A Phase Ib/II, Dose Escalation and Dose Expansion Study of Valemetostat Tosylate (DS-3201b) with Atezolizumab and Bevacizumab in Advanced Hepatocellular Carcinoma (HCC)

This is a phase Ib/II, dose escalation and dose expansion study of valemetostat (DS-3201) with atezolizumab and bevacizumab in patients advanced Hepatocellular carcinoma (HCC) who did not receive prior systemic therapy for advanced HCC.

Start Date31 Dec 2024

Sponsor / Collaborator

The University of Alabama at Birmingham

NCT05879484 / Not yet recruitingPhase 1/2IIT

A Phase Ib/II Multicenter Study of Front Line Pembrolizumab and Valemetostat in PD-L1 Positive, HPV-Negative Recurrent/Metastatic Squamous Cell Carcinoma (SCC) of the Head and Neck: The PANTHERAS

Background:
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide. These cancers have different causes, with smoking/tobacco exposure and human papilloma virus infection being the most common. . When HNSCC occurs in people who are not infected with HPV, the cancers are more likely to return after treatment; when this happens, overall survival is only about 10 months, thus better treatments are needed.
Objective:
To test a combination treatment using 2 drugs (valemetostat and pembrolizumab) in people with HNSCC. Phase 1b of the study will determine a recommended dose of the 2 drugs and evaluate how safe the combination is.; this will include patients with HPV-positive and HPV-negative HNSCC, as well as squamous cell NSCLC that have progressed on anti-PD-1/anti-PD-L1 therapies.Phase II will determine how effective the combination is and will focus on patients with HPV-negative HNSCC.
Eligibility:
People aged 18 years and older with HPV-negative HNSCC, sinonasal carcinoma of the head and neck, or squamous non-small cell lung cancer (NSCLC).
Design:
Participants will be screened. They will have a physical exam. They will have blood and urine tests and tests of their heart function. They will have imaging scans. They may have a biopsy: A small sample of tissue will be removed from the tumor.
Treatment will be given in 21-day cycles.
Pembrolizumab is administered through a tube attached to a needle inserted into a vein in the arm. Participants will receive pembrolizumab on the first day of each cycle.
Valemetostat is a tablet taken by mouth. Participants will take the tablet once a day at home. They will record the date and time of each dose in a diary. They will also write down any adverse effects they experience.
Participants may remain in the study up to 2 years.

Start Date05 Nov 2024

Sponsor / Collaborator

National Cancer Institute

NCT06644768 / Not yet recruitingPhase 1/2

A Multicenter, Randomized, Open-Label, Phase 1b/2 Trial Of Valemetostat Tosylate Plus Pembrolizumab Vs Pembrolizumab Alone in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Whose Tumors Express PD-L1 With Tumor Proportion Score ≥50% Without Actionable Genomic Alterations

This study will compare Valemetostat Tosylate Plus Pembrolizumab vs Pembrolizumab Alone in First-line NSCLC Without Actionable Genomic Alterations

Start Date01 Nov 2024

Sponsor / Collaborator

Daiichi Sankyo Co., Ltd.

[+1]

100 Clinical Results associated with Valemetostat Tosilate

100 Translational Medicine associated with Valemetostat Tosilate

100 Patents (Medical) associated with Valemetostat Tosilate

Literatures (Medical) associated with Valemetostat Tosilate

01 Oct 2024·CPT-Pharmacometrics & Systems Pharmacology

Population pharmacokinetics of total and unbound valemetostat and platelet dynamics in healthy volunteers and patients with non‐Hodgkin lymphoma

Article

Author: Mondick, John ; Baron, Kyle ; Shimizu, Takako ; Fukae, Masato ; Tachibana, Masaya

Abstract:

Valemetostat is an EZH2/1 inhibitor that has been approved in Japan for the treatment of patients with relapsed/refractory adult T‐cell leukemia/lymphoma, based mainly on results from a single‐arm phase II trial. It is currently under investigation worldwide for the treatment of other non‐Hodgkin lymphomas (NHLs), including peripheral T‐cell lymphoma, and for solid tumors. Semi‐mechanistic population pharmacokinetic modeling of total and unbound valemetostat and an analysis of the platelet time course during treatment with valemetostat were conducted using data from five clinical trials (two in patients with NHL and three in healthy volunteers). Pharmacokinetic data, including 3162 total/1871 unbound valemetostat observations from 102 patients and 72 healthy volunteers, were described by a three‐compartment model with sequential zero‐/first‐order absorption and saturable binding in the central compartment. Alpha‐1‐acid glycoprotein (AAG) was the most influential covariate for total valemetostat exposure, yet had little impact on unbound exposure, meaning no dose adjustment was warranted based on AAG levels. The longitudinal platelet data from 101 patients (2313 observations) were adequately described by a modified Friberg model with two proliferation compartments, which characterized unique spontaneous recovery of platelet counts without dose modifications. A model‐based simulation quantitatively assessed the proposed dose‐adjustment guidance in case of platelet count decreased by comparing the probability of treatment discontinuation due to platelet count decreased with or without the dose adjustment. In summary, the models described observed total and unbound valemetostat concentrations and a unique time course of platelets during treatment, which can justify the clinical dose and provide dose‐adjustment guidance.

