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

Abstract

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. Disclosures Schuster: Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Nordic Nanovector: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding. Bartlett:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Yoon:Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MSD: Consultancy; Janssen: Consultancy; Yuhan Pharma: Research Funding. Bosch:Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sehn:Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Apobiologix: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria; TG Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Cheah:Janssen: Honoraria; Acerta: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Gilead: Honoraria; Loxo: Honoraria. Shadman:Mustang Biopharma: Research Funding; Gilead: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Atara: Consultancy; Bigene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Verastem: Consultancy; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding; Merck: Research Funding. Gregory:MSD: Other: grant pending, Research Funding; Beigene: Other: Grant pending, Research Funding; Celgene: Other: grant pending, Research Funding; Monash University: Research Funding; Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: grant pending, Research Funding; Janssen: Other: grant pending, Research Funding; Melbourne Haematology: Consultancy, Honoraria, Other: Travel fees and conference support, Speakers Bureau. Wei:Genentech, Inc./F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Yin:Genentech, Inc: Employment, Equity Ownership. Kwan:Genentech, Inc: Employment, Equity Ownership. Yousefi:F. Hoffmann-La Roche Ltd: Employment. Hernandez:Genentech, Inc.: Employment, Equity Ownership. Li:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. O'Hear:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Off Label Disclosure: Mosunetuzumab (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). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

Anti-CD20 treatment for B-cell malignancies: current status and future directions

“…Preliminary data from a Phase 1-2 study investigating glofitamab with obinutuzumab in R/R aNHL or FL demonstrated promising clinical activity with no new safety signals [209]. Similarly, the CD20/CD3 bispecific antibody mosunetuzumab has demonstrated durable efficacy and favorable tolerability in heavily pretreated R/R NHL patients in a recent report from a Phase 1 trial [197]. Table 3.…”

“…Emerging therapies in ongoing DLBCL trials involve molecules that target the immune system, including anti-CD19 CAR-T cells [195], T-cell bispecific antibodies (TCBs, e.g. blinatumomab [196], the CD20-TDB [T-cell-dependent bispecific antibody] mosunetuzumab [197,198] and the obinutuzumab-based CD20-TCB glofitamab [199]), and a mAb for CD19, tafasitamab (MOR208), which has shown promising activity as a single agent in patients with R/R DLBCL, MCL, FL, or other iNHL [200]. Tafasitamab is now being investigated further in DLBCL as a combination with lenalidomide in the single-arm Phase 2 L-MIND study in 81 patients [201,202], or with bendamustine in comparison with rituximab-bendamustine in the Phase 2/3 B-MIND study with an enrollment target of 330 [203].…”

Emerging therapies in mantle cell lymphoma

“…Mosunetuzumab is another BiTe in clinical development for B-NHL that ligates CD3 and CD20. Results of the ongoing phase 1/1b dose-escalation study were presented at the 2019 ASH conference [97]. The trial enrolled 270 patients, including 23 patients with MCL.…”

Impact and Intricacies of Bone Marrow Microenvironment in B-cell Lymphomas: From Biology to Therapy

“…Blinatumomab, a bi-specific antibody targeting CD19/CD3 has shown good efficacy in R/R NHL [132]. More recently, the data on the CD20/CD3 T-cell engaging bispecific antibodies especially mosunetuzumab has shown impressive activity in R/R B-cell NHL, including those who are refractory or relapsed following CAR-T cell therapy [133]. The preliminary data is very promising and if the results hold in validation studies, then this will provide another important treatment option, especially in those who fail to respond to CAR-T cell therapy.…”