A Study of Valemetostat Tosylate Plus Pembrolizumab Versus Pembrolizumab Alone in First-Line NSCLC Without Actionable Genomic Alterations

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

Study Overview

• Status: Active, not recruiting
• Conditions: Lung Cancer; Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: valemetostat tosylate; Drug: pembrolizumab

Detailed Description

This trial will evaluate the safety and efficacy of valemetostat tosylate (DS-3201b) in combination with fixed-dose pembrolizumab versus pembrolizumab alone in participants with advanced or metastatic NSCLC without actionable genomic alterations, whose tumor has PD-L1 TPS ≥50%, and who have not received prior systemic therapy for advanced or metastatic NSCLC. The trial will be in 2 phases, dose escalation and dose expansion phases.

• Study Type: Interventional
• Enrollment (Estimated): 137
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1426
    • Instituto Alexander Fleming
  • Buenos Aires, Argentina, 1199
    • Hospital Italiano de Buenos Aires
  • Córdoba, Argentina, X5000JHQ
    • Sanatorio Allende
  • N Salvador de Jujuy, Argentina, 4600
    • Fundacion Ars Medica
  • Rosario, Argentina, 2000
    • Instituto Médico de la Fundación Estudios Clínicos
  • Viedma, Argentina, R8500ACE
    • Clinica Viedma S.A.
• Brazil
  • Blumenau, Brazil, 89010-340
    • Centro de Pesquisas Clinica Reichow
  • ItajaĂ-, Brazil, 88301-220
    • Clínica de Neoplasias Litoral Ltda.
  • Manaus, Brazil, 69005-080
    • CINPAM Centro Integrado De Pesquisa Da Amazonia
  • Natal, Brazil, 59062-000
    • Liga Norte-Rio-Grandense Contra o Câncer
  • Porto Alegre, Brazil, 91350-280
    • Hospital Nossa Senhora da Conceicao
  • Sao Jose Rio Preto, Brazil, 15090-000
    • Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto
• China
  • Changchun, China, 130000
    • Jilin Cancer Hospital
  • Hangzhou, China, 242332
    • Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine
  • Harbin, China, 150081
    • Harbin Medical University Cancer Hospital
  • Jiamusi, China, 154007
    • Jiamusi Cancer Hospital
  • Shanghai, China, 200120
    • Shanghai East Hospital
  • Tiyuan, China, 300060
    • Tianjin Medical University Cancer Institute & Hospital
  • Zhengzhou, China, 450003
    • Henan Cancer Hospital
• Japan
  • Fukuoka, Japan, 812-8582
    • Kyushu University Hospital
  • Kashiwa, Japan, 277-8577
    • National Cancer Center Hospital East
  • Kōtoku, Japan, 135-8550
    • Cancer Institute Hospital of Jfcr
  • Nagoya, Japan, 460-0001
    • NHO Nagoya Medical Center
  • Sagamihara-shi, Japan, 252-0375
    • Kitasato University Hospital
• United States
  • California
    • La Jolla, California, United States, 92037
      • University of California San Diego (Ucsd)-Moores Cancer Center
    • Los Angeles, California, United States, 90027
      • California Research Institute
    • Los Angeles, California, United States, 90067
      • Valkyrie Clinical Trials
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Hospital
    • Plantation, Florida, United States, 33322-5426
      • BRCR Global
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Medical Center
    • Pikeville, Kentucky, United States, 41501
      • Pikeville Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55904
      • Mayo Clinic - Rochester
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University, Sidney Kimmel Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialist

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Has signed and dated the ICF, prior to the start of any trial-specific qualification procedures.
2. Is an adult ≥18 years of age or the minimum legal age (whichever is greater) at the time of informed consent. (Follow local regulatory requirements if the legal age of adult voluntary consent for trial participation is >18 years old).

3. Has histologically documented NSCLC that meets all of the following criteria:

   1. Has no prior systemic therapy for advanced or metastatic disease.
   2. Has Stage IIIB or IIIC disease and is not a candidate for surgical resection or definitive chemoradiation, or Stage IV NSCLC disease at the time of enrollment/randomization (based on the American Joint Committee on Cancer, Eighth Edition). Participants with early-stage NSCLC who have relapsed should be restaged during Screening to ensure their eligibility for the trial.