01 Oct 2024·CPT-Pharmacometrics & Systems Pharmacology

Bayesian sparse regression for exposure–response analyses of efficacy and safety endpoints to justify the clinical dose of valemetostat for adult T‐cell leukemia/lymphoma

Article

Author: Rogers, James ; Garcia, Ramon ; Fukae, Masato ; Shimizu, Takako ; Tachibana, Masaya

Abstract:

Valemetostat is an oral inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 approved in Japan for the treatment of adult T‐cell leukemia/lymphoma (ATLL). To support the approved daily dose of 200 mg and inform dose adjustments in patients with ATLL, Bayesian exposure–response analyses were conducted using data from two clinical trials. The analyses included two efficacy endpoints, overall response by central and investigator assessments in patients with ATLL (n = 38, 150–200 mg), and six safety endpoints in patients with non‐Hodgkin lymphoma (n = 102, 150–300 mg), which included grade ≥3 laboratory values for anemia, absolute neutrophil count decreased, and platelet count decreased; any grade ≥3 treatment‐emergent adverse event (TEAE); and dose reductions and dose interruptions due to TEAEs. A slightly positive relationship was observed between unbound exposure and efficacy endpoints. A steeper relationship was observed in safety endpoints, compared with efficacy. Candidate covariate effects, except intercepts of the baseline laboratory values, were regularized via spike and slab priors in a Bayesian framework; only the laboratory values for corresponding hematologic TEAEs were shown to be of substantial impact. The target exposure range was established by defining a modified region of practical equivalence (184–887 ng·h/mL), which was expected to provide satisfactory efficacy and acceptable safety within the range of available exposure data. The simulated exposure range considering inter‐individual variability showed that 200 mg could reach target exposure in the overall population and across subpopulations of interest, supporting the use of valemetostat 200 mg in patients with ATLL.

03 Sep 2024·CLINICAL CANCER RESEARCH

A Phase I/II Study of Valemetostat (DS-3201b), an EZH1/2 Inhibitor, in Combination with Irinotecan in Patients with Recurrent Small-Cell Lung Cancer

Article

Author: Heller, Glenn ; Makhnin, Alex ; Lai, W. Victoria ; Ginsberg, Michelle S. ; Choudhury, Noura J. ; Li, Bob ; Offin, Michael ; Baine, Marina K. ; Santini, Fernando C. ; Larsen, Christina ; Zhang, Xinyuan ; Lau, Yvonne ; Rekhtman, Natasha ; Eng, Juliana ; Ng, Kenneth ; Paik, Paul ; Preeshagul, Isabel ; Rudin, Charles M.

Abstract:

Purpose::

Recurrent small-cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted.

Patients and Methods::

This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety, tolerability, and a recommended phase II dose (RP2D). The phase II primary objective was overall response rate (ORR), with secondary objectives of determining duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Correlative analyses included immunohistochemistry of pretreatment and on-treatment tumor biopsies and pharmacokinetics analysis.

Results::

Twenty-two patients were enrolled (phase I, n = 12; phase II, n = 10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLT) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; three patients discontinued treatment for toxicity. Three of the first 10 patients in phase II experienced DLTs triggering a stopping rule. The ORR was 4/19 or 21% [95% confidence interval (CI), 6%–46%]. The median DoR, PFS, and OS were 4.6 months, 2.2 months (95% CI, 1.3–7.6 months), and 6.6 months (95% CI, 4.3 to not reached), respectively. SLFN11/EZH2 expression and SCLC subtyping markers did not correlate with response, but MHC-I expression did increase with treatment. Two responders demonstrated subtype switching on treatment.

Conclusions::

Combination valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat, combined with agents without overlapping toxicity, warrants further investigation in SCLC.

