Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in the United States, according to the Lymphoma Research Foundation, and worldwide, accounting for about 22% of newly diagnosed cases of B-cell NHL in the United States. More than 18,000 people are diagnosed with DLBCL each year.
It is fast-growing and can be aggressive but due to the variety of treatments available, it is potentially curable.
Napabucasin, a novel inhibitor of signal transducer and activator of transcription 3 (STAT3), is a promising candidate for patients with DLBCL, according to paper published online in Cancer Letters.
“DLBCL, the most common type of aggressive non-Hodgkin lymphoma, has highly heterogeneous molecular characteristics. Although some patients initially respond to standard R–CHOP therapy, 30% to 40% develop refractory disease or suffer relapse,” wrote researchers from Sichuan, China. “STAT3, which regulates multiple oncogenic processes, has been found to be constitutively activated in various cancers, including DLBCL, suggesting its potential as a therapeutic target.”
Among 69 patients with DLBCL, one third expressed pSTAT3 in tumor tissues, according to the study. In a dose-dependent manner, napabucasin exhibited potent cytotoxicity against non-Hodgkin lymphoma cell lines.
In mechanistic studies, napabucasin induced intrinsic and extrinsic cell apoptosis, downregulated STAT3 target gene expression, and regulated the reactive oxygen species-mediated mitogen-activated protein kinase pathway.
“Most importantly,” researchers noted, “in vivo studies revealed the suppressive efficacy of napabucasin as a monotherapy without obvious toxicity.”
In preliminary investigations, researchers added, napabucasin showed significant synergism with doxorubicin in vitro as well as in vivo.
Newly Approved Treatments
On August 3, 2020, the FDA granted accelerated approval to tafasitamab-cxix (Monjuvi; MorphoSys US) combined with lenalidomide for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including those with DLBCL arising from low grade lymphoma and who are ineligible for autologous stem cell transplantation. This application was granted priority review, and given fast track, breakthrough, and orphan product designations.
The approval was based on efficacy data from the open-label, multi-center, single-arm L-MIND trial. In this study, 81 patients received tafasitamab-cxix 12 mg/kg intravenously with lenalidomide 25 mg orally (on days 1 to 25 of each 28-day cycle) for up to 12 cycles, followed by tafasitamab-cxix monotherapy.
The main efficacy end point was investigator-assessed overall response rate.
Findings showed that the best overall response rate was 55%, with complete responses in 37% of patients and partial responses in 18%. The median response duration was 21.7 months.
Neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite were the most frequently experienced adverse events.
The immunotherapy drug tisagenlecleucel is associated with an “exceedingly high” incremental cost-effectiveness ratio for patients with relapsed or refractory who failed two or more lines of systemic therapies, according to a cost utility analysis that took a Singapore health care payer perspective. Researchers published their findings online in the Journal of Medical Economics.
“Patients with relapsed or refractory DLBCL have limited treatment options and poor prognoses,” wrote the Singapore-based research team. “Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy, has shown early promise in improving survival outcomes, but at a high upfront cost.”
Researchers investigated the cost-effectiveness of tisagenlecleucel compared with salvage chemotherapy for patients with relapsed or refractory DLBCL who failed at least two lines of systemic therapies. To do so, they developed a hybrid decision tree and three-state partitioned survival model. Survival curves from two studies were extrapolated over a 15-year time horizon to estimate underlying progression-free survival and overall survival. Direct costs were sourced from healthcare facilities in Singapore.
According to the analysis, tisagenlecleucel was associated with a base-case incremental cost-effectiveness ratio (ICER) US$508,530 per quality adjusted life year gained, and US$320,200 per life year gained, compared with salvage chemotherapy.
Even under favorable assumptions, the ICERs remained high, researchers noted. Substantial price reductions would be required to reduce the ICER.
For patients with relapsed or refractory DLBCL who failed prior lines of systemic therapies, tisagenlecleucel “is unlikely to represent good use of health care resources,” researchers concluded. “Comparative clinical evidence from the ongoing trials might provide more insight into future evaluations.” ν
- Li X, Wei Y, Wei X. Napabucasin, a novel inhibitor of STAT3, inhibits growth and synergises with doxorubicin in diffuse large B-cell lymphoma [published online ahead of print, 2020 Aug 14]. Cancer Lett. 2020;491:146-161. doi:10.1016/j.canlet.2020.07.032
- US Food and Drug Administration. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. August 3, 2020. www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-tafasitamab-cxix-diffuse-large-b-cell-lymphoma. Accessed August 3, 2020.
- Cher BP, Gan KY, Aziz MIA, et al. Cost utility analysis of tisagenlecleucel vs salvage chemotherapy in the treatment of relapsed/refractory diffuse large B-cell lymphoma from Singapore's healthcare system perspective [published online ahead of print, 2020 Aug 25]. J Med Econ. 2020;1-9. doi:10.1080/13696998.2020.1808981