Tirabrutinib shows significant activity for R/R MCL without major drug-related toxicities in a 3-year follow-up study

Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma that results due to the neoplastic transformation of B lymphocytes.¹ Bruton’s tyrosine kinase (BTK) is a key component in B lymphocyte signalling pathways, thus BTK inhibitors are pharmaceutically exploited for the treatment of patients with relapsed/refractory (R/R) MCL.² However, some, such as ibrutinib, are associated with significant side effects that require careful management.² Second-generation BTK inhibitors, like tirabrutinib (GS/ONO-4059) have greater selectivity and seek to overcome the off-target effects seen with their predecessors. Tirabrutinib has demonstrated preliminary activity and was well tolerated in a phase I study in the R/R B-cell malignancy setting and in a 3-year follow-up of patients with chronic lymphocytic leukemia.^3,4 In a letter to the editor recently published in Leukemia, Simon Rule, Plymouth University, Plymouth, UK, and colleagues, presented the 3-year follow-up data from a phase I extension study (NCT02457559) of tirabrutinib treatment in patients with MCL.⁵

Study design

• Tirabrutinib was evaluated for safety and tolerability in six patient cohorts with R/R B-cell malignancies (dose range 20–600mg daily) during the POE001 phase I clinical study (NCT01659255)
  • Of the 90 patients treated between September 2012 and January 2015, 16 patients with R/R MCL and ongoing response or stable disease were enrolled in this long-term extension study
• Study endpoints included progression-free survival (PFS), overall response rate (ORR), duration of response (DOR) and overall survival (OS)
• The median patient age was 64 years (range, 52–81) and the majority of patients were male (75%)
• Patients had a median of three prior therapies (range, 2–8) and 31% had received previous hematopoietic transplantation
• At data cut-off (May 30, 2017), 11 patients had discontinued treatment for the following reasons:
  • Progressive disease (PD): nine patients
  • Death: one patient
  • Treatment discontinuation for allogeneic stem cell transplantation

Results

• At data cut-off, 11 of 16 patients had responded (ORR, 68.8%), including six (55%) patients who achieved a complete response (CR) and five (45%) who achieved a partial response (PR)
• Median treatment duration was 97.3 weeks (range, 0–173) and median time to response was 1.9 months (range, 1.9–16.8)
• There was no significant improvement in ORR with extended follow-up
• The responses were durable with the median DOR not reached and the estimated median PFS was 25.8 months
• The 24-month estimates of PFS and OS were 55.6% (95% CI, 28.6–75.9) and 67.0% (95% CI, 37.9–84.7), respectively
• Six patients (38%) experienced serious adverse events (AEs), however none were considered related to tirabrutinib. Table 1 shows the most common grade ≥3 AEs experienced.

Table 1. Most common grade ≥3 AEs

 Conclusions

No tirabrutinib discontinuations as a result of AEs were observed in this long-term follow-up study in contrast with similar studies using ibrutinib in R/R MCL (median follow-up 26.7 months), where 11% of patients had discontinued ibrutinib due to AEs. Off-target effects, such as atrial fibrillation and grade 3 or higher bleeding events and headache were absent or markedly less frequent in this study compared to phase II studies of other second generation BTK inhibitors (acalabrutinib). The results of this study support persistent, robust efficacy and safety of tirabrutinib even after multiple lines of therapy in the R/R MCL setting.