New data for valemetostat tosylate (DS-3201b), being developed by Daiichi Sankyo, shows promising and durable tumor response in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) and adult T-cell leukemia/lymphoma (ATL).[1][2]

The investigational drug is a potential first-in-class specific and potent dual inhibitor of EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2), presented during an oral presentation (Abstract #S218) at the Annual Congress of the European Hematology Association (#EHA2021),

Rare and heterogeneous diseases
PTCL is a group of rare and heterogeneous malignancies, including ATL, which represent about 10-15% of all non-Hodgkin lymphomas (NHL).[3] The majority of patients with PTCL experience disease progression following initial treatment with a multi-drug chemotherapy-based regimen, and the median overall survival following relapse is approximately 5.8 months.[4] New innovative treatment strategies are needed to improve survival in these patients because each year approximately 544,000 new cases of NHL were diagnosed worldwide in 2020.[5]

There are at least 29 recognized subtypes of PTCL, which occur with a significant geographic variation.[6] The most common subtypes of PTCL occur frequently in Western countries and in Asia, while ATL is generally more frequent in Japan and parts of the Caribbean and Latin America.[7][8]

  • ATL is associated with the human T-cell lymphotropic virus type 1 (HTLV-1).[7]
  • PTCL tends to be aggressive and the prognosis is generally poor, with five-year overall survival at 32% in two common PTCLs (PTCL-NOS and AITL) and at 14% for ATL.[7]

EZH1 and EZH2 enzymes are part of polycomb protein complexes and act through histone methylation to regulate the expression of genes involved in maintaining hematopoietic stem cells. [9] These enzymes are thought to contribute to the silencing of genes that suppress tumor cell growth and proliferation.[10]

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EZH1 and EZH2 are recurrently highly expressed or mutated in many hematologic malignancies.[10] Research shows that both EZH1 and EZH2 enzymes have a role in hematologic cancer progression and that simultaneous inhibition would be effective in targeting the cancers.[1] Today, there are no dual EZH1/2 directed therapies approved for cancer treatment. Valemetostat is the first investigational potent dual inhibitor of EZH1 and EZH2.

Study design
In an open-label, single-arm, multi-center, first-in-human, two-part phase 1 study researchers are evaluating the safety and efficacy of valemetostat in adult patients with relapsed/refractory NHL, including B-cell and T-cell lymphomas. Following the dose-escalation portion of the study, which evaluated safety, pharmacokinetics and determined the recommended dose for expansion (200 mg once daily), the dose-expansion part enrolled patients into one of two cohorts based on NHL subtype (PTCL and ATL) to further evaluate the safety and assess preliminary efficacy.

In this first-in-human phase 1 study of valemetostat in B-cell and T-cell NHL, data were reported at EHA in the subset of patients with relapsed/refractory PTCL and ATL. The objective response rate (ORR), based on the investigator’s assessment, was 54.5% (CI 95%: 38.8-69.6) in 44 patients with PTCL including 12 complete responses (CRs) and 12 partial responses (PRs). Median duration of response (DOR) of 56.00 weeks (CI 95%: 44.43-NE) and a median progression-free survival (PFS) of 52.00 weeks (CI 95%: 16.14-NE) were observed after a median follow-up of 19.93 weeks (range: 3.1-68.1).

The ORR in 14 patients with ATL was 57.1% (CI 95%: 28.9-82.3), with four CRs and four PRs. Median DOR and PFS were not estimable for patients with ATL after a median follow-up of 23.07 weeks (range: 3.3-125.0). Twelve patients with PTCL and six patients with ATL remained on treatment with valemetostat at the time of data cut-off on November 2, 2020.

Safety profile
The safety profile of valemetostat in patients with PTCL and ATL (n=58) was similar with that seen across all patients with NHL (n=77). Grade 3 or higher treatment emergent adverse events (TEAEs) occurred in 54 of 77 NHL patients (70.1%) and included neutrophil count decrease (23.4%), lymphocyte count decrease (22.1%), platelet count decrease (16.9%), white blood cell count decrease (15.6%), anemia (11.7%), diarrhea (1.3%) and alanine aminotransferase (ALT) increase (1.3%). Dose interruption or reductions due to TEAEs occurred in 41.6% (n=32) and 10.4% (n=8) of all patients with NHL, respectively.

“The proportion of patients who responded to valemetostat and the durability of responses observed in this trial are very encouraging for patients with PTCL, including ATL, which remains one of the most significant areas of unmet need in the treatment of hematologic cancers,” said Shigeru Kusumoto, MD, Associate Professor, Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Japan.