News (Medical) associated with Valemetostat Tosilate

04 Sep 2024

·www.businesswire.com

Daiichi Sankyo Unveils New Research Across Industry-Leading ADC Portfolio in Multiple Cancers at WCLC and ESMO

BASKING RIDGE, N.J.--( BUSINESS WIRE )--Daiichi Sankyo (TSE: 4568) will present new clinical research across its antibody drug conjugate (ADC) portfolio with more than 25 abstracts across multiple types of cancer at the IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (#WCLC24) and the 2024 European Society for Medical Oncology (#ESMO24). Data at WCLC and ESMO showcasing Daiichi Sankyo’s progress towards its goal of creating new standards of care for patients with cancer will include six late-breaking presentations, including two back-to-back presentations during Presidential Symposium 1 featuring datopotamab deruxtecan (Dato-DXd) data at WCLC, and the first presentation of clinical data of DS-9606, a CLDN6 directed modified pyrrolobenzodiazepine (PBD) ADC from Daiichi Sankyo’s second ADC platform, at ESMO. “ New data in lung, breast, gastric, ovarian, endometrial and other cancers from several of our DXd antibody drug conjugates demonstrates how we are making substantial progress toward creating new standards of care for patients with cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “ We look forward to presenting initial clinical data from our second antibody drug conjugate platform at ESMO, which underscores how Daiichi Sankyo is applying our expertise in this technology to craft new innovation for patients.” Progress in Lung Cancer at WCLC and ESMO Late-breaking data at WCLC to be reported during back-to-back presentations at Presidential Symposium 1 will highlight the first interim results from the NeoCOAST-2 phase 2 platform trial evaluating novel perioperative treatment combinations including one arm studying datopotamab deruxtecan with durvalumab and chemotherapy as neoadjuvant treatment followed by adjuvant treatment with durvalumab in patients with resectable early-stage (IIA to IIIB) non-small cell lung cancer (NSCLC). The second Presidential Symposium 1 presentation will feature results from the application of quantitative continuous scoring (QCS), AstraZeneca’s proprietary computational pathology platform, to measure TROP2 in tissue samples collected in the TROPION-Lung01 phase 3 trial that evaluated datopotamab deruxtecan versus docetaxel in patients with locally advanced or metastatic NSCLC treated with at least one prior line of therapy. Overall survival results from TROPION-Lung01 also will be presented as a late-breaking oral presentation. Other data at WCLC include two oral presentations featuring the interim results from the dose optimization part of the IDeate-Lung01 phase 2 trial of ifinatamab deruxtecan (I-DXd) in patients with pretreated extensive-stage small cell lung cancer and results from the ENHERTU ® (trastuzumab deruxtecan) monotherapy arm of the DESTINY-Lung03 phase 1b trial in patients with previously treated HER2 overexpressing unresectable, locally advanced or metastatic NSCLC. A trial-in-progress poster from the NSCLC cohort of a phase 1b trial evaluating the combination of datopotamab deruxtecan and valemetostat, a dual inhibitor of EZH1 and EZH2, in previously treated locally advanced, unresectable or metastatic nonsquamous NSCLC with or without actionable genomic alterations also will be highlighted. At ESMO, additional data in lung cancer being reported include poster presentations featuring a post-hoc analysis of patients with nonsquamous NSCLC by baseline brain metastases status in the TROPION-Lung01 phase 3 trial of datopotamab deruxtecan and intracranial responses seen in the IDeate-Lung01 phase 2 trial of ifinatamab deruxtecan, as well as a trial-in-progress poster featuring the design of the IDeate-Lung03 phase 1b/2 trial of ifinatamab deruxtecan in combination with atezolizumab with or without carboplatin as first-line induction or maintenance therapy in patients with extensive-stage small cell lung cancer. Continued Innovation in Breast Cancer at ESMO Late-breaking presentations in breast cancer at ESMO will include a proffered paper session featuring the primary results of the DESTINY-Breast12 phase 3b/4 trial evaluating ENHERTU in patients with HER2 positive advanced or metastatic breast cancer with or without brain metastases, and two mini oral sessions highlighting patient reported