Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier
Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are limited, with no established standard of care, and prognosis remains poor, with a median survival of only 4 to 6 months. Avadomide (CC-122), a cereblon-modulating agent, has both immunomodulatory and direct antitumor activities. This phase 1 dose-expansion study evaluated the 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 high immune cell infiltration, was shown to predict better responses to avadomide in R/R DLBCL. A total of 97 patients with R/R DLBCL, including 12 with transformed lymphoma, received avadomide (3 to 5 mg) on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Among these, 82 patients (85%) experienced at least one grade 3/4 treatment-emergent adverse event (AEs), with the most common being neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Ten percent of patients discontinued treatment due to AEs. The introduction of an intermittent 5/7-day schedule improved tolerability, reducing the frequency and severity of neutropenia, febrile neutropenia, and infections. In the 84 patients with de novo R/R DLBCL, the overall response rate (ORR) was 29%, including 11% with complete response (CR). Responses were independent of cell-of-origin. Classifier-positive de novo DLBCL patients had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR, compared to 19% ORR, 1.5 months mPFS, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being further investigated in combination with other antilymphoma agents. This trial was registered at www.clinicaltrials.gov as #NCT01421524.