Introduction: PTCL is an aggressive non-Hodgkin lymphoma with limited treatment options for patients with R/R disease. Phased variant (PV) enrichment and detection sequencing (PhasED-Seq) has been successfully utilized in diffuse large B-cell lymphoma. Detection of genetic aberrances implicated in PTCL could inform disease monitoring and clinical decision making in PTCL.

Valemetostat tosylate (valemetostat) is a novel and potent dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1 approved in Japan for the treatment of R/R PTCL and adult T-cell leukemia/lymphoma. VALENTINE-PTCL01 (DS3201-A-U202; NCT04703192) was an open-label, single-arm, global phase 2 trial of valemetostat in patients with R/R PTCL. To explore patient-specific PhasED-Seq as a potential biomarker for disease status in R/R PTCL, we assessed changes in ctDNA prior to and following valemetostat treatment and correlations with clinical response in a subset of patients from VALENTINE-PTCL01.

Methods: Biomarker-eligible patients were ≥ 18 years of age with confirmed PTCL, R/R disease after ≥ 1 prior line of systemic therapy, and a sufficient baseline (BL) sample. Patients received oral valemetostat 200 mg/day in continuous 28-day cycles until disease progression or unacceptable toxicity. PVs for ctDNA detection (ie, ctDNA-measurable residual disease [MRD]) were identified by comparing whole genome sequences of BL tumors to paired normal tissues. Custom capture panels were used to monitor ctDNA-MRD in plasma on cycle 1 day 1 (C1D1), C2D1, and C5D1. Response was assessed via a computed tomography scan according to Lugano 2014 criteria.

Results: VALENTINE-PTCL01 included 133 patients with PTCL, and 41 had samples for PV assessment; of these, 9 were excluded due to low tumor purity, precluding PV detection. The 32 remaining cases had ≥ 2 PVs, allowing for PhasED-Seq ctDNA-MRD disease monitoring. PTCL subtypes included PTCL, not otherwise specified (n = 15), angioimmunoblastic T-cell lymphoma (n = 7), T-follicular helper phenotype PTCL (n = 1), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 1), and other PTCLs (n = 8). Of the 32 patients with ≥ 2 PVs, ctDNA-MRD was detected in samples from at least 1 timepoint (C1D1, C2D1, or C5D1) in 31 (97%). Compared with sequencing data from a panel focused on T-cell lymphoma driver variants, mean variant allele frequency (VAF) for identified PVs correlated with panel-based VAF (Pearson R > 0.8), confirming that identified PVs were specific for PTCL tumor cells. ctDNA-MRD concentration at C1D1 closely correlated with tumor burden (ie, tumor size and VAF levels) (R > 0.9, P = 7.9×10-14), thus demonstrating its applicability as a marker of disease dynamics.

Overall, 19/31 patients achieved a response, including 8 with a complete response (CR) and 11 with a partial response (PR); 4 achieved stable disease (SD) as best overall response (BOR), 6 had progressive disease (PD), and 2 had no BOR data available. All patients that achieved CRs had at least a 5-fold decline in ctDNA-MRD between BL and C2D1; this threshold was thus used to predict clinical response. Among patients with samples at C1D1 and C2D1, those with > 5-fold decreases in ctDNA-MRD over that period (7/7 [100%] CR, 7/8 [87.5%] PR, 0/8 [0%] SD, 1/4 [25%] relapse/PD) achieved longer median PFS than patients that had < 5-fold ctDNA-MRD decreases (> 5-fold decrease, 11.1 months [median follow up (mFU) 8.3 months]; < 5-fold decrease, 3.5 months [mFU 3.2 months]; p < 0.0001). At C5D1, patients who achieved a CR had the lowest ctDNA-MRD, followed by those with PR, and then nonresponders (SD/PD) (median ctDNA for CR, PR, and nonresponders was 0.26, 1.49, and 172.0 hGE/mL, respectively; CR/PR vs SD/PD Wilcoxon p = 0.017). Of the 3 patients with undetectable ctDNA-MRD at C5D1, 1 ultimately relapsed (mFU 8.3 months) and 2 maintained their responses (mFU 8.3 and 13.8 months), indicating that ctDNA-MRD concentrations at C5D1 could predict disease status.