   3. Has documented negative test results for EGFR, ALK, and ROS1 actionable genomic alterations based on analysis of tumor tissue. If test results for EGFR, ALK, and ROS1 are not available, participants are required to undergo testing with approved and/or validated tests per local regulations for these genomic alterations.

      Participants with squamous NSCLC are only required to undergo EGFR, ALK, and ROS1 testing if they have no history of tobacco smoking or were diagnosed with NSCLC at <40 years of age.

   4. Has no known actionable genomic alterations in NTRK, BRAF, RET, MET, or other actionable oncogenic drivers with locally approved therapies (testing for genomic alterations besides EGFR, ALK, and ROS1 is not required prior to enrollment/randomization). Participants whose tumors harbor KRAS mutations are eligible for the trial.
4. Has measurable disease on CT or MRI based on local imaging assessment using RECIST v1.1
5. Has a tumor expressing PD-L1 TPS ≥50% as determined by local testing using 22C3 pharmDx PD-L1 IHC assay. In regions where PD-L1 (TPS ≥50%) testing by 22C3 pharmDx is not considered SOC, PD-L1 expression levels will be determined by central testing (minimum of 6 slides).
6. Has provided an archival formalin-fixed tumor tissue sample for the assessment of biomarkers. If archival tissue is not available, a new pretreatment biopsy is required, if clinically feasible.
7. Has an ECOG PS of 0 or 1 at Screening.

Key Exclusion Criteria

1. Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant setting:

   1. Any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, or CD137).
   2. Has previously been treated with any enhancer of zeste homolog inhibitors.
2. Participants who received adjuvant or neoadjuvant therapy other than those listed in the exclusion criterion above are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the current diagnosis of advanced or metastatic disease.
3. Has received a live vaccine or live attenuated vaccine within 30 days prior to the first dose of trial intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccines. Note: Administration of killed vaccines is allowed.

4. Has an active, known, or suspected autoimmune disease that has required systemic treatment in the past 2 years- except for Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid).

   Inhaled, intranasal, intraocular, intra-articular, or topical steroids and adrenal replacement steroids are permitted in the absence of active autoimmune disease.

5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (at doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial intervention. Note: Short-course systemic corticosteroids (eg, prevention of/treatment for transfusion reaction) or steroid use for a noncancer indication (eg, adrenal replacement) is permissible.
6. Has a known active or untreated CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate, provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note: repeat imaging should be performed during trial screening), clinically stable, and without requirement of steroid treatment for at least 14 days before the first dose of trial intervention. Note: A CT scan or MRI scan of the brain at Baseline is required for all participants. For participants in whom CNS metastases are first discovered at Screening, the treating investigator should delay trial intervention to complete any necessary treatment followed by a proper washout period and document the stability of CNS metastases with repeat imaging at least 4 weeks later (in which case repetition of all screening activities may be required).