outcomes and determination of the HER2 low and HER2 ultralow status of tumors from the DESTINY-Breast06 phase 3 trial in patients with HR positive, HER2 low and HER2 ultralow metastatic breast cancer. Two proffered paper sessions will highlight results from the ICARUS-BREAST01 phase 2 study of patritumab deruxtecan (HER3-DXd) in patients with HR positive, HER2 negative advanced breast cancer with disease progression following two or more treatments and the investigator-initiated ERICA phase 2 trial evaluating olanzapine-based triplet antiemetic therapy for prevention of nausea and vomiting in combination with ENHERTU in patients with metastatic breast cancer. A mini oral session will feature a supplementary biomarker analysis from the DAISY phase 2 trial evaluating ENHERTU in three cohorts of patients with HER2 expressing metastatic breast cancer and a poster presentation will report on an exploratory biomarker analysis of ENHERTU in patients with HR positive, HER2 low metastatic breast cancer from the DESTINY-Breast04 phase 3 trial. A poster reporting on exposure-adjusted incidence rates of adverse events from the TROPION-Breast01 phase 3 trial of datopotamab deruxtecan versus chemotherapy in patients with previously treated HR positive, HER2 negative metastatic breast cancer also will be featured. Data from Daiichi Sankyo’s Second ADC Platform and DXd ADC Data in Multiple Additional Cancers at ESMO At ESMO, a proffered paper session will highlight preliminary results from a phase 1 trial of DS-9606, a CLDN6 directed modified PBD ADC from Daiichi Sankyo’s second ADC platform, in patients with solid tumors known to express CLDN6. Results from the DESTINY-Gastric03 phase 1b/2 trial evaluating ENHERTU monotherapy or ENHERTU combinations with chemotherapy and/or immunotherapy in patients with HER2 expressing advanced/metastatic gastric or gastroesophageal junction carcinoma also will be presented at a proffered paper session. A mini oral session will feature results from the TROPION-PanTumor03 phase 2 trial of datopotamab deruxtecan in patients with previously treated recurrent endometrial or ovarian cancer. Trial-in-progress poster presentations will highlight the HERTHENA-PanTumor01 phase 2 trial evaluating patritumab deruxtecan in patients with a broad range of solid tumors including bladder, cervical, endometrial, esophageal, gastric, head and neck, melanoma, ovarian, pancreatic and prostate and a phase 1 trial of DS-1471, a CD147 monoclonal antibody, in patients with locally advanced or metastatic solid cancers. Investor Conference Call Following ESMO Daiichi Sankyo will hold a virtual conference call for investors on Tuesday, September 17, 2024 from 8:00 to 9:30 am EDT / 9:00 to 10:30 pm JST. Executives from Daiichi Sankyo will provide an overview of the WCLC and ESMO research data and address questions. WCLC and ESMO Data Highlights Highlights of data from Daiichi Sankyo’s ADC portfolio at WCLC 2024 include: Presentation Title Author Abstract Presentation (PDT) NSCLC NeoCOAST-2: efficacy and safety of neoadjuvant durvalumab (D) + novel anticancer agents + CT and adjuvant D ± novel agents in resectable NSCLC T. Cascone PL02.07 Presidential Symposium 1 Sunday, September 8 8:30 - 10:00 am Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung01 M.C. Garassino PL02.11 Presidential Symposium 1 Sunday, September 8 8:30 - 10:00 am Datopotamab deruxtecan vs docetaxel in patients with non-small cell lung cancer: final overall survival from TROPION-Lung01 J. Sands OA08.03 Oral Presentation Monday, September 9 10:45 - 12:00 pm Trastuzumab deruxtecan monotherapy in pretreated HER2 overexpressing nonsquamous non-small cell lung cancer: DESTINY-Lung03 part 1 D. Planchard OA16.05 Oral Presentation Tuesday, September 10 1:30 - 2:45 pm Valemetostat and datopotamab deruxtecan in previously treated, advanced, unresectable, or metastatic non-squamous NSCLC A. Spira P2.10A.04 Poster Session Sunday, September 8 6:15 - 7:45 pm SCLC Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer (ES-SCLC): interim analysis of IDeate-Lung01 C. Rudin OA04.03 Oral Presentation Sunday, September 8 2:00 - 3:15 pm Exposure-response analyses to support phase 3 dose selection for I-DXd (ifinatamab deruxtecan) in extensive stage SCLC patients N. Midde P1.13A.12 Poster Session Sunday, September 8 12:00 - 2:00 pm Highlights of data from Daiichi Sankyo’s ADC portfolio at ESMO 2024 