Results from a phase I/Ib dose-escalation study of mosunetuzumab in high-risk non-Hodgkin lymphoma patients

Significant progress was made in the last 15-20 years in the treatment of patients with B-cell non-Hodgkin lymphoma (NHL). However, in patients with relapsed/refractory (R/R) lymphoma prognosis is still poor and approaches such as chimeric antigen receptor T-Cell (CAR-T) therapies, can be useful in this population.¹ Unfortunately, there are patients who relapse after an initial response to CAR-T therapy. For these patients, new therapeutic approaches are needed. One of these approaches is the use of bispecific antibodies (BsAb) that can bind to two different antigens, one on T-cells and the other one on tumor target cells leading to the lysis of cancer cells and resulting in the elimination of the tumor.²

During the plenary session, at the 61^st American Society of Hematology (ASH) Annual Meeting & Exposition, Stephen Schuster from the Abramson Cancer Center, University of Pennsylvania, PA, US, presented the ongoing open-label, multicentre, phase I/Ib dose-escalation and expansion study (GO29781; NCT02500407) of mosunetuzumab (M), a bispecific antibody targeting CD3 and CD20, for R/R B-cell NHL. The primary objectives of the study were safety, tolerability, maximum tolerated dose (MTD), and best objective response rate (ORR).³

Study design³

• Patients (N= 270) with R/R B-cell NHL who failed at least one prior regimen and for whom there is no available therapy improving survival, were recruited:
  • Aggressive NHL (aNHL) patients (n= 180):
    • Diffuse large B-cell lymphoma (DLBCL, n= 117)
    • Transformed FL (tFL, n= 32)
    • Mantle cell lymphoma (MCL, n= 23)
    • Other (n= 8)
  • Indolent NHL (iNHL) patients (n= 85):
    • Follicular lymphoma (FL, n= 82)
    • Other (n= 3)
  • Cycle 1: weekly administration of M with step-up dosing on days 1, 8, and 15, and then a fixed dose on day 1 of each subsequent 21-day cycle (maximum 17 cycles)
  • After 8 cycles:
  • If complete remission (CR) achieved, treatment was discontinued
  • If partial response (PR) or stable disease (SD), treatment was continued for up to 17 cycles
  • For CR patients who relapsed, re-treatment was allowed
  • Median prior systemic therapies were 3 (range, 1–14)
  • Thirty patients received prior CAR-T therapy (17, DLBCL; 8, tFL; 5, FL), with a median of 5 lines of prior systemic therapies (range, 3−14)

Results³

Safety

• M showed a tolerable profile with the most common adverse events (AEs) represented by:
  • Cytokine release syndrome (CRS, 28.9%)
  • Neutropenia (24.1%)
  • Fatigue (20.4%)
  • Hypophosphatemia (19.3%)
  • Diarrhea (16.7%)
  • Pyrexia (16.3%)
  • Headache (15.6%)
  • Nausea (15.2%)
• Neurological AEs (NAEs) were reported in 118 patients and the most common NAEs were:
  • Headache (15.6%)
  • Insomnia (9.3%)
  • Dizziness (9.3%)
  • Potential immune effector cell-associated neurotoxicity syndrome (ICANS)-like NAEs were confusion (n= 2) and lethargy (n= 1)
• Among the four patients who were re-treated with M, no CRS was observed and NAEs were reported in one patient
• Among the 30 patients who were R/R to CAR-T therapy, CRS occurred in eight patients and NAEs in 13 patients, with no ICANS-like events
• The 95% of AEs occurred in cycle 1 with no increase in CRS frequency due to dose-escalation

Efficacy

• Among efficacy-evaluable patients across all dose levels (from 2.8mg to 40.5mg), ORR and CR rates were:
  • In aNHL patients:
    • ORR: 37.1% (46/124)
    • CR: 19.4% (24/124)
    • 17 CR patients (70.8%) in remission up to 16 months after treatment discontinuation
  • In iNHL patients:
    • ORR: 62.7% (42/67)
    • CR: 43.3% (29/67)
    • 24 CR patients (82.8%) in remission up to 26 months after treatment discontinuation
  • Patients with prior CAR-T therapy showed an ORR of 38.9% (7/18) and a CR of 22.2% (4/18)
  • Re-treatment with M was allowed in CR patients who relapsed:
    • Four patients received M re-treatment: one achieved CR and two PR. All three responses are ongoing, with the CR patient in second remission for 13 months

Conclusions³

• M monotherapy showed a tolerable profile in patients with R/R B-cell NHL
• CRs were reported in high-risk patient population, including patients with prior CAR-T therapy
• CRs have been maintained after completion of therapy
• Based on preliminary data, re-treatment with M is possible