Alisertib monotherapy for PTCL patients: Results from a phase III trial

On 1 February 2019, Owen O’Connor from Columbia University Medical Centre, New York, NY, USA and colleagues, published in the Journal of Clinical Oncology a phase III study (LUMIERE) investigating the efficacy of alisertib in relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) patients.

Alisertib is an investigational Aurora A kinase inhibitor. Aurora A kinase is involved in cell mitosis and accumulating evidence indicates its pathological upregulation in PTCL. From phase I-II studies the recommended dose and treatment pattern of alisertib monotherapy have been established, together with its promising activity in various lymphomas, including R/R B-cell and T-cell lymphomas. The aim of this randomized, multicenter, two-arm, open-label, phase III trial (NCT01482962) was to investigate the efficacy of alisertib monotherapy versus investigator’s choice treatment in R/R PTCL patients. The primary endpoints of this study were overall response rate (ORR), and progression-free survival (PFS). Secondary endpoints included, overall survival (OS), safety, complete response (CR) rate, time-to-progression (TTP), time-to-partial response (TTR), and duration of response (DoR). 

Study design & baseline characteristics

• N = 271 R/R PTCL patients after ≥ 1 prior system therapy, aged ≥ 18 were enrolled
• PTCL subtypes included:
  • PTCL-not otherwise specified (NOS)
  • Anaplastic large-cell lymphoma
  • Angioimmunoblastic T-cell lymphoma
  • Enteropathy associated T-cell lymphoma
  • Hepatosplenic T-cell lymphoma
  • Subcutaneous panniculitis-like T-cell lymphoma
  • Transformed mycosis fungoides
  • Extranodal natural killer/T-cell lymphoma nasal type
• Patients were stratified according to:
  • Extranodal disease
  • International Prognostic Index (IPI) score:
    • low/intermediate versus intermediate/high
  • Region:
    • North America and European Union versus the rest of the world
  • Patients were randomized in two arms:
    • Alisertib (Arm A; n = 138): orally, 50 mg twice daily on Days 1−7 (21-day cycles)
    • Investigator’s choice monotherapy (Arm B; n = 133), intravenously either of the following:
      • Gemcitabine (n = 30): 1000 mg/m² over 30 min, on Days 1, 8, and 15 (28-day cycles)
      • Pralatrexate (n = 80): 30 mg/m² over 3−5 min once weekly for six weeks (7-week cycles)
        • These patients also received vitamin B₁₂ (1 mg every 8−10 weeks) and oral folic acid (1.0−25 mg daily)
      • Romidepsin (n = 23; USA only): 14 mg/m² over 4 h on Days 1, 8, and 15 (28-day cycles)
    • Alisertib dose reductions with minimum 10 mg decrements per cycle and a maximum of two dose reductions were allowed in case of toxicity
    • Baseline characteristics were well-balanced between the arms
    • Median number or prior lines: 2
    • Data cut-off: 30 June 2015

Key findings

• In the alisertib arm:
  • Median number of treatment cycles (range) = 4 (0−50) cycles
  • Mean treatment duration (range) = 20.8 (1−148) weeks
  • Mean relative dose intensity = 92.9%
• In the comparator arm:
  • Median number of treatment cycles (range) = 2 (0−17) cycles
  • Mean treatment duration (range) = 16.6 (1−115) weeks
  • Mean relative dose intensity = 66.1%
• ORR:
  • Alisertib: 33% (n = 34/102 patients)
  • Comparator arm: 45% (n = 41/92 patients)
  • Comparison: odds ratio = 0.60 (95% CI, 0.33−1.08)
  • Gemcitabine: 35% (n = 8/23)
  • Pralatrexate: 43% (n = 22/51)
  • Romidepsin: 61% (n = 11/18)
• CR rate:
  • Alisertib: 18%
  • Comparator arm: 27%
• Although the number of patients in the alisertib and comparator arms were balanced across regions, there was a greater difference in ORR between treatment arms in North America (29%  alisertib versus 59% comparator) than in other regions (Western Europe: 33% versus 36%; rest of world: 36% versus 41%, respectively)
• Progressive disease (PD) was the most common reason for a PFS event in both arms
• Median PFS:
  • Alisertib: 115 days
  • Comparators: 104 days
    • Gemcitabine: 57 days
    • Pralatrexate: 101 days
    • Romidepsin: 242 days
  • Comparison: HR = 0.87, (95% CI, 0.644−1.162)
• Median follow-up duration for OS:
  • Alisertib: 519 days
  • Comparators: 586 days
• Median OS:
  • Alisertib: 415 days
  • Comparators: 367 days
  • Comparison: HR = 0.98, (95% CI, 0.707−1.369)
• Twelve-month survival:
  • Alisertib: 53.7%
  • Comparators: 51.5%
• Twenty-four-month survival:
  • Alisertib: 35%
  • Comparators: 35%
• Median DoR:
  • Alisertib: 225 days
  • Comparators: 172 days
    • Gemcitabine: 134 days
    • Pralatrexate: 162 days
    • Romidepsin: 473 days
  • Median TTR:
    • Alisertib: 62 days
    • Comparators: 64 days
      • Gemcitabine: 90 days
      • Pralatrexate: 67 days
      • Romidepsin: 61 days
    • Median TTP:
      • Alisertib: 162 days
      • Comparators: 116 days
      • Comparison: HR = 0.95, (95% CI, 0.679−1.329)
    • At 24 months, patients who had not experienced PD:
      • Alisertib: 12.8%
      • Comparators: 14.3%
    • Median time to subsequent antineoplactic therapy:
      • Alisertib: 336 days
      • Comparators: 233 days
        • Gemcitabine: 144 days
        • Pralatrexate: 233 days
        • Romidepsin: not estimable
      • Comparison: HR = 0.98, (95% CI, 0.692−1.385)

Safety

• Most common any cause Grade ≥ 3 adverse events (AEs; alisertib versus comparators):
  • Neutropenia: 43% versus 25%
  • Thrombocytopenia: 29% versus 27%
  • Anemia: 33% versus 11%
• Most common treatment-emergent AEs (TEAEs; alisertib versus comparators):
  • Neutropenia: 45% versus 30%
  • Thrombocytopenia: 34% versus 38%
  • Anemia: 43% versus 24%
  • Diarrhea: 32% versus 19%
  • Stomatitis: 31% versus 42%
• Serious AEs occurred in:
  • Alisertib: 55%
  • Comparators: 54%
• Overall, 26 study deaths occurred (alisertib, 11 [8%]; comparators, 15 [12%])
  • Of these, n = 3 in the alisertib and n = 1 in the comparator arm were drug-related

Conclusions

• Alisertib did not lead to superior outcomes (PFS, ORR) versus comparator drugs (gemcitabine, pralatrexate or romidepsin) when administered to R/R PTCL patients