Novel agent appears safe, effective for relapsed, refractory diffuse large B-cell lymphoma
The novel cereblon-modulating agent avadomide demonstrated preliminary clinical efficacy among patients with relapsed or refractory diffuse large B-cell lymphoma, according to results of a phase 1 study published in Blood.
Monotherapy with avadomide (CC-122) also appeared well-tolerated.
Additionally, researchers observed median PFS of 6 months among patients identified by a novel gene expression classifier as having enriched infiltration of T cells and macrophages in the tumor microenvironment (classifier-positive disease), compared with 1.5 months among those with a predominance of intratumoral B cells (classifier-negative disease).
“Patients with refractory DLBCL, defined as progressive or stable disease as best response to chemotherapy or relapse [12 months or less after] autologous stem cell transplant, have a poor prognosis, with median OS of 4 to 6 months,” Cecilia Carpio, MD, of the department of hematology at Vall d’Hebron University Hospital in Barcelona, Spain, and colleagues wrote. “In patients with relapsed or refractory disease who are not candidates for potentially curative therapies, including anti-CD19 chimeric antigen receptor T-cell therapy, DLBCL remains a high unmet need for which new treatment options are necessary.”
In the dose-expansion portion of the phase 1, multicenter CC-122-ST-001 trial, Carpio and colleagues sought to assess the safety and clinical activity of 3 mg to 5 mg avadomide — which induces direct cell autonomous activity against malignant B cells and immunomodulatory effects — among 97 patients (median age, 62 years; 57% men; 36% aged 65 years or older) with relapsed or refractory de novo DLBCL, including 12 patients with transformed lymphoma. Treatment continued until unacceptable toxicity, disease progression or study withdrawal.
The majority (65%) of patients had received three or more lines of systemic anticancer therapy; 91% had received R-CHOP or equivalent anti-CD20-containing intensive chemotherapy; 49% had primary refractory disease; and 19% had undergone at least one autologous stem cell transplant.
Results of an analysis of peripheral blood samples collected 5 hours after patients received avadomide showed levels of the hematopoietic transcription factor Aiolos had been reduced by a median 59% in CD19-positive B cells and a median 45% in CD3-positive T cells.
Eighty-five percent of patients experienced one or more grade 3 or grade 4 treatment-associated adverse events, including neutropenia (51%), infections (24%), anemia (12%) and febrile neutropenia (10%). Ten percent of patients discontinued treatment due to adverse events.
“Introduction of an intermittent 5- to 7-day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia and infections,” the researchers wrote.
Researchers reported an overall response rate of 29% among the 84 patients with de novo relapsed or refractory DLBCL, including a complete response of 11%. Responses occurred independent of cell origin.
Those with classifier-positive disease had an ORR of 44%, median PFS of 6 months and a complete remission rate of 16%. Conversely, those with classifier-negative disease had an ORR of 19%, median PFS of 1.5 months and a complete remission rate of 5% (P = .0096).
Avadomide is being investigated in combination with other antilymphoma agents, according to the researchers.
Patients with relapsed diffuse large B-cell lymphoma who fail to respond to salvage chemotherapy or who rapidly progress after stem cell transplantation are a very challenging group of patients to treat, as most of them do not benefit from further chemotherapy. These patients typically have a very poor prognosis and median survival of less than 6 months. Novel therapies that are effective in this population of patients are, therefore, desperately needed.
Avadomide, which has both antitumor and immune-activating effects, has been shown to have activity in this subgroup of patients with DLBCL, with an overall response rate of 29%. Although this response rate is somewhat modest, the patients treated in this trial were very resistant to prior treatment and 65% had received at least three lines of prior therapy. Most were refractory to treatment and only 19% had been able to receive a prior autologous stem cell transplant. The durable responses seen in some of these patients are quite notable.
An additional important finding of this study was that treatment with avadomide was associated with an increase in intratumoral immune cells and a decrease in proliferating malignant B cells. This information allowed for the use of a tumor microenvironment gene expression classifier to identify patients more likely to respond to the drug. The classifier separated tumors with increased numbers of intratumoral macrophages and T cells (classifier positive) from those with increased numbers of B cells (classifier negative). Patients who were classifier positive had an ORR of 44% and median PFS of 6 months, suggesting that these patients benefit from this treatment. In contrast, patients who were classifier negative had a very low response rate and most progressed within one to two cycles of treatment. Moving forward, this information allows for patients with DLBCL who would not benefit from this treatment to be considered for other therapies. It also allows for future studies to focus on patients with an immune-activated tumor microenvironment (classifier positive), and may lead to promising combination approaches that promote a more effective antitumor immune response in DLBCL. – by Jennifer Southall