Summary
Background
Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas with limited treatment options for relapsed/refractory (R/R) disease. Valemetostat tosylate (valemetostat) is a potent, novel dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1. We investigated the clinical efficacy and safety of valemetostat in patients with R/R PTCL, and safety in patients with R/R adult T-cell leukaemia/lymphoma (ATLL).
Methods
VALENTINE-PTCL01 was an open-label, single-arm, phase 2 trial performed at 47 sites in 12 countries. Patients ≥ 18 years of age with an ECOG PS 0–2 received oral valemetostat 200 mg/day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with PTCL was the computed tomography (CT)-based objective response rate (ORR) by blinded independent central review (BICR) using Lugano 2014 response criteria. Patients required a confirmed eligible PTCL subtype on central review for inclusion in efficacy analyses. The primary endpoint for patients with ATLL was the safety of valemetostat. The trial is registered with ClinicalTrials.gov (NCT04703192) and EudraCT (EudraCT 2020-004954-31) and is closed to enrolment.
Findings
A total of 155 patients with R/R PTCL (N = 133) and ATLL (N = 22) were enrolled between June 16, 2021–August 10, 2022, with a median age of 69‧0 and 66‧5 years in the PTCL and ATLL cohorts, respectively, and most patients were male (PTCL cohort, 68‧4%; ATLL cohort, 68‧2%). The median prior lines of therapy were two in both cohorts. The median follow-up time was 12·3 months (95% confidence interval [CI], 11·8–13·8). Among efficacy-evaluable patients with R/R PTCL, the ORR was 43·7% (52/119 patients; 95% CI, 34·6–53·1), including 17 (14·3%) complete responses by BICR CT-based assessment. The median time to first response was 8·1 weeks (interquartile range, 7·8–8·3) and median duration of response was 11·9 months (95% CI, 7·8–not evaluable). Serious treatment-emergent adverse events (TEAEs) were reported in 53 patients (39‧8%) and 15 patients (68‧2%) in the PTCL and ATLL cohorts, respectively. Maximum mean plasma concentrations of total and unbound valemetostat were observed at 4 hours post-dose on cycle 1 day 1 in both cohorts, and steady states were achieved by 15 days. Cytopenias were the most common of any grade and grade ≥ 3 TEAEs, particularly grade ≥ 3 thrombocytopenia (PTCL cohort, 23%; ATLL cohort, 50%), and grade ≥ 3 anaemia (PTCL cohort, 19%; ATLL cohort, 45%). TEAEs were manageable and infrequently required treatment discontinuation (PTCL cohort, 9·8%; ATLL cohort, 9·1%).
Interpretations
These data demonstrate that valemetostat provides clinically meaningful, durable responses for patients with R/R PTCL, with a generally favourable safety profile.
Funding
Daiichi Sankyo.
Introduction
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas (NHLs) that account for approximately 10% of NHL cases in Western countries and approximately 20% of lymphomas in Eastern Asia.1
Approximately 50–80% of nodal PTCLs are comprised of three major subtypes: PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic lymphoma kinase (ALK)-positive or ALK-negative systemic anaplastic large cell lymphoma (sALCL). The remaining subtypes are rare and include adult T-cell leukaemia/lymphoma (ATLL) and enteropathy-associated T-cell lymphoma (EATL), among others.2 Subtypes differ by geographic distribution, disease characteristics, and prognoses.3 Across subtypes, patients with PTCL generally have a poor prognosis,3 with unfavourable rates of 5-year overall survival ([OS], ~ 35%) and progression-free survival ([PFS], ~ 25%).4
Treatment of relapsed/refractory (R/R) PTCL remains a major challenge, and prognosis after relapse remains poor.5 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend participation in clinical trials for patients with R/R PTCL.6 Outside of a clinical trial, treatment options for certain patients include multiagent chemotherapy and single agents such as, belinostat, pralatrexate, romidepsin, and brentuximab vedotin (for CD30+ PTCL) among others.6 In the US, belinostat and pralatrexate are approved for the treatment of R/R PTCL, with response rates of 25·8% and 27%, respectively,7,8 and brentuximab vedotin is approved for R/R sALCL.9 Data for the therapies above come from single-arm phase 1 and 2 studies and clinical series; therefore, there is no optimal or standard approach for patients with R/R PTCL. ATLL is a subtype of PTCL that arises due to infection with human T-cell leukaemia virus type-1.10 As in PTCL, the limited choices of therapies for R/R ATLL come from small, early phase trials and no universal standard exists.