include: Presentation Title Author Abstract Presentation (CEST) NSCLC Datopotamab deruxtecan (Dato-DXd) vs docetaxel in patients with advanced nonsquamous non-small cell lung cancer with brain metastases: results from TROPION-Lung01 E. Pons-Tostivint 1312P Poster Session Saturday, September 14 SCLC Intracranial response in patients with baseline brain metastases and extensive-stage small cell lung cancer treated with ifinatamab deruxtecan (I-DXd) in the IDeate-Lung01 study M. Johnson 1787P Poster Session Saturday, September 14 IDeate-Lung03: a phase 1b/2 study of ifinatamab deruxtecan (I-DXd) plus atezolizumab with or without carboplatin as first line induction or maintenance in patients with extensive stage small cell lung cancer C. Rudin 1812TiP Poster Session Saturday, September 14 BREAST Trastuzumab deruxtecan (T-DXd) in patients with HER2+ advanced/metastatic breast cancer with or without brain metastases: primary results from DESTINY-Breast12 N. Lin LBA18 Proffered Paper Session Friday, September 13 4:00 - 5:30 pm HER2 low and HER2 ultralow status determination in tumors of patients with HR+ mBC in DESTINY-Breast06 G. Viale LBA 21 Mini Oral Session Sunday, September 15 8:30 - 10:00 am Effects of trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice on patient-reported outcomes in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2) low/ultralow metastatic breast cancer: results from DESTINY-Breast06 X. Hu LBA22 Mini Oral Session Sunday, September 15 8:30 - 10:00 am Efficacy, safety and biomarker analysis of ICARUS-BREAST01: a phase 2 study of patritumab deruxtecan (HER3-DXd) in patients with HR+/HER2- advanced breast cancer B. Pistilli 340O Proffered Paper Session Friday, September 13 4:00 - 5:30 pm A multicenter, randomized, double-blind, placebo-controlled study of olanzapine-based triplet antiemetic therapy for prevention of delayed and persistent nausea and vomiting induced by trastuzumab deruxtecan in patients with metastatic breast cancer: ERICA study H. Sakai 1816O Proffered Paper Session Saturday, September 14 2:45 - 4:25 pm Unraveling the mechanisms of action and resistance to trastuzumab deruxtecan (T-DXd): supplementary biomarker analyses from DAISY trial F. Mosele 343MO Mini Oral Session Sunday, September 15 8:30 - 10:00 am Exploratory biomarker analysis of trastuzumab deruxtecan versus treatment of physician’s choice in HER2-low, hormone receptor-positive metastatic breast cancer in DESTINY-Breast04 N. Ueno 432P Poster Session Monday, September 16 Exposure-adjusted incidence rates of adverse events from the TROPION-Breast01 study of datopotamab deruxtecan (Dato-DXd) vs investigator’s choice of chemotherapy in patients with pretreated, inoperable/ metastatic HR+/HER2- breast cancer H. Rugo 431P Poster Session Monday, September 16 Treatment patterns and outcomes in HER2 low, HR+ metastatic breast cancer patients previously treated with endocrine therapy in the United States S. Modi 399P Poster Session Monday, September 16 OTHER SOLID TUMORS Preliminary results from a phase 1, first-in-human study of DS-9606a, a Claudin 6 (CLDN6) directed antibody drug conjugate, in patients with tumor types known to express CLDN6 M. Patel 610O Proffered Paper Session Sunday, September 15 2:45 - 4:15 pm Trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients with advanced/metastatic HER2 positive esophageal, gastric or gastroesophageal junction adenocarcinoma: DESTINY-Gastric03 Y. Janjigian 1401O Proffered Paper Session Saturday, September 14 8:30 - 10:00 am Datopotamab deruxtecan (Dato-DXd) monotherapy in patients with endometrial or ovarian cancer: results from the phase 2 TROPION-PanTumor03 study A. Oaknin 714MO Mini Oral Session Sunday, September 15 2:45 - 4:15 pm HERTHENA-PanTumor01: A global phase 2 trial of HER3-DXd in metastatic solid tumors T. Powles 690TiP Poster Session Saturday, September 14 A phase 1, first-in-human study of DS-1471 in patients with advanced/metastatic solid tumors S. Koganemaru 682TiP Poster Session Saturday, September 14 Claudin-6 expression in primary and recurrent epithelial ovarian cancer: a potential therapeutic target for high-grade serous ovarian cancer D. Shintani 771P Poster Session Saturday, September 14 About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified PBD payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical needs. For more information, please visit www.daiichisankyo.com .