Conclusions: Analysis of ctDNA-MRD by PhasED-Seq is applicable in PTCL utilizing a customized approach. Declines in ctDNA-MRD at C2D1 and C5D1 correlated with response to therapy and PFS. These data suggest that ctDNA-MRD monitoring could serve as a noninvasive biomarker assessment to help predict response and survival in patients with R/R PTCL and during valemetostat treatment.

Disclosures

Mehta-Shah:Celgene: Research Funding; Corvus Pharmaceuticals: Research Funding; Yingli Pharmaceuticals: Research Funding; Verastem Oncology: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dizal Pharmaceuticals: Research Funding; Genetech/Roche: Consultancy, Research Funding; Morphosys: Research Funding; Innate Pharmaceuticals: Research Funding; Johnson & Johnson/Janssen: Consultancy; Secura Bio: Consultancy, Research Funding; Pfizer: Consultancy; Astra Zeneca: Consultancy, Research Funding; Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy, Research Funding; Kyowa Hakko Kirin, Karyopharm Therapeutics: Consultancy. Horwitz:Auxilius Pharma, Abcuro Inc., Corvus, CTI BioPharma Corp, Daiichi Sankyo, DrenBio, Kyowa Hakko Kirin, March Bio, ONO Pharmaceuticals, Pfizer, SecuraBio, SymBio and Takeda Pharmaceuticals.: Honoraria; Auxilius Pharma, Abcuro Inc., Corvus, Daiichi Sankyo, DrenBio, Farallon Capital Management, L.L.C., Kyowa Hakko Kirin, March Bio, Neovii Pharmaceuticals AG, ONO Pharmaceuticals, Pfizer, SecuraBio, SymBio, Treeline Bio and Takeda Pharmaceuticals.: Consultancy; ADC Therapeutics, Affimed, Celgene, Crispr Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio.: Research Funding. Zinzani:MSD, EUSAPHARMA, NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION, GILEAD, JANSSEN-CILAG, BMS, SERVIER, ASTRAZENECA, TAKEDA, ROCHE, KYOWA KIRIN, Incyte, Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SECURA BIO, ADC Therap, Sandoz: Membership on an entity's Board of Directors or advisory committees. Barta:BMS: Consultancy; Daiichi Sankyo: Consultancy; Kyowa Kirin: Consultancy; Acrotech: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees. Yamagishi:Daiichi Sankyo, Inc: Research Funding; Agilent Technologies, Astellas Pharma Inc., Auxilius Pharma, Abcuro Inc., Chugai Pharmaceutical Co., Ltd., Corvus, CTI BioPharma Corp, Daiichi Sankyo Co., Ltd, DrenBio, Illumina K.K., Kyowa Hakko Kirin, March Bio, ONO Pharmaceuticals, Pfizer, SecuraBio, S: Honoraria; Daiichi Sankyo Co., Ltd Mitsubishi Tanabe Pharma: Patents & Royalties. Kurtz:Foresight Diagnostics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Takayama:Daiichi Sankyo Co., Ltd: Current equity holder in publicly-traded company; Daiichi Sankyo, Inc: Current Employment. Hizukuri:Daiichi Sankyo, Inc.: Current Employment; Daiichi Sankyo Company, Limited: Current equity holder in publicly-traded company. Feng:Daiichi Sankyo, Inc: Current Employment. Chang:Daiichi Sankyo: Ended employment in the past 24 months. Moriyama:Daiichi Sankyo, Inc: Current Employment. Nakajima:Bayer: Current equity holder in publicly-traded company; Daiichi-Sankyo: Current equity holder in publicly-traded company; Daiichi-Sankyo Inc: Current Employment. Inoue:Genmab: Current Employment; Daiichi Sankyo: Ended employment in the past 24 months. Bachy:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Other: Personal Fees, Research Funding; Novartis: Honoraria, Other: Personal Fees; Amgen: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie, Roche, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; ADC Therapeutics: Honoraria; Pfizer: Honoraria, Other: Personal Fees; Kite, a Gilead Company: Consultancy, Honoraria, Other: Personal Fees.

This content is only available as a PDF.
2024
Sign in via your Institution