Recent evidence has suggested that PTCL (including the early development of ATLL) may be driven by epigenetic dysregulation, including the polycomb repressive complex 2 (PRC2)-mediated trimethylation of histone H3 at lysine 27 (H3K27me3) by silencing tumour suppressor genes associated with leukemic progression.11 The key catalytic subunits of PRC2, histone-lysine N-methyltransferases (EZH)2 and EZH1, are involved in H3K27me3 and have been identified as potential therapeutic targets.11 In PTCL, EZH2 overexpression is associated with tumour proliferation, more aggressive disease, and poor prognosis.12 Gain-of-function gene mutations in enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2 and EZH1 are rare in PTCL.13 Epigenetic modifiers, including romidepsin, belinostat, and azacytidine, are effective and among the most frequently used agents in patients with PTCL.7,14,15 Valemetostat tosylate (valemetostat) is a novel, oral, and potent dual inhibitor of EZH2 and EZH1. Valemetostat prevents H3K27me3, thereby, increasing the expression of genes silenced by H3K27me3, including genes associated with the regulation of cell proliferation and differentiation.16 The first-in-human, phase 1 dose-escalation and dose-expansion study of valemetostat in patients with R/R NHLs (NCT02732275), reported by Maruyama et al. in an accompanying article in this issue, established the recommended single-agent phase 2 valemetostat dose of 200 mg/day in continuous 28-day cycles and demonstrated encouraging clinical activity of valemetostat monotherapy in patients with R/R PTCL and ATLL. A subsequent phase 2 trial was conducted in 25 Japanese patients with R/R ATLL, which led to regulatory approval for this indication in Japan.17,18 Here, we report primary results for patients with R/R PTCL and R/R ATLL treated with valemetostat monotherapy in the open-label, single-arm, global, phase 2 VALENTINE-PTCL01 study (ClinicalTrials.gov NCT04703192, EudraCT 2020–004954-31).
Methods
Study design and participants
VALENTINE-PTCL01 was a global, open-label, single-arm, two-cohort, phase 2 trial that enrolled patients at 47 sites in 12 countries across North America, Europe, Asia, and Oceania (appendix p 7). Patients were enrolled independently into two cohorts comprising patients with (1) R/R PTCL and (2) R/R ATLL. The study was approved by an institutional review board or central ethics committee at each participating institution and was conducted according to the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation consolidated Guideline E6 for Good Clinical Practice, and applicable regulatory requirements.
Eligible patients were ≥ 18 years of age and had a locally confirmed diagnosis of PTCL according to World Health Organization (WHO) 2016 classification2 or ATLL according to Lymphoma Study Group diagnostic criteria.10 Additional key inclusion criteria were: an Eastern Cooperative Oncology Group performance status score of ≤ 2, an estimated life expectancy over three months based on investigator’s opinion, R/R disease after ≥ one prior line of systemic therapy (prior treatment with brentuximab vedotin was a requirement for patients with ALCL), and at least one measurable lesion. Eligible PTCL subtypes included AITL, PTCL-NOS, ALK-positive or ALK-negative ALCL, EATL, nodal PTCL with T follicular helper (TFH) phenotype (PTCL-TFH), follicular T-cell lymphoma (FTCL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), hepatosplenic T-cell lymphoma, primary cutaneous γδ T-cell lymphoma (PCγδTCL), and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (CD8+ PCAECTCL). Eligible ATLL clinical subtypes included acute, lymphoma and unfavourable chronic types.10 Full eligibility criteria are listed in the appendix (p 1–4). Patients provided written informed consent prior to undergoing any study procedures.
Procedures
Eligible patients received valemetostat 200 mg orally once daily under fasting condition in continuous 28-day treatment cycles until disease progression, unacceptable toxicity, or withdrawal of consent. Two dose-level reductions to 150 and 100 mg/day were allowed for management of adverse events according to prespecified dose modification guidelines (appendix p 4–5, 8–11). Central pathology confirmation for PTCL eligibility was performed after patient enrolment for inclusion in the efficacy analysis set.
After discontinuation, patients were followed for 30 days for safety and all patients entered the long-term follow-up, where information on subsequent lymphoma treatment, response status, haematopoietic cell transplantation (HCT), and survival were collected. Clinical response was assessed using radiographic and bone marrow assessments for evaluable patients with PTCL. Response assessments were determined by blinded independent central review (BICR) and by investigator assessment according to CT-based response criteria using the 2014 Lugano classification19 in patients with PTCL. Computed tomography (CT) scans were performed at baseline, every 8 weeks until cycle seven, every three cycles thereafter until cycle 40, and then every six cycles until the end of treatment; fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT scans were performed at baseline, cycle 5, cycle 13, and at the end of treatment for patients that were FDG-avid at baseline. Bone marrow biopsy was required to confirm normal cell morphology and declare a complete response (CR) in patients with positive, indeterminate, or unknown lymphoma involvement in bone marrow at baseline. Patients’ sex was collected during patient visits or from patient records, as appropriate, and ethnicity was self-reported.
Treatment-emergent adverse events (TEAEs) were evaluated from the time of first dose of study drug through 30 days after the last dose and were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5·0. After discontinuing study drug, patients were followed for survival at least every 3 months until death, withdrawal of consent, loss to follow-up, or study closure.
