Phase 1 Study of ARV-393, a PROTAC BCL6 Degrader, in Advanced Non-Hodgkin Lymphoma

Background and Significance: Non-Hodgkin lymphoma (NHL) represents a biologically and clinically diverse group of hematologic malignancies originating from B cells, T cells, and/or natural killer cells, with those of B-cell origin constituting ~80%-85% of all NHL cases. The BCL6 transcription factor is a key oncogenic driver of B-cell lymphomagenesis, and deregulated BCL6 expression is a common feature of diffuse large B-cell lymphoma (DLBCL), the most common type of NHL. BCL6 translocations have been observed in follicular lymphomas, the second most prevalent NHL, with studies suggesting that these translocations may portend a higher risk of transformation into aggressive lymphoma. BCL6 is also a lineage-defining transcription factor of T follicular helper cells, the cell of origin for nodal T-follicular helper cell lymphoma, angioimmunoblastic-type (nTFHL-AI), also known as angioimmunoblastic T-cell lymphoma. Moreover, BCL6 expression has been identified in biopsies of patients with nTFHL-AI, and its continued expression was required for tumor growth in a mouse model of nTFHL-AI, supporting BCL6 as a cancer driver in this type of NHL as well.

ARV-393 is an orally administered small-molecule PROteolysis TArgeting Chimera (PROTAC) BCL6 degrader, consisting of a BCL6-binding domain joined by a linker to a cereblon E3 ubiquitin ligase-binding domain. ARV-393 induces ubiquitination of BCL6 and its subsequent degradation by the proteasome. In preclinical studies, ARV-393 induced tumor regressions in several NHL patient-derived xenograft models. Additionally, ARV-393 demonstrated dose-responsive tumor growth inhibition that correlated with BCL6 degradation in several cell line-derived xenograft models of NHL, including the aggressive high-grade B-cell lymphoma triple-hit SU-DHL-4 model, supporting further investigation in patients with NHL.

Study Design and Methods: This multicenter, first-in-human, phase 1 study (NCT06393738) is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ARV-393 in patients with advanced B-cell NHL or nTFHL-AI. Eligible patients (aged ≥18 years) have relapsed/refractory mature B-cell NHL and ≥2 prior systemic therapies, or histologically confirmed nTFHL-AI that has recurred or progressed following institutional standard of care therapy. Patients must also have ≥1 measurable lesion at study entry, Eastern Cooperative Oncology Group performance status of 0 or 1, freshly biopsied or archival tumor tissue available, adequate organ function, no active central nervous system involvement, no significant acute or chronic medical illness (including hypereosinophilic syndrome, active interstitial lung disease or pneumonitis, or active or uncontrolled infection), and no prior allogeneic stem cell transplant or solid organ transplantation. Autologous stem cell transplant must not have occurred ≤100 days and previous chimeric antigen receptor T-cell therapy ≤60 days prior to initiating ARV-393 treatment. ARV-393 will be administered orally in 28-day cycles with dose escalation according to a Bayesian optimal interval design. The primary objectives are to evaluate the safety and tolerability of ARV-393, determine the maximum tolerated dose, if necessary, and identify the recommended phase 2 dose(s) and dosing schedule. Secondary objectives are to characterize the pharmacokinetic profile of ARV-393 and evaluate its preliminary antitumor activity. Enrollment is currently ongoing.

Caimi:Abbvie: Honoraria, Research Funding; Genmab: Research Funding; Luminary Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Sobi: Honoraria; ADC Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Abcon Therapeutics: Current holder of stock options in a privately-held company; Recordati: Honoraria, Research Funding. Huntington:ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy; Flatiron Health Inc.: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Thyme Inc.: Consultancy; Arvinas: Consultancy; Pharmacyclics: Consultancy, Honoraria; Servier: Consultancy; Bayer: Honoraria; Ipsen: Honoraria; Novartis: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Merck: Consultancy; Epizyme: Consultancy. Landrette:Arvinas, Inc.: Current Employment. Gough:Arvinas, Inc.: Current Employment. Dai:Arvinas, Inc.: Current Employment. Jackson:Arvinas, Inc.: Current Employment. Yu:Arvinas, Inc.: Current Employment. Chavez:Arvinas, Inc.: Current Employment. Tannenbaum-Dvir:Arvinas, Inc.: Current Employment. Matasar:Johnson & Johnson: Consultancy, Honoraria, Research Funding; BMS/Celgene: Honoraria; Immunovaccine Technologies: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees; GM Biosciences: Consultancy, Research Funding; ADC Therapeutics: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Allogene: Membership on an entity's Board of Directors or advisory committees; Merck: Current equity holder in publicly-traded company; Bayer: Consultancy, Honoraria, Research Funding; Kite: Honoraria; Epizyme: Honoraria; IMV Therapeutics: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Regeneron Pharmaceuticals, Inc.: Honoraria.