7. Has uncontrolled or significant cardiovascular disease, including the following:

   1. Mean QT interval corrected for heart rate using Fridericia's formula >470 ms (based on the average of screening triplicate 12-lead ECG determinations)
   2. Myocardial infarction within 6 months prior to Screening
   3. Uncontrolled angina pectoris within 6 months prior to Screening
   4. New York Heart Association Class 3 or 4 congestive heart failure
   5. Uncontrolled hypertension (resting systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg)
8. Has a history of (noninfectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
9. Has a history of radiation pneumonitis.
10. Has had an allogenic tissue/solid organ transplant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1b: Pembrolizumab + Valemetostat Tosylate; Participants will be provided with pembrolizumab at standard dose of 200 mg intravenously (IV) Q3W, and valemetostat will be provided per a dose escalation schedule, with an initial starting dose of 150 mg by mouth once daily.	Drug: valemetostat tosylate; Valemetostat will be administered orally once daily until RP2D of valemetostat is determined.; Other Names: DS-3201b; valemetostat; Drug: pembrolizumab; One IV infusion Q3W on D1 of each 21-day cycle for a maximum of 35 cycles.; Other Names: MK-3475; KEYTRUDA®
Experimental: Phase 2: Pembrolizumab + Valemetostat Tosylate; Participants will be provided with pembrolizumab at standard dose of 200 mg IV Q3W, and valemetostat will be provided per recommended phase 2 dose (RP2D)	Drug: valemetostat tosylate; Valemetostat will be administered orally once daily until RP2D of valemetostat is determined.; Other Names: DS-3201b; valemetostat; Drug: pembrolizumab; One IV infusion Q3W on D1 of each 21-day cycle for a maximum of 35 cycles.; Other Names: MK-3475; KEYTRUDA®
Active Comparator: Phase 2: Pembrolizumab; Participants will be provided with pembrolizumab at standard dose of 200 mg IV Q3W	Drug: pembrolizumab; One IV infusion Q3W on D1 of each 21-day cycle for a maximum of 35 cycles.; Other Names: MK-3475; KEYTRUDA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Number of Participants with Dose-Limiting Toxicities	Total number of participants with A Dose-Limiting Toxicity (DLT) at each dose level of valemetostat in combination with pembrolizumab per National Cancer Institute - Common Terminology Criteria for Adverse Events version 5.0.	From day of first dose on Day 1 to Day 21 in Cycle 1 (21 days), or before the administration of Cycle 2, up to 24 days
Phase 1b: Number of Participants with Treatment-Emergent Adverse Events	Incidence of TEAEs, Grade 3 or 4 TEAEs, deaths, TESAEs, TEAEs leading to dose modifications (including interruption, reduction, and discontinuation), and AESIs using the National Cancer Institute - Common Terminology Criteria for Adverse Events version 5.0	From date of first dose to 30 days after last dose, up to approximately 31 months
Phase 2: Progression-Free Survival by BICR	PFS is the time from the date of randomization to the date of radiographic disease progression as assessed by blinded independent central review (BICR) per RECIST v1.1 or death from any cause, whichever occurs first.	From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2: Objective Response Rate	Objective Response Rate (ORR) is the proportion of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) assessed by BICR.	From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months
Phase 2: Duration of Response	Duration of Response (DoR) is the time from the date of first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the date of the first documentation of objective tumor progression or to death from any cause, whichever occurs first, assessed by BICR.	From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months
Phase 2: Disease Control Rate	Disease control rate (DCR) is the proportion of participants who achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD), assessed by BICR.	From date of randomization up to approximately 31 months
Phase 2: Overall Survival	Overall Survival (OS ) is the time from the date of randomization to the date of death from any cause.	From date of randomization the date of death from any cause, up to approximately 31 months
Phase 2: Progression-Free Survival by Investigator	PFS is the time from the date of randomization to the date of radiographic disease progression as assessed by the investigator per RECIST v1.1 or death from any cause, whichever occurs first.	From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months
Phase 1 and 2: Total and Unbound Plasma Concentration of Valemetostat		Cycle 1: Day 1- Pre-dose, 2, 4, 5 hrs post-dose, Day 8- Pre-dose, Day 15- Pre-dose and post-dose. Cycles 2- 5: Day 1- Pre-dose

Collaborators and Investigators

• Sponsor: Daiichi Sankyo
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2024
• Primary Completion (Estimated): March 30, 2028
• Study Completion (Estimated): April 30, 2030

Study Registration Dates

• First Submitted: October 1, 2024
• First Submitted That Met QC Criteria: October 14, 2024
• First Posted (Actual): October 16, 2024

Study Record Updates

• Last Update Posted (Actual): July 28, 2026
• Last Update Submitted That Met QC Criteria: July 24, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; pembrolizumab; MK-3475; Immune checkpoint inhibitor; Tumor; Programmed Cell Death 1 Ligand 1; DS-3201b; valemetostat tosylate; EZH inhibitor
• Additional Relevant MeSH Terms: Neoplasms by Site; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab
• Other Study ID Numbers: DS3201-330; MK-3475-F85 (Other Identifier: Merck Sharp & Dohme LLC); KEYNOTE-F85 (Other Identifier: Merck Sharp & Dohme LLC); 2024-519671-26-00 (Ctis); jRCT2031240572 (Other Identifier: JAPIC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No