Long-term efficacy of bexarotene for cutaneous T-cell lymphoma: Results from a phase II trial

On 15 May 2019, Toshihisa Hamada from Okayama University, Okayama, JP, and colleagues published results from a phase II clinical trial in cutaneous T-cell lymphoma (CTCL) in the Journal of Dermatology.¹ The trial investigated the efficacy and safety of bexarotene in Japanese patients with CTCL. Bexarotene is a synthetic retinoid that has been approved by the Food and Drug Administration and European Medicines Agency for the treatment of refractory CTCL.^2,3 This report presented the long-term efficacy and safety data for bexarotene following on from their initial 24-week phase I clinical trial (B-1101) in the same population.

The primary endpoint of this multicenter, open-label, single-arm, phase II trial was objective response rate (ORR), while secondary objectives included time-to-response (TTR), time-to-disease progression (TTP), safety, and duration of response (DoR).

Study design & baseline characteristics

• N = 16 patients, aged ≥20 years with refractory CTCL, who had completed a prior 24-week bexarotene trial (B-1101)
  • Patients with progressive disease (PD) at the end of the previous B-1101 trial were excluded
• Patient diagnosis:
  • Mycosis fungoides (MF): n = 15
  • Primary cutaneous anaplastic large cell lymphoma: n = 1
• Disease stage in MF patients:
  • Early stage (IB): n = 7 patients
  • Advanced stage (IIB and IIA): n = 8 patients
• Dosing (n= 10):
  • The patients included in this analysis continued to receive either 150mg/m² (n = 2) or 300 mg/m² (n= 8) of bexarotene as per their dosage in the previous B-1101 trial

Key findings

• Median treatment duration (range): 380 (33–1674) days
  

Table 1. ORRs

 

N

ORR

95% CI

Full analysis set

16

56.3%

29.9–80.2

Patients who received 300mg/m² bexarotene

8

53.8%

25.1–80.8

Patients with early stage MF (IB)

5

60%

-

Patients with advanced stage MF (IIB, IIA)

7

57.1%

-

• Number of patients achieving an objective response: n= 7
• Complete response (CR) was achieved by one patient at week 40 (150mg/m² bexarotene cohort)
• Median TTR (range): 58 (27–168) days
• Number of patients maintaining treatment for >1300 days: n = 3
• Median DoR: not reached within the study period
• Longest DoR at the end of the trial: 1618 days

Safety

• Dose-limiting toxicities (DLTs):
  • 300mg/m² cohort: in 38.5% of patients (n= 5/13)
  • 150mg/m² cohort: none
  • All DLTs recovered following bexarotene discontinuation
• Bexarotene dose reduction were required for n= 9 patients (56.3%):
  • In the 150mg/m² group: 8 patients
  • In the 300mg/m² group: 1 patient
  • Only 30% of patients maintained the initial bexarotene dose throughout the study
• In the full analysis set (N= 16), the following most common adverse events (AEs) were observed:
  • Hypothyroidism: n = 15 (93.8%)
  • Hypercholesterolemia: n= 13 (81.3%)
  • Hypertriglyceridemia: n= 13 (81.3%)
  • White blood cell reduction: n= 11 (68.8%)
  • Decreased neutropils: n= 9 (56.3%)
• Median time to hypothyroidism, hypercholesterolemia or hypertriglyceridemia was 8 days
• Leukopenia (76.9%) and neutropenia (69.2%) occurred frequently in the 300 mg/m² cohort
• Median time to leukopenia: 15 days
• Median time to neutropenia: 13 days
• Grade 3 neutropenia occurred in 4 patients
• Grade 4 hypertriglyceridemia occurred in 1 patient as DLT
• Treatment-related AEs were observed in 9 out of 16 patients in the full analysis set
• Severe AEs occurred in n = 3 patients all in the 300 mg/m² cohort:
  • Bile duct stones
  • Excessive drug intake
  • Hypertriglyceridemia
• No deaths occurred during either phase I or II studies

Conclusions

There was a high rate of bexarotene dose reductions observed in this study and the long-term ORR in the 300mg/m² cohort was reduced when compared to the ORR from the initial B-1101 phase I trial (56.3% versus 61.5%). Due to the limited sample size and limitations of this phase II trial, further studies are needed for the evaluation of the long-term efficacy and safety of bexarotene in CTCL.