Histone deacetylase (HDAC) inhibitors
Romidepsin (ROMI) is an HDAC inhibitor that is being investigated in PTCL. Other HDAC inhibitors under investigation include belinostat and chidamide.3 ROMI is approved by the FDA for PTCL following one line of prior therapy and CTCL following one prior systemic therapy.4
Vorinostat is another HDAC inhibitor that is approved for CTCL that is progressive, persistent or recurrent following two systemic therapies, which is considered SOC in this setting.5
Hypomethylating agents (HMA)
HMAs such as azacitidine (AZA) address the hypomethylating defects commonly seen in T-cell lymphomas, such as mutations in TET2, IDH and DNMT3. Interestingly, HMAs have effects both on the PTCL, and also the microenvironment. Adding an HMA to an HDAC inhibitor is hypothesized to be efficacious in PTCLs; this concept is discussed later in the article.
Pralatrexate is a novel anti-folate which received FDA approval for relapsed/refractory (R/R) PTCL.6 The phase II PROPEL study evaluated single-agent pralatrexate in patients with R/R PTCL. The results indicated an overall response rate (ORR) of 29% with a median OS of 14.5 months.3
Immune checkpoint inhibitors
Results from a phase II trial (NCT02535247) investigating pembrolizumab, a programmed cell death -1 (PD-1) inhibitor, in patients with R/R mature T-cell lymphoma, found pembrolizumab had modest efficacy with an expected safety profile, though studies with larger sample sizes are required to confirm the results.
Phosphoinositide 3-kinase (PI3K) inhibitors
Duvelisib is an oral inhibitor of two PI3Ks – PI3K-δ and PI3K-γ. The ongoing phase II PRIMO study (NCT03372057) is investigating duvelisib as a monotherapy in patients with R/R PTCL. Duvelisib has been granted both orphan drug designation and fast track designation by the FDA for R/R PTCL. Another PI3K inhibitor under investigation is copanlisib.3
Aurora A kinase inhibitors
Alisertib is an aurora A kinase inhibitor. The phase III LUMIERE trial (NCT01482962) sought to compare alisertib monotherapy, to investigator’s choice in patients with R/R PTCL. PTCL subtypes included PTCL-NOS, AITL and ENKTL. However, this study did not find a significant improvement in outcomes with alisertib compared to comparator drugs (such as gemcitabine, pralatrexate or ROMI).
Tipifarnib is a selective inhibitor of farnesyltransferase that is being investigated in patients with R/R T-cell lymphomas. Results of a phase II trial (NCT02464228) were presented at the 61st meeting of the American Society of Hematology (ASH). Tipifarnib was recently granted fast track designation by the FDA for R/R T-cell lymphomas including AITL and nodal PTCL with a TFH phenotype.
Dual SYK/JAK inhibitors
Cerdulatinib is a dual inhibitor of SYK and JAK that has previously been granted orphan drug designation by the FDA for R/R PTCL. In a phase IIa dose-expansion study patients with R/R PTCL or CTCL were treated with cerdulatinib monotherapy. The ORR in patients with PTCL was 35%, predominantly seen in patients with AITL/TFH subtype.7
For patients with CTCL, bexarotene, a synthetic retinoid related to vitamin A, was approved in 1999. Long-term follow-up data indicate it is well-tolerated and effective in both early and advanced CTCL.8
Immunotherapies are another class of novel agent that could provide a benefit to patients with PTCL. Some examples of these therapies are discussed below, including both approved and investigatory agents.
Monoclonal antibodies (mAbs)
Mogamulizumab is a mAb that targets chemokine receptor type 4 (CCR4).9 The phase III MAVORIC trial (NCT01728805), comparing vorinostat to mogamulizumab in patients with previously treated CTCL (R/R mycosis fungoides or Sézary syndrome), found mogamulizumab led to significant improvements in PFS and ORRs compared to vorinostat. Mogamulizumab was also found to have a comparable safety profile to vorinostat, indicating this novel therapy may have potential in R/R CTCL. Mogamulizumab is approved by the FDA for patients with mycosis fungoides or Sézary syndrome.10
Lacutamab is a first-in-class anti-killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2) mAb being investigated in advanced T-cell lymphomas. The phase II TELLOMAK study (NCT03902184) is an open-label, multi-cohort study investigating lacutamab as monotherapy and in combination with chemotherapy. The study was placed on a partial hold by the FDA in January 2020 due to Good Manufacturing Practice (GMP) deficiencies at a subcontractor site.
As discussed above, brentuximab vedotin is approved for the frontline treatment of PTCL by the FDA. Brentuximab vedotin is an antibody-drug conjugate that targets CD30. It is conjugated to the anti-microtubule agent monomethyl auristatin E which, upon binding, is released into the cell leading to cell cycle arrest and apoptosis.11
Bispecific cell engagers
AFM13 is a first-in-class tetravalent bispecific innate cell engager that binds to CD30 on tumor cells and CD16A on NK cells. It is in development for the treatment of CD30+ lymphomas, including PTCL. An ongoing phase II study called REDIRECT (NCT04101331) is investigating AFM13 as monotherapy in patients with R/R CD30+ PTCL. AFM13 was recently granted orphan drug designation for the treatment of T-cell lymphomas including PTCL by the FDA.
Chimeric antigen receptor (CAR) T-cell therapy
CAR T-cell therapy products have been approved for B-cell NHLs such as diffuse large B-cell lymphoma. There is hope that these products may be effective in CD30+ T-cell lymphomas as well.1
Generating a new backbone therapy
Whilst response rates with single-agent ROMI are in the mid 20% mark, using ROMI in combination with other agents has led to much higher ORRs. Using such epigenetic strategies as the backbone to subsequent combination therapies appears to be a promising strategy.
A phase I/II study (NCT01998035) is studying the combination of AZA, an HMA, and ROMI for newly diagnosed and R/R PTCL. Results from the phase I portion of the study were published in Blood in November 2019 and found patients with PTCL responded better than patients with non-T-cell lymphoma who were included in the study, with a 73% response rate. The phase II results were presented at the ICML in June 2019 and showed AZA + ROMI was particularly active in patients with AITL and PTCL-TFH. During ICML 2019, the Lymphoma Hub also spoke to Lorenzo Falchi about how AZA + ROMI might fit into the treatment pathway in T-cell lymphoma. Watch the interview below.