Pharmacokinetics (PK) sample time collection and methodology are provided in the appendix (p 1). Total concentrations of valemetostat and its major metabolite CALZ-1809a were measured in the plasma using liquid chromatography coupled with tandem mass spectrometry detection (LC-MS). The fraction unbound value for valemetostat in the plasma was determined using rapid equilibrium dialysis apparatus by LC-MS measurement. The fraction unbound value and total plasma concentration were used to derive the unbound plasma concentration of valemetostat.
To assess the frequency of common gene mutations in PTCL20 and direct inhibitory targets of valemetostat, assessment of tet methylcytosine dioxygenase 2 (TET2), ras homolog family member A (RHOA), EZH2, and EZH1 gene mutations was performed at baseline using formalin-fixed, paraffin-embedded lymph node biopsied samples from a total of 57 patients with available tissue sources and consent. Additional methodological details of gene mutation analyses are provided in the appendix (p 1).
Outcomes
The primary efficacy endpoint for the PTCL cohort was the objective response rate (ORR), defined as the proportion of patients with a best overall response of CR or partial response (PR), per CT-based BICR assessment. Secondary efficacy endpoints for the PTCL cohort were CR rate (CRR), partial response rate, duration of response (DOR), duration of complete response (DOCR), PFS (per CT-based BICR assessment), and OS. Investigator-assessed response rates and durations were also included as secondary endpoints for the PTCL cohort. The safety and tolerability of valemetostat was the primary endpoint in the ATLL cohort and a secondary endpoint of the PTCL cohort. Secondary PK endpoints included total and unbound valemetostat and total CALZ-1809a concentrations in the plasma. Clinical response by PET-CT–based assessment was an exploratory endpoint in patients with PTCL.
The primary endpoint of the ATLL cohort was amended from efficacy to safety, and enrolment was closed after valemetostat received regulatory approval for R/R ATLL in Japan. Enrolment closure occurred at approximately the same time as enrolment completion of the PTCL cohort. The objective of the ATLL cohort was to assess signal seeking and the safety of valemetostat in a global setting for patients with R/R ATLL as disease characteristics can vary between Japanese and EU/US patients.
DOR was the time from first documented CR or PR until disease progression or death, whichever occurred first; DOCR was the time from achieving first CR until progression or death. PFS was the time from the date of first study dose to disease progression or death, whichever occurred first, and OS was the time from first study dose until death.
Statistical analysis
The estimated required sample size of the R/R PTCL cohort was 128 patients. This assumed 90% of enrolled patients with R/R PTCL (n = 115) had PTCL histology confirmed by central pathology review. The sample size of 115 patients with R/R PTCL provides sufficient statistical precision for the inference of the ORR. With a sample size of 115 patients, the probability of observing the lower bound of the 95% confidence interval (CI) > 27% (historical ORR rate; belinostat [25·8%], romidepsin [25%], and pralatrexate [27%]) is at least 90%, if the expected ORR with valemetostat is 42%.7,14,21 The sample size of the R/R ATLL cohort (N = 22) was not based on statistical considerations.
The efficacy-evaluable population included all patients who received valemetostat and had an eligible PTCL subtype confirmed by central pathology review. Patients with no imaging scans or clinical data available for assessment were defined as not assessable and were not evaluated for efficacy assessment. Frequency tables were prepared for ORR, with 95% CIs for the proportion of each response calculated using the Clopper-Pearson method. ORR by number of prior lines of therapy was assessed as post hoc analyses using the same statistical method. The Kaplan-Meier method was used to estimate DOR, PFS, and OS, including Kaplan-Meier curves for each, and medians with corresponding 95% CIs were calculated using the Brookmeyer-Crowley method. For the primary analysis of DOR and PFS based on the BICR and investigator assessment, patients who started subsequent anticancer therapy or HCT before BICR-assessed disease progression were censored at the last evaluable tumour assessments prior to or on the date of initiation of the subsequent anticancer therapy or HCT. Full censoring rules for the primary and sensitivity analyses of DOR and PFS are shown in the appendix (p 12). Sensitivity analyses were conducted by not censoring subsequent anticancer therapy or HCT. OS and PFS rates at fixed timepoints were derived from Kaplan-Meier estimates, and corresponding CIs were derived based on the Greenwood formula for variance derivation and on log-log transformations applied to the survival function. The safety population included all patients who received ≥ one dose of valemetostat. The biomarker analysis set comprised patients with PTCL who received ≥ one dose of valemetostat, provided specimens for the biomarker study, and had usable data. This study is registered with ClinicalTrials.gov (NCT04703192) and EudraCT (EudraCT 2020-004954-31).
Role of the funding source
The funder was involved in study design, providing the study drug, protocol development, obtaining regulatory and ethics approvals, safety monitoring, collecting data, data analysis, and data interpretation, in collaboration with the study authors. The funder supplied financial support for editorial and writing assistance, provided by Excerpta Medica BV (Amstelveen, NL), and in accordance with Good Publication Practice (GPP) guidelines. All authors had full access to study data and share the final responsibility for the decision to submit for publication.