ADCClinical ResultPhase 1Phase 2Phase 3

25 Jun 2024

·pipelinereview.com

EZHARMIA® Approved in Japan as First Dual EZH1 and EZH2 Inhibitor Therapy for Patients with Peripheral T-Cell Lymphoma

TOKYO, Japan I June 24, 2024 I Daiichi Sankyo’s (TSE: 4568) EZHARMIA® (valemetostat tosilate) has been approved in Japan for the treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). EZHARMIA is now the first dual inhibitor of EZH1 and EZH2 to be approved for PTCL after receiving SAKIGAKE designation for this indication. PTCL is a group of rare and often aggressive blood cancers, which represent about 10 to 15% of all non-Hodgkin lymphomas (NHL).1 PTCL is more common in Asia, including in Japan, compared to other parts of the world.2 A majority of patients with PTCL experience disease progression following initial treatment with a multi-drug chemotherapy-based regimen and median overall survival following relapse is approximately 5.8 months.1 The approval of EZHARMIA by the Japan Ministry of Health, Labour and Welfare (MHLW) is based on results of the VALENTINE-PTCL01 phase 2 trial, which were presented at the 2023 American Society of Hematology (ASH) Annual Meeting. In VALENTINE-PTCL01, an objective response rate (ORR) of 43.7% (n=52, 95% CI: 34.6-53.1) was observed for EZHARMIA in 119 efficacy evaluable patients with relapsed or refractory PTCL as assessed by CT-based blinded independent central review (BICR). Seventeen complete responses (CRs) and 35 partial responses (PRs) were observed. Responses were seen across a variety of PTCL subtypes including angioimmunoblastic T-cell lymphoma (AITL), PTCL not otherwise specified (PTCL-NOS) and other PTCL subtypes. “This second indication for EZHARMIA in Japan is an important advance for the treatment of relapsed or refractory peripheral T-cell lymphoma, as new and effective treatment options are needed to improve patient outcomes,” said Toshinori Agatsuma, PhD, Executive Officer, Head of R&D Division in Japan, Daiichi Sankyo. “EZHARMIA exemplifies the innovative research being conducted by Daiichi Sankyo aimed at creating new medicines with potential to change the standard of care for patients with cancer.” The safety profile of EZHARMIA in VALENTINE-PTCL01 was consistent with previous clinical trials. Treatment-related adverse events occurred in 106 of 133 patients (79.7%) with the most common including platelet count decrease (44.4%), anemia (27.1%), dysgeusia (24.8%) and neutrophil count decrease (21.1%). About VALENTINE-PTCL01 Trial VALENTINE-PTCL01 is a global, open-label, single-arm, two-cohort phase 2 study evaluating the efficacy and safety of EZHARMIA in patients with relapsed or refractory PTCL and adult T-cell leukemia/lymphoma (ATLL) who received at least one systemic therapy and were ineligible for hematopoietic stem cell transplant at the time of screening. One cohort enrolled patients with PTCL and a second cohort enrolled patients with ATLL. The primary endpoint of VALENTINE-PTCL01 is ORR assessed by CT-based BICR. Secondary endpoints include duration of response, CR, PR, duration of CR and progression-free survival – all assessed by both BICR and investigator assessment – as well as ORR assessed by investigator, overall survival, safety and pharmacokinetics. Exploratory endpoints include PET-CT-based BICR and biomarker mutational status. Responses were evaluated based on Lugano 2014 response criteria. VALENTINE-PTCL01 enrolled 133 patients at multiple sites in Asia, Europe, North America and Oceania. For more information about this study, visit ClinicalTrials.gov. About Peripheral T-Cell Lymphoma PTCL is a group of rare and often aggressive blood cancers, which represent 10 to 15% of all NHLs.1 Approximately 553,000 new cases of NHL were diagnosed worldwide in 2022.3 There are at least 29 recognized subtypes of PTCL, which occur with significant geographic variation.4 PTCL is more common in Asia, including in Japan, compared to other parts of the world.2 Prognosis of PTCL is generally poor, with a five-year overall survival rate of 32% in AITL and PTCL-NOS, and 7% or lower in certain subtypes.5 A majority of patients with PTCL experience disease progression following initial treatment with a multi-drug chemotherapy-based regimen and median overall survival following relapse is approximately 5.8 months.1 Development of more effective medicines for PTCL continues to be an unmet clinical need, particularly in the relapsed or refractory setting.1 About EZH1 and EZH2 The EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2) enzymes help regulate the expression of genes involved in maintaining healthy hematopoietic stem cells (immature blood cells).6 Both enzymes are recurrently mutated or overexpressed in hematologic malignancies, including T-cell lymphomas, and research shows they contribute to the silencing of tumor suppressor genes and drive oncogenic growth. 7,8 About EZHARMIA EZHARMIA (valemetostat tosilate) is first-in-class dual inhibitor of EZH1 and EZH2 that was discovered by Daiichi Sankyo. EZHARMIA is approved in Japan for the treatment of patients with relapsed or refractory PTCL and for the treatment of patients with relapsed or refractory ATLL. It is an investigational medicine in all countries outside of Japan. About EZHARMIA Clinical Development Program A global clinical development program is underway for EZHARMIA in hematologic and solid cancers. In addition to VALENTINE-PTCL01, EZHARMIA is being evaluated in the VALYM phase 2 trial in patients with relapsed or refractory B-cell lymphomas, which is being conducted under a strategic research collaboration with the LYSA-LYSARC-CALYM group in Europe, and a phase 1b study in combination with DXd antibody drug conjugates ENHERTU® (trastuzumab deruxtecan) and datopotamab deruxtecan (Dato-DXd) in patients with solid cancers. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com . References 1 Bellei et al. haematologica. Vol. 103 No. 7 (2018): July 2018 2 Vose JM et al. J Clin Oncol. 2008;26:4124-4130 3 Global Cancer Observatory. Cancer Fact Sheet. February 2024 4 Liang X et al. Medicine 2021; 2021 Apr 2;100(13): e25194. 5 Vose JM et al. J Clin Oncol. 2008;26:4124-4130 6 Honma D et al. Cancer Sci. 2017 Oct; 108(10): 2069–2078 7 Nakagawa M and Kitabayashi I. Cancer Sci. 2018;109:2342–2348 8 Yamagishi et al. Cell Reports. 2019; 29, 2321–2337

