Entospletinib monotherapy for iNHL and MCL patients: Results from a phase II trial

The results of an open-label, multicenter phase II trial on the use of entospletinib in indolent non-Hodgkin lymphoma (iNHL) and mantle cell lymphoma (MCL) were recently published in the British Journal of Haematology, by David Andorsky from the Rocky Mountain Cancer Centers, CO, USA, and colleagues.

Entospletinib (GS-9973) is a competitive inhibitor of the spleen tyrosine kinase (Syk). Syk is actively involved in the B-cell receptor (BCR) signalling pathway as it is believed to act upstream of both the Bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K). Syk has been associated with lymphoma cell survival and proliferation in many B-cell malignancies and thus provides a great pharmacological target. The aim of this phase II trial (NCT01799889) was to assess the efficacy and tolerability of entospletinib in relapsed or refractory (R/R) iNHL or MCL patients. The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC). Key secondary endpoints included safety and overall response rate (ORR).

Study overview

• In total, N = 114 patients with iNHL diagnosis (n = 41 follicular lymphoma [FL; Grade 1,2 and 3a], n = 17 marginal zone lymphoma [MZL], n = 17 lymphoplasmacytic lymphoma/Waldenström’s macroglobulinaemia [LPL/WM], and n = 39 MCL) were included in this study
• Eligible patients needed to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and should have received two or more prior lines of treatment with cytotoxic chemotherapy and anti-CD20 monoclonal antibody or radioimmunotherapy
• Entospletinib dosing: patients received 800 mg of the original monomesylate formulation of entospletinib orally twice daily under fasting conditions for 28 days (cycle 1). Dose reductions to 600 mg, 400 mg, and 200 mg were allowed if toxicity occurred
• Median number of prior lines (range) for all cohorts = 3 (1–14) lines
• Median duration on treatment (range) for all cohorts = 16.6 (0.7–182.6) weeks

Key findings

• In FL patients:
  • 24-week PFS = 51.5% (95% CI, 32.8–67.4)
  • Median PFS = 5.7 months (95% CI, 3.6–11.2)
  • ORR = 17.1% (95% CI, 8.3–29.7)
  • Stable disease (SD) achieved in n = 21 (51%) patients
  • Progressive disease (PD) in n = 11 (27%) patients
• In LPL/WM patients:
  • 24-week PFS = 69.8% (95% CI, 31.8–89.4)
  • Median PFS = 10.9 months (95% CI, 2.1–13.7)
  • ORR = 35.3% (95% CI, 16.6–58.0)
  • SD achieved in n = 5 (29%) patients
  • PD in n = 1 (6%) patients
• In MZL patients:
  • 24-week PFS = 46.2% (95% CI, 18.5–70.2)
  • Median PFS = 5.5 months (95% CI, 3.5–22.1)
  • ORR = 11.8% (95% CI, 2.1–32.6)
  • SD achieved in n = 12 (71%) patients
  • PD in n = 2 (12%) patients
• In MCL patients:
  • 16-week PFS = 63.9% (95% CI, 45.0–77.8)
  • 24-week PFS = 56.6% (95% CI, 37.5–71.8)
  • Median PFS = 5.6 months (95% CI, 3.6–8.9)
  • ORR = 17.9% (95% CI, 8.7–31.1)
  • SD achieved in n = 22 (56%) patients
  • PD in n = 7 (18%) patients
• In all cohorts, no patient achieved a complete response (CR) but achieved either partial responses or minor responses (in the LPL/WM cohort)

Safety

• As of April 2017, > 95% of patients in all cohorts had discontinued treatment, with most common reasons for discontinuation:
  • PD
  • Treatment-emergent adverse events (TEAEs).
• Almost all patients (99%) across cohorts experienced a TEAE with Grade ≥ 3 TEAES occurring in the range of 65–82% depending on the cohort
• Serious AEs occurred in the range of 22–41% depending on the cohort
• Death-incurring TEAEs within 30 days of the last dose occurred in n = 1 patient (6%) in the LPL/WM cohort and n = 4 patients (13%) in the MCL cohort
• Most common TEAEs across cohorts were:
  • Fatigue
  • Nausea
  • Diarrhea
  • Vomiting
  • Constipation
  • Pyrexia
  • Decreased appetite
• Dose reduction and discontinuation due to toxicity occurred in 28% and 15% of patients, respectively across cohorts

The results of this phase II trial indicate that entospletinib monotherapy leads to low response rates in R/R iNHL and MCL patients, despite its tolerable profile. The investigators proposed that entospletinib should be investigated in combination with other pharmacological agents in patients with hematological malignancies.