Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on multiple myeloma (MM) cells than on normal B cells. Cevostamab is a FcRH5xCD3 bispecific antibody that facilitates T cell-mediated killing of MM cells. In an ongoing Phase I dose-escalation and dose-expansion study (GO39775; NCT03275103), cevostamab monotherapy demonstrated target dose (TD)-dependent activity and manageable safety in patients (pts) with heavily pretreated RRMM (Trudel et al. ASH 2021). We report updated efficacy and safety data from pts who received cevostamab once every 3 weeks (Q3W) at the 160mg TD level.
Methods: Eligible pts were those with RRMM for which no established therapy was available or appropriate. Cevostamab was initiated with Cycle (C) 1 single-step (SS) dosing, double-step (DS) dosing (Trudel et al. ASH 2021), or triple-step (TS) dosing (step doses on D1, D2 [or D3 or D4 depending on the emergence and resolution of cytokine release syndrome [CRS] with the previous administration], and D8, TD on D9 [or D10 or D11]). Cevostamab was then continued at the TD on D1 of each subsequent 21-day cycle. Cevostamab was continued for 17 cycles, unless disease progression or unacceptable toxicity occurred.
Results: As of February 23, 2024, 167 pts (median age: 66 years, range: 40-90; ECOG PS: 0, 35% or 1, 65%; median time from first MM therapy: 6.3 years, range: 0.3-21.8) had received cevostamab at the 160mg TD level (SS: n=10; DS: n=97; TS: n=60); 28% of pts had extramedullary disease and 38% of pts with a conclusive assay result (38/100) had high-risk cytogenetics (t(4;14), t(14;16), or del(17p)). The median number of prior lines of therapy was 6 (range: 2-18). Almost all pts (95.8%) were triple-class refractory and 73.7% were penta-drug refractory; 85.0% were refractory to their last prior therapy. A majority (57%) of pts had received ≥1 prior B-cell maturation antigen (BCMA)-targeted therapy. Twenty four percent of pts had received ≥1 prior bispecific antibody.
Median observation time was 11.3 months (range: 0.5-42.8). The overall response rate (ORR) in all pts who received cevostamab at the 160mg TD level was 43.1% (72/167 pts); 6.6% achieved a stringent complete response (CR), 6.6% a CR, 12.6% a very good partial response (VGPR), and 17.4% a partial response (PR). The VGPR or better rate was 25.7%. Median time to first response (PR or better) was 1.4 months (range: 0.6-4.6) and to best response was 2.4 months (range: 0.7-13.4). Median duration of response was 10.4 months (95% CI: 6.8, 10.5). ORR was 30.2% (29/96) in pts with ≥1 prior BCMA-targeted therapy and 60.6% (43/71) in those without. ORR was 30.0% (12/40) in pts with ≥1 prior bispecific antibody, 33.3% (20/60) with ≥1 prior chimeric antigen receptor (CAR) T-cell, and 41.2% (14/34) with ≥1 prior antibody-drug conjugate.
Common (≥20%) adverse events (AEs) included CRS (74.3%; Grade [Gr] 1: 52.7%; Gr 2: 19.8%; Gr 3: 1.2%; Gr 4: 0.6%), neutropenia (31.1%; Gr 1-2: 3.0%; Gr 3: 12.0%; Gr 4: 16.2%), cough (30.5%; Gr 1-2: 29.9%; Gr 3: 0.6%), nausea (28.1%; Gr 1-2: 27.5%; Gr 3: 0.6%), diarrhea (24.0%; all Gr 1-2), anemia (23.4%; Gr 1-2: 5.4%; Gr 3: 17.4%; Gr 4: 0.6%), and fatigue (21.0%; Gr 1-2: 19.8%; Gr 3: 1.2%). Possible immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 13.2% of pts (Gr 1: 6.0%; Gr 2: 5.4%; Gr 3: 1.8%). Infections occurred in 53.9% of pts, with serious events and Gr ≥3 events in 22.2% and 19.2%, respectively. Treatment-related AEs leading to cevostamab discontinuation occurred in 11 pts (6.6%) and treatment-related Gr 5 (fatal) AEs in 3 pts (1.8%; hemophagocytic lymphohistiocytosis, n=2; disseminated intravascular coagulation and pseudomonal sepsis, n=1).
In the 0.3/1.2/3.6/160mg TS cohort, CRS occurred in 19/30 pts (63.3%) and was all Gr 1 (46.7%) or Gr 2 (16.7%). Pts with CRS were managed with tocilizumab (47.4%), steroids (21.1%), or both agents (10.5%). No pts discontinued cevostamab due to CRS and all events were resolved at cut-off.
