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

Abstract

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.

Graphical abstract

Figure 1.

Avadomide effects on immune activation in peripheral blood. (A) Aiolos expression in peripheral CD19⁺ B and CD3⁺ T cells. (B) Ex vivo IFN-γ production in response to anti-CD3 stimulation. (C) Total peripheral blood CD8⁺ T cells and shifts in CD8⁺ T-cell subsets (naive, activated, memory). (D) TCR-β expression levels (log10-transformed number of CDR3 reads) at baseline vs on-treatment are plotted. Color indicates a significant differential expression (red, not significant; blue, significant; adjusted P < .001) or publicly identified TCR sequence with known antigen (green). Changes in TCR-β productive clonality and richness from baseline to end of cycle 2 are shown for each patient. Extent of change in percentage of baseline (0 indicating no change) is plotted.

Figure 2.

Avadomide effects signaling pathways and immune cell infiltration in DLBCL tumors. (A) RNA sequencing with immune cell deconvolution performed on screening and on-treatment (C1D10/15) biopsy specimens, showing enrichment/depletion relative to screening biopsy. (B) Cellular composition in paired tumor biopsy specimens by immunohistochemistry. Original magnification, ×20. (C) Intratumoral cell counts in screening vs on-treatment biopsy specimens by immunohistochemistry (CD20⁺ B cells; CD3⁺ T cells; CD163⁺ macrophages; CD56⁺ NK cells). DAPI, 4′,6-diamidino-2-phenylindole.

Figure 3.

Best percentage reduction in target lesion burden over baseline in all response-evaluable patients. Dotted line indicates 50% reduction, consistent with a response (per investigator assessment, according to revised 2007 International Working Group [IWG] criteria). Blue, DLBCL de novo; red, transformed lymphoma.

Figure 4.

Progression-free survival (PFS) in de novo R/R DLBCL. PFS by COO (A) and gene expression classifier status (B). PFS was assessed by investigators. Asterisks represent censored observations. N/A, not available.