Avadomide Demonstrates Preliminary Activity in Diffuse Large B-cell Lymphoma

Avadomide (CC-122), an anti-lymphoma agent, may be active in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to data from a cohort of a phase Ia/Ib trial.

The study is evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of avadomide in patients with advanced solid tumors, non-Hodgkin lymphomas (NHLs), or multiple myeloma (NCT01421524). Findings from the DLBCL cohort were published in Blood.

The study included 97 patients with DLBCL overall. Eighty-four patients in the study had de novo DLBCL and 12 had transformed lymphoma. Baseline characteristics showed that a majority of patients had an ECOG performance status of 0 or 1, with the exception of 6% of patients whose ECOG performance status was 2.

Patients received avadomide on intermittent schedules which was 4 mg, 5/7 days for 39 patients, 4 mg, 21/28 days for 3 patients and 5 mg, 5/7 days for 5 patients.

In terms of prior therapy, 65% of participants had received 3 or more lines of prior systemic anticancer therapy (range, 1-13). Eighty-nine patients had received prior rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or an equivalent anti-CD20–containing intensive chemotherapy. Disease settings in the enrolled patients included primary refractory disease (50 patients, 49%), relapse within 12 months of autologous stem cell transplant (ASCT) in 14%, and 64% of patients had chemotherapy-refractory DLBCL.

The overall response rate (ORR) achieved with avadomide was 28% (95% CI, 19%-38%), which included complete responses (CRs) in 9 patients with DLBCL. Better efficacy outcomes were observed in patients with de novo DLBCL versus those with transformed lymphoma, according to the progression-free survival (PFS) rates observed. For those with de novo DLBLC, the 6-month PFS rate was 28% (95% CI, 19%-37%) compared with 8% (95% CI, 8%-31%) in the transformed lymphoma population. The CR rates observed in these groups were 11% and 0%, respectively.

The median duration of response (DOR) observed in this analysis was 31 weeks (95% CI, 18-73) in all patients with DLBCL and 33 weeks (95% CI, 20-not reached [NR]) in patients with de novo DLBCL. From baseline to efficacy evaluation, the lesion sizes in both groups of patients were similar.

Efficacy was also assessed in patients with germinal center B-cell (GCB)–like DLBCL compared with activated B-cell (ABC)–like DLBCL. The assessment included the 84 patients with de novo DLBCL and excluded those with transformed lymphoma. The ORR for GCB DLBCL was 33% (95% CI, 19%-51%) compared with ABC DLBCL, which had an ORR of 25% (95% CI, 9%-49%). At 6 months, the PFS rates observed in the GCB DLBCL group versus the ABC DLBCL group, respectively, were 35% and 21%, and the 12-month PFS rate was 18% versus 14%. The median DOR in each group, respectively, was 24 weeks (95% CI, 8-NR) and 68 weeks (95% CI, 4-68). No correlation was found for cell of origin (COO) and PFS in patients with de novo DLBCL who received avadomide. The intermittent 5/7-day schedule also had no bearing on efficacy in this group.

To identify 2 patient subgroups based on tumor microenvironment characteristics separate from COO, the study investigators developed a novel gene expression classifier, which obtained information from a publicly available gene expression dataset. This analysis was based on a hypothesis that patients with classifier-positive tumors would derive more benefit from avadomide than classifier-negative tumors.

There were 32 patients with classifier-positive tumors overall. The ORR achieved with avadomide in this group was 44% (95% CI, 26%-62%) and the median PFS was 27 weeks (95% CI, 7-27). Additionally, the 6-month PFS rate in the classifier-positive tumors was 62% and the 12-month PFS rate was 29%. For classifier-negative tumors, the ORR was 19% and the median PFS was 7 weeks. The 6-month and 12-month PFS rates in the classifier-negative group, respectively, were 12% and 9%. Classifier status was not associated with lesion size reduction from baseline.

Overall, classifier-positive status were found to be associated with PFS rate in patients with de novo DLBCL (HR, 0.490; 95% CI, 0.280-0.857; P = .0096), which may demonstrate its value as an enrichment strategy for avadomide response. In addition, a post hoc subgroup analysis revealed a clinical benefit in patients with classifier-positive status, low ECOG performance status, and normal lactate dehydrogenase (LDH) levels.

In the multicenter, open-label, dose-finding study, patients received a median of 56 days of avadomide (range, 7-1240). In the safety analysis, the goal was to determine the maximum tolerated dose (MTD) of the drug and determine the overall safety profile.

After multiple-dose changes due to toxicities like mature neutrophil counts, it was determined that patients could handle a 16.5 mg/week with 3 mg avadomide hydrochloride (HCl) continuously dosed versus 19 mg/week with 4 mg avadomide HCl on 5/7 days. In total, 35 patients had at least 1 dose reduction, of which 89% were related to adverse events (AEs). Notably, more dose reductions occurred in patients who received 3 mg of avadomide versus 4 mg of the agent.

Eighty-three patients were evaluable for the dose-limiting toxicity assessment. Fourteen patients experienced a dose-limiting toxicity and 10 of these required a dose reduction or interruption.

All 97 patients experienced at least 1 treatment-emergent adverse event (AE). The most commonly observed treatment-emergent AEs of any grade were neutropenia (66%), infections (57%), and asthenia (46%). Treatment-emergent AEs of grade 3 or 4 occurred in 85% of patients, of which the most common were neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). There was also 1 grade 5 pneumonia event that may have been related to avadomide. Twenty-five patients died during the study, and of these deaths, 21 were caused by disease progression, and 3 were related to other causes not related to avadomide.

An immune deconvolution analysis was conducted in the study as well. This showed that avadomide monotherapy elicits immunomodulatory effects, which include an increase in the number of T cells, natural killer cells, and macrophages, as well as a decrease in proliferating B cells within the tumor. The analysis included 8 patients who were screened and examined 2 weeks after treatment initiation for changes in gene expression and immune cell composition.

The investigators determined that avadomide is a pharmacodynamic biomarker that shows signs of clinical activity in NHL. Based on these findings from the dose-escalation phase, the dose-expansion phase studied multiple tumor types, including glioblastoma, hepatocellular carcinoma, multiple myeloma, and NHL.

Looking ahead, further study of avadomide may bring better knowledge to the treatment landscape, the study authors wrote. “An understanding of the interplay between avadomide effects and the tumor microenvironment, as well as the biology associated with defined cell types within classifier-positive tumors, can inform patient selection strategies and combination strategies.”

_Reference:

_{Carpio C, Couabdallah R, Ysebaert L, et al. Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier. Blood. 2020;135(13);996-1007. doi: 10.1182/blood.2019002395.}