“Because both EZH1 and EZH2 play important roles for the pathophysiology of PTCL and ATL, dual targeting of EZH1 and EZH2 with valemetostat may be an innovative approach for these difficult-to-treat diseases.”

“We are committed to translating the novel mechanism of valemetostat into a potential treatment option for patients with PTCL and ATL in various regions around the world where these types of blood cancers are most prevalent,” said Ken Takeshita, MD, Global Head of Research and Development, Daiichi Sankyo.

“Based on the promising clinical activity seen in this phase 1 study, we have initiated VALENTINE-PTCL01, a global pivotal study that will further evaluate the efficacy and safety of valemetostat in patients with relapsed or refractory PTCL including ATL.”

Patients with PTCL enrolled in the study had received a median of two prior treatments (range: 1- 8), including prior hematopoietic stem cell transplantation (HSCT; 20.5%). Patients with ATL had received a median of two prior treatments (range: 1- 8), including HSCT (14.3%).

Clinical trials
Valemetostat Tosylate (DS-3201b), an Enhancer of Zeste Homolog (EZH) 1/2 Dual Inhibitor, for Relapsed/Refractory Peripheral T-Cell Lymphoma (VALENTINE-PTCL01) – NCT04703192

[1] Honma D, Kanno O, Watanabe J, Kinoshita J, Hirasawa M, Nosaka E, Shiroishi M, Takizawa T, Yasumatsu I, Horiuchi T, Nakao A, Suzuki K, Yamasaki T, Nakajima K, Hayakawa M, Yamazaki T, Yadav AS, Adachi N. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 2017 Oct;108(10):2069-2078. doi: 10.1111/cas.13326. Epub 2017 Aug 8. PMID: 28741798; PMCID: PMC5623739.
[2] Yamagishi M, Hori M, Fujikawa D, Ohsugi T, Honma D, Adachi N, Katano H, Hishima T, Kobayashi S, Nakano K, Nakashima M, Iwanaga M, Utsunomiya A, Tanaka Y, Okada S, Tsukasaki K, Tobinai K, Araki K, Watanabe T, Uchimaru K. Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas. Cell Rep. 2019 Nov 19;29(8):2321-2337.e7. doi: 10.1016/j.celrep.2019.10.083. PMID: 31747604.
[3] Leukemia and Lymphoma Society. PTCL Facts. 2020. Online. Last accessed on June 10, 2020.
[4] Bellei M, Foss FM, Shustov AR, Horwitz SM, Marcheselli L, Kim WS, Cabrera ME, Dlouhy I, Nagler A, Advani RH, Pesce EA, Ko YH, Martinez V, Montoto S, Chiattone C, Moskowitz A, Spina M, Biasoli I, Manni M, Federico M; International T-cell Project Network. The outcome of peripheral T-cell lymphoma patients failing first-line therapy: a report from the prospective, International T-Cell Project. Haematologica. 2018 Jul;103(7):1191-1197. doi: 10.3324/haematol.2017.186577. Epub 2018 Mar 29. PMID: 29599200; PMCID: PMC6029527.
[5] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.
[6] Ma H, Marchi E, O’Connor OA. The peripheral T-cell lymphomas: an unusual path to cure. Lancet Haematol. 2020 Oct;7(10):e765-e771. doi: 10.1016/S2352-3026(20)30207-6. PMID: 32976753.
[7] Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008 Sep 1;26(25):4124-30. doi: 10.1200/JCO.2008.16.4558. Epub 2008 Jul 14. PMID: 18626005.
[8] Schmitz N, de Leval L. How I manage peripheral T-cell lymphoma, not otherwise specified and angioimmunoblastic T-cell lymphoma: current practice and a glimpse into the future. Br J Haematol. 2017 Mar;176(6):851-866. doi: 10.1111/bjh.14473. Epub 2016 Dec 16. PMID: 27982416.
[9] Honma D et al. 2017 ASH Annual Meeting Poster Presentation. Abstract #2073.
[10]Nakagawa M, Kitabayashi I. Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies. Cancer Sci. 2018 Aug;109(8):2342-2348. doi: 10.1111/cas.13655. Epub 2018 Jun 27. PMID: 29845708; PMCID: PMC6113435.

Featured image: Before COVID-19 – the 2019 annual EHA meeting. Photo courtesy: © 2019 EHA.  Used with permission.

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