StemCell Therapy

Introduction:Improved treatments are needed for relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) pts. Options are particularly limited for pts with B-cell NHLs who are R/R to CAR-T therapies or for whom a delay in effective therapy precludes this approach. Mosunetuzumab (M; RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). In an ongoing Phase I/Ib study (GO29781; NCT02500407), promising efficacy and favorable tolerability were observed in R/R NHL pts (Budde et al. ASH 2018; Bartlett et al. ASCO 2019). We report complete remissions (CRs) with M in NHL pts who are R/R to CAR-T therapy, as well as activity with M re-treatment.

Methods:GO29781 is an open-label, multicenter, Phase I/Ib, dose escalation and expansion study of M in R/R B-cell NHL. Data is presented from Group B, in which M is administered with step-up dosing on Days 1, 8, and 15 of Cycle 1, and then as a fixed dose on Day 1 of each subsequent 21-day cycle (maximum 17 cycles). Outcome measures include best objective response rate (ORR) by revised International Working Group criteria, maximum tolerated dose (MTD), and tolerability.

Results:As of June 4, 2019, 218 pts in Group B had received any amount of M. Indolent NHL (iNHL) pts (n=72) were mainly follicular lymphoma (FL, n=69). Aggressive NHL (aNHL) pts (n=141) were mainly diffuse large B-cell lymphoma (DLBCL, n=87) or transformed FL (trFL, n=29). Median prior systemic therapies was 3 (range: 1-14). Twenty-three pts had prior CAR-T therapy (12 DLBCL, 6 trFL, 5 FL), and 16 were efficacy evaluable (7 DLBCL, 5 trFL, 4 FL). ORR and CR rates were 43.8% (7/16) and 25.0% (4/16, 2 DLBCL and 2 FL), respectively. Expansion of previously administered CAR-Ts after M administration was detected by quantitative PCR, in line with the mechanism of action of M.

Dose escalation is ongoing, supported by a positive exposure-response relationship for efficacy and broad therapeutic window with step-up dosing (Li et al. ASH 2019). Among efficacy-evaluable pts across all dose levels, ORR and CR rates were 64.1% (41/64) and 42.2% (27/64) in iNHL pts and 34.7% (41/119) and 18.6% (22/119) in aNHL pts, respectively.

CRs appeared durable, with 25/27 (92.6%) iNHL pts (median time from first CR: 5.8 months; range: 0.2-28.9) and 15/22 (68.2%) aNHL pts (median time from first CR: 8.8 months; range: 0.0-25.4) who achieved CR remaining in remission. Re-treatment with M was allowed in CR pts who relapsed. Four pts, including 1 in Group A who was initially treated with a fixed, non-step-up dosing schedule, received M re-treatment. One CR and 2 partial responses were observed. All three responses are ongoing, with the CR pt in second remission for 314 days.

The MTD of M has not been reached at doses up to 1/2/60mg (Cycle 1 Day 1, 8, and 15). Adverse events (AEs) leading to treatment withdrawal were uncommon (12/218, 5.5%). Cytokine release syndrome (CRS), graded by Lee criteria (Lee et al. Blood 2014;124:188-95), was observed in 28.4% of pts, and was mostly Grade (Gr) 1 (21.1%) or Gr 2 (6.0%); Gr 3 CRS occurred in 1.4% of pts. Most CRS events occurred in Cycle 1; 5 pts (2.7%) had CRS during or after Cycle 2. Three of 218 pts (1.4%) received tocilizumab for CRS management; all 3 events resolved without sequelae (for 1 pt, CRS resolved after the cutoff date). Neurological AEs (NAEs) were reported in 44% of pts (Gr 1, 28.0%; Gr 2, 12.8%; Gr 3, 3.2%). Common NAEs were headache (14.7%), insomnia (10.1%), and dizziness (9.2%). Potential immune effector cell-associated neurotoxicity syndrome (ICANS)-like NAEs of Gr 1 or Gr 2 confusional state occurred in 3 pts (1.4%) during cycles 1 and 2. The frequency of CRS and NAEs did not correlate with M exposure, likely due to step-up dosing, which effectively mitigates acute toxicities and allows administration of higher doses (Bartlett et al. ASCO 2019; Li et al. ASH 2019). Among the 4 pts who were re-treated with M, no CRS was observed and NAEs were reported in 1 pt (Gr 1 headache and insomnia). Among the 23 pts who were R/R to CAR-T therapy, CRS occurred in 5 pts (21.7%; Gr 1, 13.0%; Gr 2, 4.3%; Gr 3, 4.3%) and NAEs in 8 pts (34.8%; Gr 1, 17.4%; Gr 2, 13.0%; Gr 3, 4.3%), with no ICANS-like events.

Conclusions:M has favorable tolerability and durable efficacy in pts with heavily pre-treated R/R B-cell NHL, including CRs in pts with disease progression after CAR-T therapies. Preliminary data support the possibility for re-treatment with M.

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Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After...

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