High response rates were observed for patients with relapsed/refractory Hodgkin lymphoma treated with the combination of vorinostat and an mTOR inhibitor, according to findings published in Clinical Cancer Research.1
Although the majority of patients diagnosed with Hodgkin lymphoma are considered to be cured following first-line treatment with standard therapy, 5-year survival rates for those with relapsed/refractory disease following primary treatment can be as low as 30%.2
Despite US Food and Drug Administration (FDA) approvals of brentuximab, a CD30 antibody-drug conjugate, and the programmed cell death 1 (PD-1) inhibitors pembrolizumab and nivolumab for the treatment of patients with relapsed/refractory Hodgkin lymphoma, an unmet need remains for new therapies in this setting.
Based on prior preclinical and early clinical evidence supporting the potential efficacy of dual histone deacetylase (HDAC) and AKT/mTOR inhibition for those with relapsed/refractory Hodgkin lymphoma, the cohort of patients with heavily pretreated Hodgkin lymphoma enrolled in a nonrandomized, open-label, dose-escalation phase 1 study (ClinicalTrials.gov Identifier: NCT01087554) investigating the combination of vorinostat, an HDAC inhibitor, with an mTOR inhibitor in advanced cancer was expanded.
The rationale for such an approach was grounded in evidence implicating HDAC overexpression and associated aberrant gene expression in relapsed/refractory Hodgkin lymphoma, as well as a possible role for mTOR signaling as a pathway for resistance to HDAC inhibition in this setting.2,3
At baseline, the 40 patients included in this analysis were aged at least 18 years; the median patient age was 33 years. Regarding race/ethnicity, 55%, 27.5%, 12.5%, and 5% of these patients were White, Hispanic, Black, and Asian, respectively. Stage IV disease was present in 65% of patients, and Eastern Cooperative Oncology Group (ECOG) performance status was 0 (30%), 1 (50%), and 2 (20%). The median number of prior treatments was 5, with previous therapies including brentuximab vendotin, autologous hematopoietic stem cell transplantation (HSCT), and allogeneic HSCT in 97.5%, 65%, and 30% of patients, respectively.
None of these patients had received prior treatment with a PD-1 inhibitor.
Vorinostat, in combination with either siroliumus and everolimus, was administered to 22 and 18 patients, respectively.
For those patients treated with vorinostat plus siroliumus, the complete response (CR) and partial response (PR) rates were both 27%. At a median follow-up of 43.3 months, median progression-free survival (PFS) was 5.8 months.
In the subgroup receiving vorinostat plus everolimus, the CR and PR rates were 11% and 22%, respectively, and, at a median follow-up of 21 months, the median PFS was 4.8 months. A comparison of median PFS for those treated with either sirolimus or everolimus did not show a significant difference (P =.13)
“Of note, responses were seen even in patients who received prior treatment with AKT or HDAC inhibitors,” the study authors commented.
Regarding the safety of combination therapy with an HDAC and an mTOR inhibitor, the most commonly reported grade 3/4 adverse events (AEs) in the overall study population were neutropenia, thrombocytopenia, and anemia. However, while the frequencies of grade 4 neutropenia, thrombocytopenia, and anemia for those treated with sirolimus were 9%, 36%, and 0%, respectively, the corresponding rates were 0%, 11%, and 9% for the subgroup receiving everolimus. No treatment-related grade 5 AEs were reported.
In their concluding remarks, the study authors noted that “combined HDAC and mTOR inhibition has encouraging activity in patients with relapsed and/or refractory Hodgkin lymphoma and warrants further investigation.”
- Janku F, Park H, Call SG, et al. Safety and efﬁcacy of vorinostat plus sirolimus or everolimus in patients with relapsed refractory Hodgkin lymphoma. Clin Cancer Res. Published online October 14, 2020. doi:10.1158/1078-0432.CCR-20-1215
- American Association for Cancer Research (AACR). Combined inhibition of HDAC and mTOR may improve outcomes in patients with relapsed/refractory Hodgkin lymphoma. Published October 14, 2020. Accessed October 20, 2020.
- Chen I-C, Sethy B, Liou J-P. Recent update of HDAC inhibitors in lymphoma. Front Cell Dev Biol. Published online September 3, 2020. doi:10.3389/fcell.2020.576391