DLBCL,   FL,  MCL

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 61st 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
References
  1. Schuster S.J. et al., Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56. DOI: 10.1056/NEJMoa1804980
  2. Baeuerle P.A.Reinhardt C., Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009 Jun 15;69(12):4941-4. DOI: 10.1158/0008-5472.CAN-09-0547
  3. Schuster S.J. et al., Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines. Oral Abstracts #6. 2019 Dec 8. 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Orlando, FL, US
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