Results
A total of 133 patients with R/R PTCL and 22 patients with R/R ATLL were enrolled between June 16, 2021–August 10, 2022, and received at least one dose of valemetostat (Figure 1). PTCL subtype was centrally confirmed in 119 patients, with AITL (42 patients [35·3%]) and PTCL-NOS (41 patients [34·5%]) being the most common subtypes (Table 1). PTCL subtype was undetermined for 13 patients due to inconclusive central diagnoses with two or more possible eligible subtypes, but these patients remained eligible for efficacy evaluation. Six patients with undetermined eligibility due to limited sample tumour tissue and eight patients with either no sample or a sample insufficient for review were not included in the efficacy analysis set but remained eligible for safety evaluation. The data cutoff date for primary analysis was May 5, 2023, with a median follow-up time of 12·3 months (95% CI, 11·8–13·8) from the first study dose. At data cutoff, 32 patients (24·1%) with PTCL and two (9·1%) patients with ATLL were still receiving valemetostat on-study. Baseline characteristics of the PTCL and ATLL cohorts are shown in Table 1. Median treatment duration was 18·0 weeks (IQR, 6·7–48·0) in the PTCL cohort and 9·1 weeks (3·4–22·4) in the ATLL cohort. The median relative dose intensity was 97·1% and 91·7% in the PTCL and ATLL cohorts, respectively. Reasons for valemetostat discontinuation are shown in Figure 1.
Figure 1: Trial profile for the PTCL [A] and ATLL [B] cohort.
aThe reasons for screening failure were not recorded. bCauses of death were unrelated to the study drug and include two patients with disease progression, and one patient with necrotising fasciitis. cCause of death was disease progression.
ATLL, adult T-cell leukaemia/lymphoma; HCT, haematopoietic cell transplantation; PTCL, peripheral T-cell lymphoma; R/R, relapsed/refractory.
Table 1:
Baseline characteristics
| Characteristic | R/R PTCL (N = 133) | R/R ATLL (N = 22) |
|---|---|---|
| Age, years | 69·0 (58–74) | 66·5 (54–73) |
| Sex | ||
| Male | 91 (68·4%) | 15 (68·2%) |
| Female | 42 (31·6%) | 7 (31·8%) |
| Race | ||
| White | 80 (60·2%) | 1 (4·5%) |
| Black or African American | 6 (4·5%) | 10 (45·5%) |
| Asian | 34 (25·6%) | 8 (36·4%) |
| American Indian or Alaska Native | 1 (0·8%) | – |
| Native Hawaiian or Other Pacific Islander | – | – |
| Other/specify | 12 (9·0%) | 3 (13·6%) |
| Not allowed in France | 1 (0·8%) | – |
| Not applicable | 2 (1·5%) | – |
| Not reported | 8 (6·0%) | 1 (4·5%) |
| Unknown | 1 (0·8%) | 2 (9·1%) |
| ECOG PS score | ||
| 0 | 58 (43·6%) | 6 (27·3%) |
| 1 | 65 (48·9%) | 13 (59·1%) |
| 2 | 9 (6·8%) | 3 (13·6%) |
| 3 | 1 (0·8%) | 0 (0·0%) |
| PTCL subtypesa | ||
| ALCL, ALK positive | 2 (1·5%) | – |
| ALCL, ALK negative | 7 (5·3%) | – |
| AITL | 42 (31·6%) | – |
| Follicular T-cell lymphoma | 3 (2·3%) | – |
| MEITL | 1 (0·8%) | – |
| Nodal PTCL with TFH phenotype | 8 (6·0%) | – |
| PTCL-NOS | 41 (30·8%) | – |
| CD8+ PCAECTCL | 1 (0·8%) | – |
| PCγδTCL | 1 (0·8%) | – |
| Other T-cell lymphomab | 13 (9·8%) | – |
| Non-T-cell lymphoma or undeterminedc | 6 (4·5%) | – |
| Missingd | 8 (6·0%) | – |
| ATLL subtypes | ||
| Acute | – | 10 (45·5%) |
| Lymphoma | – | 12 (54·5%) |
| Prior lines of therapy | 2·0 (1–3) | 2·0 (1–3) |
| 1 | 36 (27·1%) | 8 (36·4%) |
| 2 | 36 (27·1%) | 6 (27·3%) |
| 3 | 29 (21·8%) | 6 (27·3%) |
| ≥ 4 | 32 (24·1%) | 2 (9·1%) |
| Prior HCT for PTCL or ATLL | 35 (26·3%) | 4 (18·2%) |
| Autologous | 32 (24·1%) | 2 (9·1%) |
| Allogenic | 5 (3·8%) | 1 (4·5%) |
| Other | 0 (0·0%) | 1 (4·5%) |
Data are n (%) or median (IQR).
PTCL subtypes in this table were based on central diagnosis according to WHO 2016 classification.2
Other T-cell lymphomas included three patients with follicular T-cell lymphoma, one with PCγδTCL, one with CD8+ PCAECTCL, one with MEITL, and 13 with other eligible, but undetermined, PTCL subtypes.