Phase 2Clinical ResultDrug ApprovalASHPhase 1

24 Jun 2024

·www.pharmaceutical-technology.com

Daiichi Sankyo peripheral T-cell lymphoma therapy approved in Japan

The asset previously received SAKIGAKE designation in Japan. Credit: Nemes Laszlo / Shutterstock. Daiichi Sankyo has announced approval from the Japan Ministry of Health, Labour and Welfare for EZHARMIA (valemetostat tosilate) to treat relapsed or refractory (r/r) peripheral T-cell lymphoma (PTCL). EZHARMIA is the first dual EZH1 and EZH2 inhibitor to receive approval for this indication. The asset previously received the SAKIGAKE designation. Its approval is grounded in the outcomes of the global, open-label, single-arm, two-cohort VALENTINE-PTCL01 Phase II trial. The trial assessed the efficacy and safety of EZHARMIA in patients with relapsed or refractory PTCL and adult T-cell leukemia/lymphoma who had previously undergone at least one systemic therapy and were ineligible for a hematopoietic stem cell transplant at screening. See Also: Johnson & Johnson seeks FDA approval for Tremfya for Crohn’s disease AstraZeneca’s Truqap and Faslodex combo receives approval in EU It enrolled 133 patients across multiple sites in Europe, Asia, North America and Oceania, The primary endpoint of the trial was objective response rate (ORR) with secondary endpoints being the duration of response, complete response (CR), partial response (PR), duration of CR, progression-free survival, overall survival, safety and pharmacokinetics. In the study, EZHARMIA demonstrated an ORR of 43.7% in 119 efficacy-evaluable patients with relapsed or refractory PTCL. The treatment also led to 17 CRs and 35 PRs, with responses observed across various PTCL subtypes, including angioimmunoblastic T-cell lymphoma, PTCL not otherwise specified and other PTCL subtypes. Daiichi Sankyo Japan research and development division head and executive officer Toshinori Agatsuma stated: “This second indication for EZHARMIA in Japan is an important advance for the treatment of relapsed or refractory peripheral T-cell lymphoma, as new and effective treatment options are needed to improve patient outcomes. EZHARMIA exemplifies the innovative research being conducted by Daiichi Sankyo aimed at creating new medicines with the potential to change the standard of care for patients with cancer.”

Clinical ResultDrug ApprovalPhase 2Cell TherapyImmunotherapy

100 Deals associated with Valemetostat Tosilate

External Link

KEGG	Wiki	ATC	Drug Bank
D11551 D16662	-	-	-

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Adult T-Cell Leukemia-Lymphoma	JP	Daiichi Sankyo Co., Ltd.	26 Sep 2022
Peripheral T-Cell Lymphoma	JP	Daiichi Sankyo Co., Ltd.	26 Sep 2022

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Small Cell Lung Cancer	Phase 2	-	Daiichi Sankyo Co., Ltd.	01 Nov 2024
Follicular Lymphoma	Phase 2	US	Daiichi Sankyo Co., Ltd.	19 May 2023
B-Cell Lymphoma	Phase 2	EU	Daiichi Sankyo Co., Ltd.	30 Jan 2022
B-cell lymphoma refractory	Phase 2	BE	Daiichi Sankyo Co., Ltd.	11 Jun 2021
B-cell lymphoma refractory	Phase 2	FR	Daiichi Sankyo Co., Ltd.	11 Jun 2021
Adult T-cell lymphoma/leukaemia refractory	Phase 2	JP	Daiichi Sankyo Co., Ltd.	21 Nov 2019
Advanced Malignant Solid Neoplasm	Phase 1	US	Daiichi Sankyo Co., Ltd.	16 Feb 2024
Advanced Malignant Solid Neoplasm	Phase 1	JP	Daiichi Sankyo Co., Ltd.	16 Feb 2024
Liver Diseases	Phase 1	US	Daiichi Sankyo, Inc.	21 Nov 2019
Acute Lymphoblastic Leukemia	Phase 1	US	Daiichi Sankyo, Inc.	05 Apr 2017

