Researchers sought to evaluate everolimus, a mammalian target of rapamycin inhibitor (mTORi), an panobinostat, the histone deacetylase inhibitor (HDACi), in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). The team assessed these treatments as single-agent regiments and in combination with one another. Despite Prioty Islam, MD, and colleagues’ promising findings from pre-clinical lymphoma models, as well as both treatments’ demonstrated utility as a single-agent, the study found “minimal single-agent activity and prohibitive toxicity with combination therapy.”
Their report in Cancer Investigation noted that the single-agent phase yielded only one response. Although 25% of patients responded to the combination therapy, the responses were not durable and there were significant toxicity concerns, particularly thrombocytopenia.
The trial’s single-agent followed by doublet therapy design was intended to evaluate as many novel treatment lines as possible within one study. The authors had theorized the treatments would strengthen each other by “by targeting separate, complementary pathways vital to lymphomagenesis,” and also that patients who did not respond to single-agent treatment could still benefit from the combination treatment.
The combination of everolimus and panobinostat demonstrated “modest efficacy” with an overall response rate (ORR) of 25% in patients with R/R DLBCL. However, most patients experienced grade III or IV adverse events, including thrombocytopenia (83%) and fatigue (55%). The researchers reduced the dose of both agents, but toxicity did not improve. They noted that their efficacy and safety findings were consistent with a DLBCL subgroup in a previous phase I study.
While the article reported that this study found minimal efficacy and prohibitive toxicity rates for everolimus plus panobinostat for patients with R/R DLBCL, it noted that other studies have found modest clinical efficacy in patients with targeted mutations. The authors warned future investigators of the toxicity concerns, and concluded that, “these agents may be better suited to the treatment of indolent lymphoma, in which lower doses and longer treatment periods may result in better tolerability and response.”