Included patients with undetermined eligibility due to the limited tumour tissues.
No sample or no sufficient sample. AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; ATLL, adult T-cell leukaemia/lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; HCT, haematopoietic cell transplant; IQR, interquartile range; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma; NOS, not otherwise specified; CD8+ PCAECTCL, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma; PCγδTCL, primary cutaneous gamma delta T-cell lymphoma; PTCL, peripheral T-cell lymphoma; R/R, relapsed/refractory; TFH, T follicular helper; WHO, World Health Organization.
Fifty-two patients (43·7%; 95% CI, 34·6–53·1) with PTCL achieved a confirmed objective response (OR) by independent central review of CT scans, with 17 (14·3%; 95% CI, 8·5–21·9) achieving CR and 35 (29·4%; 21·4–38·5%) achieving PR (Table 2). Median time to first response (TTR) was 8·1 weeks (IQR, 7·8–8·3) and median DOR was 11·9 months (95% CI, 7·8–not evaluable [NE]), with a median follow-up time of 9·7 months (95% CI, 8·8–12·0; Figure 2). The median DOCR was 11·2 months (95% CI, 4·2–NE). Median PFS was 5·5 months (95% CI, 3·5–8·3), with a median follow-up of 11·3 months (11·1–13·8). For patients who achieved a CR and PR, median PFS was 16·6 months (95% CI, 9·7–NE) and 11·3 months (6·1–NE), respectively. Estimated median OS was 17·0 months (95% CI, 13·5–NE), with a median follow-up time of 12·3 months (11·8–13·8) (Figure 2). Ten of 119 patients (8·4%) in the efficacy-evaluable PTCL population proceeded to allogeneic (allo)-HCT, with a median time from first valemetostat dose to HCT of 6·7 months (IQR, 4·5–8·1); six of these patients were in CR at the time of allo-HCT (investigator assessment). Forty-seven of 119 patients who discontinued valemetostat in the efficacy analysis set received post-valemetostat treatment.
Table 2:
Clinical response in evaluable patients with R/R PTCL (N = 119)
| Response | BICR assessment of CT | Investigator assessment of CT | BICR assessment of PET-CT |
|---|---|---|---|
| Objective response rate,a n (%) | 52 (43·7%) | 55 (46·2%) | 62 (52·1%) |
| 95% CI | 34·6–53·1% | 37·0–55·6% | 42·8–61·3% |
| Best response, n (%) | |||
| Complete responseb | 17 (14·3%) | 20 (16·8%) | 32 (26·9%) |
| Partial responseb | 35 (29·4%) | 35 (29·4%) | 30 (25·2%) |
| Stable disease | 21 (17·6%) | 20 (16·8%) | 10 (8·4%) |
| Progressive disease | 27 (22·7%) | 25 (21·0%) | 28 (23·5%) |
| No evidence of diseas ec | 1 (0·8%) | 1 (0·8%) | 1 (0·8%) |
| Not available/not assessabled | 18 (15·1%) | 18 (15·1%) | 18 (15·1%) |
| Time to first response,a weeks, median (IQR) | 8·1 (7·8–8·3) | 8·6 (7·9–15·3) | NDe |
| Duration of response,a months, median (95% CI) | 11·9 (7·8–NE) | NE (6·9–NE) | NDe |
| Duration of complete response, months, median (95% CI) | 11·2 (4·2–NE) | NE (6·0–NE) | NDe |
Objective response rate, time to first response, and duration of response include patients achieving complete or partial response.
Includes complete metabolic response and partial metabolic response for the PET-CT–based response assessment.
No evidence of disease at baseline or post-baseline.
No imaging scans available after receiving first study dose.
Time to first response, duration of response, and duration of complete response were not evaluable for PET-CT–based assessment due to the infrequent PET-CT measurement time-points (C5D1, C13D1). BICR, blinded independent central review; CI, confidence interval; CT, computed tomography; IQR, interquartile range; ND, not done; NE, not evaluable; PET, positron emission tomography; PTCL, peripheral T-cell lymphoma; R/R, relapsed/refractory.
Figure 2: Duration of response [A], progression-free survival [B], and overall survival [C] for patients with R/R PTCL.
CI, confidence interval; NE, not evaluable; PTCL, peripheral T-cell lymphoma; R/R, relapsed/refractory.
CT-based ORRs by PTCL subtype were 54·8% (23/42; 95% CI, 38·7–70·2) in AITL, 31·7% (13/41; 18·1–48·1) in PTCL-NOS, 33·3% (3/9; 7·5–70·1) in ALCL, 50% (4/8; 15·7–84·3) in PTCL-TFH, and 47·4% (9/19; 24·4–71·1) in other PTCL subtypes (appendix p 13). The investigator-assessed CT-based ORR and CRR were similar to those by BICR assessment, at 46·2% and 16·8%, respectively (Table 2).
