of the study was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). Secondary endpoints include overall response rate (ORR), overall survival (OS), safety, rate of undetectable minimal residual disease (MRD), and PFS by IRC in the high-risk population.

Study design & baseline characteristics

• N = 229 previously-untreated CLL/SLL patients, aged ≥ 65 or < 65 with ≥ 1 co-existing condition (CIRS > 6; CrCl < 70 ml/min; del(17p) or TP53 mutation)
• Median age (range) = 71 (40−87) years
• Randomized 1:1 dosing:
  • Ibrutinib & Obinutuzumab (Ibr-G; six 28-day cycles; n = 113 patients):
    • 420 mg ibrutinib once daily until disease progression (PD) or unacceptable toxicity
    • 1000 mg obinutuzumab split on Days 1−2, and on Day 8 and 15 (cycle 1) then on Day 1
  • Chlorambucil & Obinutuzumab (Clb-G; six 28-day cycles; n = 116 patients):
    • 5 mg/kg on Days 1 and 15
    • 1000 mg obinutuzumab split on Days 1−2, and on Day 8 and 15 (cycle 1) then on Day 1
    • After IRC-confirmed PD patients in this arm were allowed single-agent ibrutinib
  • Sixty-five percent of patients from both arms had high-risk genomic features

Results

• Median follow-up (range): 31.3 (0.2−36.9) months
• Median PFS by bulky disease status:
  • Ibr-G: not reached
  • Clb-G: 14.7 months
• Median PFS by high-risk features:
  • Unmutated IGHV: not reached in the Ibr-G arm, 14.6 months in the Clb-G
  • Del(11q): not reached in the Ibr-G arm, 15.2 months in the Clb-G
  • Del(17p): not reached in the Ibr-G arm, 11.3 months in the Clb-G
• Estimated PFS at 30 months:
  • Ibr-G: 79%
  • Clb-G: 31%
• IRC-assessed ORR rates were (P < 0.01):
  • Ibr-G: 88%
  • Clb-G: 73%
• IRC-assessed complete response (CR/CRi) rates were (P < 0.01):
  • Ibr-G: 19%
  • Clb-G: 8%
• IRC-assessed partial response (PR) rates were:
  • Ibr-G: 65%
  • Clb-G: 66%
• IRC-assessed stable disease (SD) rates were:
  • Ibr-G: 6%
  • Clb-G: 21%
• In the high-risk population, IRC-assessed ORR rates were:
  • Ibr-G: 90%
  • Clb-G: 68%
• In the high-risk population, IRC-assessed CR/CRi rates were:
  • Ibr-G: 14%
  • Clb-G: 4%
• In the high-risk population, there was 85% reduction in risk of progression or death with Ibr-G
• Among high-risk CLL patients without del(17p), there was 84% reduction in risk of progression or death with Ibr-G
• Among unmutated IGHV patients without del(17p), there was 85% reduction in risk of progression or death with Ibr-G
• Forty percent (n =46/116) of patients randomized to Clb-G crossed over to receive single-agent ibrutinib
• No significant difference in OS was observed between Clb-G and Ibr-G patients at the median follow-up
• In the Ibr-G arm, 70% of patients are still receiving ibrutinib treatment
• Salvage treatment for relapsed disease was required in 4% of patients in the Ibr-G versus 44% in the Clb-G group
• Patients in the Ibr-G had a 94% reduction in the need for second-line therapy

Safety

• Most frequent adverse events (AEs) of any grade:
  • Neutropenia: 43% in Ibr-G versus 63% in Clb-G
  • Thrombocytopenia: 35% in Ibr-G versus 25% in Clb-G
  • Diarrhea: 34% in Ibr-G versus 10% in Clb-G
  • Cough: 27% in Ibr-G versus 12% in Clb-G
  • Infusion-related reactions (IRRs): 25% in Ibr-G versus 58% in Clb-G
  • Arthralgia: 22% in Ibr-G versus 10% in Clb-G
  • Pyrexia: 19% in Ibr-G versus 26% in Clb-G
  • Anemia: 17% in Ibr-G versus 25% in Clb-G
  • Nausea: 12% in Ibr-G versus 30% in Clb-G
• IRRs were less frequent in the Ibr-G group when compared to the Clb-G arm (P < 0.0001)

Conclusions

• Ibr-G is an effective chemotherapy-free option for first-line CLL/SLL treatment, including high-risk populations
• Ibr-G provided greater progression and death risk reduction than Clb-G
• Patients receiving Ibr-G achieved higher CR and undetectable MRD rates
• Ibr-G was associated with a reduced risk of IRRs
• This study indicates that Ibr-G led to superior PFS when compared to the current standard-of-care chemotherapy regimens