Emerging EZH 1/2 Inhibitors Demonstrate Single-Agent Efficacy in R/R PTCL

Given its overall poor prognosis in the relapsed/refractory (R/R) setting, peripheral T-cell lymphomas (PTCLs) remain a difficult malignancy to treat, making the emergence of novel therapies that draw on various mechanisms of action of paramount importance. During his presentation at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), Matthew Lunning, DO, FACP, described the challenges of treating PTCL as a “riddle wrapped in a mystery inside an enigma.¹”

The classic study in PTCL, ECHELON-2 (NCT01777152), compared the efficacy and safety of brentuximab vedotin (Adcetris®; Seagen), cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of patients with CD30+ peripheral T-cell lymphomas.²

The double-blind, randomized trial enrolled 452 patients. Primary end points were progression-free survival (PFS) as determined by independent review and second end points were PFS in patients with anaplastic large cell lymphoma (ALCL), complete remission rate, overall survival (OS), and objective response rate (ORR).

Findings revealed that A+CHP was superior to CHOP in terms of PFS and OS and had a manageable safety profile. Subset analysis demonstrated positive findings in ALK+/– with systemic ALCL and PTCL-NOS (not otherwise specified) populations.

Despite these challenges, though, Lunning said that current methodologies have been able to better define PTCL-NOS.

“I think that angioimmunoblastic T-cell lymphoma is the most common subtype of non-peripheral T cell lymphoma,” Lunning, assistant vice chancellor of clinical research, associate vice chair of research, and associate professor, Division of Oncology & Hematology, University of Nebraska Medical Center, said.

Further, Lunning recommended working closely with the transplant doctor so that the entire care team is on the same treatment page with the appropriate strategies.

Single Agents

Lunning next turned to single agents, including belinostat (Beleodaq®; Spectrum Pharmaceuticals), romidepsin (Istodax®; Gloucester Pharmaceuticals), and pralatrexate (Folotyn®; Acrotech Biopharma).

In the CLN-19 study (NCT00865969),³ single-agent belinostat delivered complete and durable responses in patients with R/R PTCL across all major subtypes, regardless of type or prior therapies, Lunning said.

Romidepsin, the bicyclic class 1 selective histone deacetylase inhibitor, was approved based on findings from NCT00426764.⁴ In the trial, patients with PTCL who relapsed from or were refractory to ≥ 1 prior systemic therapy received romidepsin at 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles. Investigators reported highly durable responses in a subset of patients with R/R PTCL, with responses ongoing as long as 48 months.

Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant.⁵

Emerging Therapies

Duvelisib (Copiktra®; Secura Bio) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ/γ isoform. It is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic lymphoma (CLL) or small lymphocytic lymphoma (SLL) after at least 2 prior therapies.

Horwitz et al,6 reported on the phase 1 (NCT01476657) results of single-agent duvelisib in TCL. The investigators explored the dual effects in the TCL cohort in patients with R/R PTCL (n = 16) and CTCL (n = 19). The ORRs in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes.

“One of the things about this drug that I’m concerned about is its future,” Lunning said. “Not because of its activity in PTCL, but because of results from the FDA’s Oncologic Drug Advisory Committee (ODAC) meeting.”

In an 8 to 4 vote, ODAC decided that the benefit/risk profile of duvelisib is unfavorable for the treatment of adult patients with relapsed or refractory CLL or SLL after at least 2 prior therapies.⁷ Overall, the ODAC members decided that the PFS data were compelling, but the safety data were concerning. Although 4 members voted ‘yes,’ the majority who voted against duvelisib said their decision was based on safety.

The first-in-class dual inhibitor of EZH1 and EZH2, valemetostat, is currently undergoing clinical development. Ishitsuka K et al,8 reported preliminary efficacy in 45 patients with an ORR of 55.6% (95% CI, 40.0%-70.4%), including 11 patients with complete responses (CRs) and 14 with partial responses (PRs). The median duration of response was 14 months and median progression-free survival was 12 months.

Lunning also highlighted 2 agents in early development, tucidostat (HBI-8000), an HDAC inhibitor undergoing evaluation in China, and DZD4205, a JAK-1 inhibitor.

Combination Therapies

The romidepsin backbone is currently undergoing evaluation. Romidepsin and duvelisib were evaluated by Horwitz et al.⁹ The investigators reported a median PFS of 6.9 months with no increase in liver function tests compared with monotherapy.

Two phase 1 studies evaluated the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. The combinations showed activity in relapsed/refractory lymphoma with an acceptable safety profile.¹⁰

Lunning concluded, noting that novel targets continue to emerge through clinical trials, in particular EZH 1 and EZH 2 inhibitors, which have strong single-agent efficacy.

_REFERENCES:

_{1. Lunning M. Relapsed/refractory peripheral T-cell lymphoma. Presented at: 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022); September 28-October 1, 2022; Houston TX.}

_{2. Horwitz S, O'Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229-240. doi:10.1016/S0140-6736(18)32984-2}

_{3. O'Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral t-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) Study. J Clin Oncol. 2015;33(23):2492-2499. doi:10.1200/JCO.2014.59.2782}

_{4. Coiffier B, Pro B, Prince HM, et al. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014;7:11. doi:10.1186/1756-8722-7-11}

_{5. O’Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):1182-1189. doi:10.1200/JCO.2010.29.9024}

_{6. Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888-898. doi:10.1182/blood-2017-08-802470}

_{7. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. September 22, 2022. Accessed September 22, 2022. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-22-23-2022-meeting-oncologic-drugs-advisory-committee-meeting-announcement-09222022}

_{8. Ishitsuka K, Izutsu K, Maruyama D, et al. First-in-human study of the ezh1 and ezh2 dual inhibitor valemetostat tosylate (DS-3201b) in patients with relapsed or refractory non-hodgkin lymphomas. 16th International Conference on Malignant Lymphoma. 2021;39(S2):18-22. doi: 10.1002/hon.14_2879}

_{9. Horwitz SH, Moskowitz AJ, Mehta-Shah N, et al. THE combination of duvelisib and romidepsin (dr) is highly active against relapsed/refractory peripheral t-cell lymphoma with low rates of transaminitis: final results. 16th International Conference on Malignant Lymphoma. 2021;39(S2):18-22. doi: 10.1002/hon.56_2879}

_{10. Mehta-Shah N, Lunning MA, Moskowitz AJ, et al. Romidepsin and lenalidomide-based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase I studies with expansion cohorts. Am J Hematol. 2021;96(10):1211-1222. doi:10.1002/ajh.26288}