Conclusions: Cevostamab demonstrates clinically meaningful activity and manageable safety at the 160mg TD level in pts with heavily pretreated RRMM. C1 TS dosing provides effective CRS mitigation. Cevostamab combination studies may use the 0.3/1.2/3.6mg TS regimen and the Q3W 160mg TD (or similar TD exposure).
Richter:Genentech: Consultancy; Takeda: Consultancy; Sanofi: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Johnson & Johnson - Janssen: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Regeneron: Consultancy; AbbVie: Consultancy. Thomas:University of Texas MD Anderson Cancer Center: Current Employment; Mustang Bio: Consultancy, Honoraria; Sanofi: Research Funding; Bristol Myers Squibb: Research Funding; Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; Abbvie: Consultancy, Research Funding; Cellectar Biosciences: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; X4 Pharma: Research Funding; Janssen: Research Funding. Krishnan:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; City of Hope National Medical Center: Current Employment; Bristol Myers Squibb: Current holder of stock options in a privately-held company; AbbVie; Adaptive; Arcelx; GSK; Janssen; Roche; and Sanofi: Consultancy. Cohen:Novartis: Patents & Royalties; GSK, Novartis, Roche/Genentech, Janssen: Research Funding; Roche/Genentech, Janssen, GSK, AstraZeneca, BMS, Pfizer, AbbVie, iTeos, Arcellx, Legend, Sanofi: Consultancy; Ichnos: Membership on an entity's Board of Directors or advisory committees; University of Pennsylvania: Current Employment. Trudel:GSK, BMS, Roche: Consultancy, Honoraria, Research Funding; GSK, BMS, Roche, Genentech, Pfizer, Janssen, K36 Therapeutics: Research Funding; Princess Margaret Cancer Centre: Current Employment; Sanofi, GSK, Pfizer, BMS, Janssen, AstraZeneca, BMS, Forus: Honoraria. Costa:BMS: Consultancy, Honoraria, Research Funding; Caribou: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive biotechnoligies: Honoraria; Pfizer: Consultancy, Honoraria. Bahlis:AbbVie, Amgen, BMS, Celgene, Janssen, GSK, Genentech, Karyopharm, Kyte, Novartis, Pfizer, Roche, Sanofi, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer, Janssen: Research Funding. Forsberg:Colorado Blood Cancer Institute: Current Employment; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson, BMS: Membership on an entity's Board of Directors or advisory committees; University of Colorado: Ended employment in the past 24 months; Karyopharm: Research Funding. Kaedbey:Janssen, Pfizer, FORUS, Sanofi: Consultancy, Honoraria; Pfizer: Research Funding. Fonseca:Celgene, Bristol Myers Squibb, Bayer, Amgen, Janssen, Kite, a Gilead company, Merck Sharp & Dohme, Juno Therapeutics, Takeda, AbbVie, Aduro Biotech, Sanofi, OncoTracker: Honoraria; Antengene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Adaptive, Amgen, Apple, Bayer, BMS/Celgene, Gilead, GSK, Janssen, Kite, Karyopharm, Merck Sharp & Dohme, Juno Therapeutics, Takeda, Arduro Biotech, Oncotracker, Oncopeptides, Pharmacyclics, Pfizer, RA Capital, Regeneron, Sanofi: Consultancy; Patent for FISH in MM - ~$2000/year: Patents & Royalties: Patent for FISH in MM - ~$2000/year. Spencer:AbbVie: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodríguez-Otero:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Roche: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Regeneron: Other: Honoraria for lectures; Johnson & Johnson - Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Amgen: Other: Honoraria for lectures. Mateos:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Salamanca University: Current Employment; Oncopeptides: Honoraria; Celgene: Honoraria. Wong:Genentech, Inc.: Current Employment; CTMX, BMRN, UBX: Current equity holder in publicly-traded company; For Henry AHC: Membership on an entity's Board of Directors or advisory committees. Cooper:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of stock options in a privately-held company. Tyagi:F. Hoffmann-La Roche Ltd, Gilead Sciences: Current equity holder in publicly-traded company; CytoKinetics Inc: Ended employment in the past 24 months; Genentech, Inc.: Current Employment. Nakamura:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Choeurng:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Lesokhin:Pfizer: Consultancy, Honoraria, Research Funding; Serametrix, Inc.: Patents & Royalties; Arcellx: Consultancy, Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment; F. Hoffmann-La Roche Ltd, Janssen, SVB Leerink: Consultancy, Honoraria.
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