Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier

• Published in: Blood Vol. 135; no. 13; pp. 996 - 1007
• Main Authors: Carpio, Cecilia, Bouabdallah, Reda, Ysebaert, Loïc, Sancho, Juan-Manuel, Salles, Gilles, Cordoba, Raul, Pinto, Antonio, Gharibo, Mecide, Rasco, Drew, Panizo, Carlos, Lopez-Martin, Jose A., Santoro, Armando, Salar, Antonio, Damian, Silvia, Martin, Alejandro, Verhoef, Gregor, Van den Neste, Eric, Wang, Maria, Couto, Suzana, Carrancio, Soraya, Weng, Andrew, Wang, Xuehai, Schmitz, Frank, Wei, Xin, Hege, Kristen, Trotter, Matthew W.B., Risueño, Alberto, Buchholz, Tonia J., Hagner, Patrick R., Gandhi, Anita K., Pourdehnad, Michael, Ribrag, Vincent
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.03.2020; American Society of Hematology
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biomarkers; Clinical Trials and Observations; Drug Resistance, Neoplasm; Female; Humans; Immunophenotyping; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - mortality; Lymphoma, Large B-Cell, Diffuse - pathology; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Male; Middle Aged; Neoplasm Staging; Odds Ratio; Piperidones - administration & dosage; Piperidones - adverse effects; Piperidones - pharmacokinetics; Piperidones - therapeutic use; Prognosis; Quinazolinones - administration & dosage; Quinazolinones - adverse effects; Quinazolinones - pharmacokinetics; Quinazolinones - therapeutic use; Recurrence; Retreatment; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Treatment Outcome
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2019002395

Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are limited, with no standard of care; prognosis is poor, with 4- to 6-month median survival. Avadomide (CC-122) is a cereblon-modulating agent with immunomodulatory and direct antitumor activities. This phase 1 dose-expansion study assessed safety and clinical activity of avadomide monotherapy in patients with de novo R/R DLBCL and transformed lymphoma. Additionally, a novel gene expression classifier, which identifies tumors with a high immune cell infiltration, was shown to enrich for response to avadomide in R/R DLBCL. Ninety-seven patients with R/R DLBCL, including 12 patients with transformed lymphoma, received 3 to 5 mg avadomide administered on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Eighty-two patients (85%) experienced ≥1 grade 3/4 treatment-emergent adverse events (AEs), most commonly neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Discontinuations because of AEs occurred in 10% of patients. Introduction of an intermittent 5/7-day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia, and infections. Among 84 patients with de novo R/R DLBCL, overall response rate (ORR) was 29%, including 11% complete response (CR). Responses were cell-of-origin independent. Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR vs an ORR of 19%, mPFS of 1.5 months, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being evaluated in combination with other antilymphoma agents. This trial was registered at www.clinicaltrials.gov as #NCT01421524. •Avadomide monotherapy is well tolerated and demonstrates preliminary clinical efficacy in the treatment of R/R DLBCL patients.•Avadomide monotherapy resulted in mPFS of 6 months in classifier-positive vs 1.5 months in classifier-negative R/R DLBCL patients. [Display omitted]