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04703192 (VALENTINE-PTCL01, CTgov)	Phase 2	Adult T-Cell Leukemia-Lymphoma \| Peripheral T-Cell Lymphoma	155	Valemetostat Tosylate	ettioulsyq(sqglblxknn) = znpvdbzwfo yrlygldjdw (fnwgkimjvk, fxksspuwbh - izudnqqhep) View more	-	22 Jul 2024
NCT04703192 (VALENTINE-PTCL01, EHA2024) Manual	Phase 2	Peripheral T-Cell Lymphoma	119	Valemetostat tosylate 200 mg/day (pts with 1 prior LOT)	uwdtyzodve(tfprfhbgzc) = mpvbrenqtb vketsxyggc (xogpjessho, 35.5 - 69.6)	Positive	14 May 2024
NCT04703192 (VALENTINE-PTCL01, EHA2024) Manual	Phase 2	Peripheral T-Cell Lymphoma	119	Valemetostat tosylate 200 mg/day (pts with 2 prior LOT)	uwdtyzodve(tfprfhbgzc) = zqpokwfxqd vketsxyggc (xogpjessho, 28.3 - 65.7)	Positive	14 May 2024
NCT02732275 (DS3201-A-J101, EHA2024) Manual	Phase 1	Non-Hodgkin Lymphoma EZH2 mutation	90	valemetostat (PTCL)	kgqqgiypco(zjygfcwrnk) = oxpzfhxbge qcwgstqnnp (xaivzsrwdp ) View more	Positive	14 May 2024
NCT02732275 (DS3201-A-J101, EHA2024) Manual	Phase 1	Non-Hodgkin Lymphoma EZH2 mutation	90	valemetostat (ATLL)	mzgaqhdbbr(ijarpobwgb) = igukexckkt mrjcbmpunb (ifjcbmktst, 1.4 - 38.7) View more	Positive	14 May 2024
NCT03110354 (CTgov)	Phase 1	Acute Myeloid Leukemia \| Acute Lymphoblastic Leukemia	28	DS-3201b (DS-3201b 150 mg)	ebilcvobmj(wkupqgbgte) = vnyreehyzf pwpcvxtfhm (doyhmzyhzg, nasudurbor - lskkwnyhle) View more	-	30 Jan 2024
NCT03110354 (CTgov)	Phase 1	Acute Myeloid Leukemia \| Acute Lymphoblastic Leukemia	28	DS-3201b (DS-3201b 250 mg)	ebilcvobmj(wkupqgbgte) = hcmwbfespu pwpcvxtfhm (doyhmzyhzg, vmkzzhvwbz - ssothxbkav) View more	-	30 Jan 2024
ASH2023	Phase 1	B-cell lymphoma refractory	19	Valemetostat	okrrmehpum(cwapumeofx) = The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%) cykiqvxuvn (hopfcqzbpw ) View more	-	09 Dec 2023
VALENTINE-PTCL01 (ASH2023)	Phase 2	Peripheral T-Cell Lymphoma	133	Valemetostat 200 mg/day	pixpecutbi(lnjzaktdct) = xrfmuwfzuv yhupqdiqcb (imisgltpwn, 34.6 - 53.1) View more	-	09 Dec 2023
ASH2023	Phase 1	Peripheral T-Cell Lymphoma	71	Valemetostat	zoigsxkiaq(mpfzwekmbz) = mxrcelytvz abakgaryvq (kwgqnfaibv ) View more	-	09 Dec 2023
NCT04102150 (VALENTINE-PTCL01, Pubmed) Manual	Phase 2	Adult T-Cell Leukemia-Lymphoma	25	Valemetostat Tosilate	wpzjinpqqd(kaeasysgxo) = rgajgkjkql xtcoomalmf (xiweukovbx, 30.5 - 65.9) View more	Positive	23 Sep 2022
NCT04102150 (VALENTINE-PTCL01, ASH2021) Manual	Phase 2	Adult T-cell lymphoma/leukaemia refractory	25	Valemetostat Tosylate	pikovnshdh(armtyvrvqv) = lgkauvvnax tgqxtwmtvp (fskxmdilsm, 27.8 - 68.7) View more	Positive	05 Nov 2021
NCT02732275 (phase 1 trial, ICML2021)	Phase 1	Non-Hodgkin Lymphoma EZH2 \| EZH1	78	Valemetostat tosylate (DS-3201b)	vgujnkmoop(fachjeluhy) = gpkzejoyzb zudlojvjks (eanazylxwt ) View more	Positive	17 Jun 2021

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