According to PET-CT–based BICR response assessment, 62 patients (52·1%; 95% CI, 42·8–61·3) achieved an OR, including 32 patients (26·9%) with a complete metabolic response (Table 2). CT-based ORR for patients with one, two, and ≥ three prior lines of therapy were 52·8% (95% CI, 35·5–69·6), 46·7% (28·3–65·7), and 35·8% (23·1–50·2), respectively.
EZH2, EZH1, TET2 and RHOA mutation status was assessed in 57 patients with PTCL. Baseline demographics of this biomarker analysis set were generally comparable to patients not in this set (appendix p 14). Mutations in TET2 were detected in 25 patients (44%) in the biomarker cohort, and RHOA mutations were detected in 13 patients (23%). Approximately one-half of the detected TET2 and RHOA mutations were in patients with AITL (TET2, 13/25 patients; RHOA, 7/13 patients). Response rates were nominally higher in patients with TET2 or RHOA mutations compared to the wild-type gene, yet with significant overlap in the 95% CI for these rates (TET2, 48·0% [27·8–68·7] vs 28·1% [13·7–46·7]; RHOA, 46·2% [19·2–74·9] vs 34·1% [20·5–49·9], respectively; appendix p 15). Gene alterations in EZH2 and EZH1 were each detected in a single patient (c.638G > A and p.Arg213His or c.232C > A and p.Pro78Thr, respectively). The patient with the EZH2 alteration achieved a PR and had a PFS of 10·6 months. The patient with the EZH1 alteration did not achieve a clinical response. Further details of the gene mutation types detected and their gene loci are found in the appendix (p 21).
PK was evaluated in all 155 enrolled patients. The maximum mean (standard deviation) plasma concentrations of total and unbound valemetostat were observed at 4 hours post-dose on cycle 1 day 1 in both cohorts at 1990 (1740) ng/mL and 52·2 (50·8) ng/mL, respectively, for the PTCL cohort (N = 133), and 3060 (2940) ng/mL and 80 (61·3) ng/mL, respectively, for the ATLL cohort (N = 22). Valemetostat plasma concentrations reached a steady state by 15 days post-dose. For total CALZ-1809a, the maximum mean plasma concentration on cycle 1 day 1 was observed at 5 hours post-dose in both cohorts (211 ng/mL, PTCL cohort; 427 ng/mL, ATLL cohort). Almost all safety-evaluable patients experienced a TEAE during valemetostat therapy, including 96·2% of patients with PTCL and 100% of patients with ATLL (appendix p 16).
In the PTCL and ATLL cohorts, 77 patients (57·9%) and 19 patients (86·4%) experienced a grade ≥ 3 TEAE, and nine patients (6·8%) and one patient (4·5%) experienced a serious treatment-emergent adverse event considered to be treatment-related. Cytopenias, including thrombocytopenia, anaemia, and neutropenia, were the most common all-grade and grade ≥ 3 TEAEs in both cohorts (Table 3). Incidences of grade ≥ 3 thrombocytopenia, anaemia, and neutropenia were 23·3%, 18·8%, and 17·3%, respectively, in the PTCL cohort, and 50·0%, 45·5%, and 18·2%, respectively, in the ATLL cohort.
Table 3:
TEAEs by highest CTCAE grade in patients with PTCL and ATLL
| PTCL (N = 133) | ATLL (N = 22) | |||||||
|---|---|---|---|---|---|---|---|---|
| Grade 1 or 2 | Grade 3 | Grade 4 | Grade 5 | Grade 1 or 2 | Grade 3 | Grade 4 | Grade 5 | |
| Any TEAE | 51 (38·3%) | 41 (30·8%) | 21 (15·8%) | 15 (11·3%) | 3 (13·6%) | 10 (45·4%) | 4 (18·2%) | 5 (22·7%) |
| Thrombocytopeniaa | 35 (26·3) | 17 (12·8) | 14 (10·5) | 0 (0) | 2 (9·1) | 6 (27·3) | 5 (22·7) | 0 (0) |
| Anaemiab | 22 (16·5) | 23 (17·3) | 2 (1·5) | 0 (0) | 1 (4·5) | 10 (45·5) | 0 (0) | 0 (0) |
| Diarrhoea | 34 (25·6) | 5 (3·8) | 0 (0) | 0 (0) | 5 (22·7) | 1 (4·5) | 0 (0) | 0 (0) |
| Dysgeusia | 38 (28·6) | 0 (0) | 0 (0) | 0 (0) | 5 (22·7) | 0 (0) | 0 (0) | 0 (0) |
| Neutropeniac | 12 (9·0) | 12 (9·0) | 11 (8·3) | 0 (0) | 2 (9·1) | 2 (9·1) | 2 (9·1) | 0 (0) |
| COVID-19 | 24 (18·0) | 4 (3·0) | 0 (0) | 0 (0) | 3 (13·6) | 2 (9·1) | 0 (0) | 0 (0) |
| Nausea | 22 (16·5) | 1 (0·8) | 0 (0) | 0 (0) | 4 (18·2) | 0 (0) | 0 (0) | 0 (0) |
| Pyrexia | 20 (15·0) | 0 (0) | 0 (0) | 0 (0) | 4 (18·2) | 0 (0) | 0 (0) | 0 (0) |
| Cough | 20 (15·0) | 0 (0) | 0 (0) | 0 (0) | 3 (13·6) | 0 (0) | 0 (0) | 0 (0) |
