Mivavotinib, a Syk Inhibitor, in Relapsed/Refractory (R/R) Non-GCB Diffuse Large B-Cell Lymphoma (DLBCL) with or without MYD88 and/or CD79 Mutations: A Phase 2 Study

Background: Spleen tyrosine kinase (Syk) is a key signaling protein that activates survival pathways in B-cell lymphomas. The non-germinal center B-cell like (non-GCB) or activated B-cell like (ABC) cell-of-origin subtype of DLBCL has greater reliance on the B-cell receptor pathway and Syk signaling for survival, compared with the GCB subtype. Multiple signaling pathways are activated by Syk in ABC DLBCL (NF-κB and phosphoinositide 3-kinase [PI3K]), whereas only the PI3K pathway is activated by Syk in GCB DLBCL. MYD88 and/or CD79b mutations are strongly enriched within ABC DLBCL and are associated with poor prognosis. Syk hyperactivation has been observed in ABC DLBCL cell lines harboring MYD88/CD79 mutations, with activation of NF-κB via Syk-mediated signaling through both the BCR and the toll-like-receptor (TLR)-MYD88 pathways. Mivavotinib is an orally dosed, potent, and selective Syk inhibitor, which showed potent single agent activity in preclinical studies in ABC and GCB DLBCL cell lines, with the strongest activity against those harboring MYD88 and/or CD79b mutations. In the clinical setting, heavily pre-treated all-comer R/R DLBCL patients receiving single agent mivavotinib at the recommended phase 2 dose (100 mg once daily [QD]) showed an overall response rate (ORR) of 33% (16% complete responses [CR]) with durable responses (median duration of response [DoR] not reached [95% CI: 7 months - NE]) and a favorable safety profile. Subgroups by cell-of-origin showed a substantially higher ORR in patients with the non-GCB subtype (53%; 95% CI: 27, 79) than GCB (22%; 95% CI: 0.11, 0.37), and a median DoR of 15.7 months (95% CI: 2.2, NE) in non-GCB responders. CX-659-401 (NCT05319028) is an ongoing study evaluating two dosing regimens of mivavotinib monotherapy in patients with R/R non-GCB DLBCL, in whom circulating tumor DNA-based next generation sequencing (NGS) will be used to determine MYD88/CD79b mutational status. The goals of this strategy are to confirm the activity of mivavotinib previously observed in non-GCB DLBCL, evaluate its activity in DLBCL according to mutational status of MyD88/CD79b, and optimize the dose and schedule in this biomarker-defined patient population.

Methods: This multicenter, open-label, phase 2 study will enroll patients with histologically confirmed de novo or transformed DLBCL that is non-GCB by immunohistochemistry (IHC) per Hans algorithm or ABC by gene expression profiling, including primary mediastinal and primary extranodal DLBCL. Patients must have had at least 2 but no more than 5 prior lines of systemic anticancer therapy. Following standard first-line R-CHOP (or equivalent), patients must have received 2^nd-line salvage therapy with or without autologous stem cell transplant (ASCT), and/or CAR-T therapy, unless ineligible for 2^nd-line salvage, ASCT, or CAR-T. Additional key eligibility criteria include age >18 years, ECOG performance status 0-2, and FDG-PET-avid measurable disease per 2014 Lugano criteria. DLBCL patients with primary brain or secondary central nervous system involvement with active disease will be excluded. Patients will be randomized to 1 of 2 arms (n=25 planned per arm): (1) 100 mg QD; or (2) 120 mg QD for 2 weeks followed by 80 mg QD thereafter; in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoints are ORR (by independent radiology review according to 2014 Lugano Criteria) and safety/tolerability. Secondary endpoints include DoR, progression-free survival (PFS), overall survival (OS), and CR rate. Exploratory endpoints include pharmacokinetic, biomarker assessments, and investigator-assessed ORR, DoR, PFS, and CR rate. Results of this study will help to define the optimal dose and provide confirmatory efficacy and safety data of mivavotinib in patients with non-GCB DLBCL, including MYD88/CD79b-mutated DLBCL to guide further expansion in these biomarker-defined cohorts.

Karmali:BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy, Other: Advisory Board, Research Funding, Speakers Bureau; Takeda: Research Funding; Karyopharm: Consultancy; Eusa: Consultancy; Pharmacyclics: Consultancy, Other: Advisory Board; Genentech/Roche: Consultancy, Other: Advisory Board; Calithera: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Morphosys/Incyte: Consultancy, Other: Advisory Board, Speakers Bureau; AstraZeneca: Other: Advisory Board, Speakers Bureau; BeiGene: Consultancy, Other: Advisory Board, Research Funding, Speakers Bureau. Landsburg:Triphase: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Calithera: Membership on an entity's Board of Directors or advisory committees; Curis, Inc: Research Funding; Epizyme: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Westin:MonteRosa: Consultancy; Novartis: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Merck: Consultancy; Iksuda: Consultancy; Abbvie/GenMab: Consultancy; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Calithera: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; MorphoSys/Incyte Corporation: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; SeaGen: Consultancy. Leonard:Sutro: Consultancy; ADC Therapeutics: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Eisai: Consultancy; Constellation: Consultancy; Calithera: Consultancy; Bristol-Myers Squibb: Consultancy; Second Genome: Consultancy; Lilly: Consultancy; Mustang Bio: Consultancy; Incyte: Consultancy; Grail: Consultancy; Gilead/Kite: Consultancy; Genmab: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Beigene: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; BMS/Celgene: Consultancy; Regeneron: Consultancy; Miltenyi: Consultancy. Kuriakose:Calitherea Biosciences: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Sumrow:Calithera Biosciences: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Carroll:Calithera Biosciences: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Albert:Calithera Biosciences: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Akella:Calithera Biosciences: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Gordon:Ono Pharmaceuticals: Consultancy; Zylem: Current equity holder in private company, Current equity holder in publicly-traded company, Patents & Royalties: Patent on nanoparticles for lymphoma therapy; Janssen: Other: DSMB; BMS: Research Funding.

Mivavotinib is an investigational agent