| Decreased appetite | 17 (12·8) | 2 (1·5) | 0 (0) | 0 (0) | 2 (9·1) | 1 (4·5) | 0 (0) | 0 (0) |
| Fatigue | 17 (12·8) | 2 (1·5) | 0 (0) | 0 (0) | 1 (4·5) | 1 (4·5) | 0 (0) | 0 (0) |
| Oedema peripheral | 15 (11·3) | 1 (0·8) | 0 (0) | 0 (0) | 2 (9·1) | 0 (0) | 0 (0) | 0 (0) |
| AST increased | 13 (9·8) | 1 (0·8) | 0 (0) | 0 (0) | 1 (4·5) | 2 (9·1) | 0 (0) | 0 (0) |
| Leukopeniad | 5 (3·8) | 6 (4·5) | 2 (1·5) | 0 (0) | 2 (9·1) | 1 (4·5) | 1 (4·5) | 0 (0) |
| Pruritus | 16 (12·0) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) | 0 (0) | 0 (0) | 0 (0) |
| Vomiting | 12 (9·0) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) | 2 (9·1) | 0 (0) | 0 (0) |
| Acute kidney injury | 1 (0·8) | 1 (0·8) | 1 (0·8) | 0 (0) | 0 (0) | 1 (4·5) | 0 (0) | 0 (0) |
| Acute myeloid leukaemia | 0 (0) | 0 (0) | 2 (1·5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Alopecia | 14 (10·5) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Blood bilirubin increased | 8 (6·0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) | 0 (0) |
| Bronchopulmonary aspergillosis | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) |
| Cardiac failure | 1 (0·8) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Cerebral infarction | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) |
| Constipation | 12 (9·0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Coombs negative haemolytic anaemia | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) | 0 (0) |
| Cytomegalovirus viraemia | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 2 (9·1) | 0 (0) | 0 (0) |
| Dehydration | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 1 (4·5) | 2 (9·1) | 0 (0) | 0 (0) |
| Gamma-glutamyl transferase increased | 0 (0) | 1 (0·8) | 1 (0·8) | 0 (0) | 1 (4·5) | 0 (0) | 0 (0) | 0 (0) |
| General physical health deterioration | 0 (0) | 1 (0·8) | 1 (0·8) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Haemophagocytic lymphohistiocytosis | 1 (0·8) | 0 (0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Hepatic enzyme increased | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) | 0 (0) |
| Hepatic failure | 0 (0) | 0 (0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Hypercalcaemia | 0 (0) | 1 (0·8) | 1 (0·8) | 0 | 3 (13·6%) | 2 (9·1) | 1 (4·5) | 0 |
| Hyperkalaemia | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) | 0 (0) |
| Hypomagnesaemia | 4 (3·0) | 0 (0) | 0 (0) | 0 (0) | 3 (13·6) | 0 (0) | 0 (0) | 0 (0) |
| Hyponatraemia | 10 (7·5) | 0 (0) | 0 (0) | 0 (0) | 3 (13·6) | 0 (0) | 0 (0) | 0 (0) |
| Ileus | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) | 0 (0) |
| Intestinal perforation | 0 (0) | 0 (0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 1 (4·5) | 0 (0) |
| Lymphocytopeniae | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) | 1 (4·5) | 0 (0) |
| Malnutrition | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 2 (9·1) | 0 (0) | 0 (0) |
| Multiple organ dysfunction syndrome | 0 (0) | 0 (0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) |
| Necrotising fasciitis | 0 (0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Pleural effusion | 1 (0·8) | 0 (0) | 1 (0·8) | 0 (0) | 1 (4·5) | 0 (0) | 0 (0) | 0 (0) |
| Pneumonia bacterial | 0 (0) | 1 (0·8) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Pneumonia fungal | 0 (0) | 0 (0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Pseudomonal sepsis | 0 (0) | 0 (0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Pseudomonas infection | 0 (0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Shock haemorrhagic | 0 (0) | 0 (0) | 1 (0·8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Upper gastrointestinal haemorrhage | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (4·5) | 0 (0) |
Data are n (%). TEAEs occurring in 10% or more of patients, TEAEs of grade 3 occurring in 5% or more patients, and all occurrences of TEAEs grade 4 or 5 are shown.
Thrombocytopenia also includes platelet count decreased.
Anaemia also includes haemoglobin decreased and red blood cell count decreased.
Neutropenia includes neutrophil count decreased.
Leukopenia includes white blood cell count decreased.
Lymphocytopenia includes lymphocyte count decreased.
AST, aspartate aminotransferase; ATLL, adult T-cell leukaemia/lymphoma; COVID-19, coronavirus disease 2019; CTCAE, Common Terminology Criteria for Adverse Events; PTCL, peripheral T-cell lymphoma; TEAE, treatment-emergent adverse event.
In the PTCL and ATLL cohorts, TEAEs required treatment interruption for 49·6% and 68·2% of patients, dose reductions for 15·8% and 4·5%, and treatment discontinuation in 9·8% and 9·1%, respectively (appendix p 17). Thrombocytopenia was the most common TEAE leading to dose modifications in patients with PTCL, including study drug discontinuation in 2·3% of patients, dose-reduction in 5·3%, and interruption in 16·5%. The median time from the first dose of valemetostat to onset of new grade 3 thrombocytopenia (platelet count < 50×109/L) was 18 and 21 days in patients with PTCL and ATLL, respectively, and the median time to recovery was 12 days for the PTCL cohort and 11 days for the ATLL cohort. Thrombocytopenia was not frequent during later cycles. In addition to dose modifications, cytopenias were managed with platelet and red blood cell transfusions, and with granulocyte colony-stimulating factors (appendix p 18). Two patients (1·5%) with PTCL developed secondary acute myeloid leukaemia at 462 and 552 days after first valemetostat dose and discontinued treatment (appendix p 19). Grade 3 febrile neutropenia was reported in two patients with PTCL, and in no patients with ATLL. Fifty-two patients (39·1%) with PTCL and 16 patients (72·7%) with ATLL died before data cut off, with all deaths unrelated to the study drug (appendix p 20).
Discussion
This phase 2 clinical trial demonstrated a favourable risk/benefit profile of valemetostat monotherapy in patients with R/R PTCL, with high and durable responses to valemetostat monotherapy and an acceptable safety profile with mostly manageable TEAEs in patients with R/R PTCL and ATLL. Treatment options are limited for patients with R/R T-cell lymphomas, and thus a great need exists for additional effective therapies. Gain-of-function EZH2 mutations are rare in PTCL,13 however, EZH2 overexpression can occur without mutation and is associated with tumour proliferation, more aggressive disease, and poor prognosis.12 Valemetostat dual inhibition of EZH2 and EZH1 prevents H3K27me3 and increases expression of genes silenced by H3K27me3, ultimately attenuating the proliferation of EZH2- and EZH1-dependent cancer cells.16,21 In this study, valemetostat demonstrated high ORR in CT- and PET-CT–based assessments and durable clinical responses in patients with R/R PTCL. Responses were generally prompt, with almost half of patients achieving a response at the first post-baseline tumour assessment of 8 weeks (median TTR, 8·1 weeks). Responses were observed across PTCL subtypes, although response rates were numerically higher among patients with subtypes with the TFH phenotype, ie, AITL and PTCL-TFH. Time to disease progression from the first study dose was longer in patients who achieved a CR than for those with a PR. Response rates were nominally higher with fewer lines of prior treatments (one prior treatment, 52·8% vs ≥ three prior lines of treatment, 35·8%). The R/R PTCL patient population in this study was representative of those with a high unmet need, with over 25% receiving prior HCT.
While cross-trial comparisons are difficult due to potential differences in patient populations and trial design, the overall response rate with valemetostat of 43·7% compares favourably with several monotherapy treatments for PTCL, and the median DOR of 11·9 months is similar. Belinostat, romidepsin, and pralatrexate have been associated with an ORR of 25·8%, 25%, and 29%, and median DOR of 13·6, 17, and 10·1 months, respectively.7,14,22 While brentuximab vedotin showed an ORR of 86% in patients with R/R ALCL, including 57% of patients achieving a CR,23 valemetostat clinical activity is comparable to the brentuximab vedotin phase 2 study in non-ALCL patients with R/R CD30+ PTCL (AITL, n = 13; PTCL-NOS, n = 22), where 41% of patients achieved an OR and 24% achieved a CR with a median DOR of 7·6 months (range, 1·3–14+).24 Ten patients (8·4%) with PTCL in our phase 2 study had valemetostat treatment consolidated with allo-HCT, including six who achieved CRs to valemetostat by CT-based assessment, with a median time from first dose to HCT of 6·7 months, supporting the use of valemetostat as a bridge to potentially curative therapy.
FDG-PET/CT is recommended as the preferred imaging modality for interim restaging in the 2023 NCCN Guidelines®6, and in clinical practice, PET-CT is commonly used for PTCL response assessments. However, not all patients have PET-avid tumours (approximately 90%),25 and Lugano 2014 response criteria does not specify a preferred technical imaging approach between CT or PET-CT.19 Therefore, CT-based response assessments were carried out per 2014 Lugano criteria as primary and secondary endpoints, and clinical response by PET-CT assessment was an exploratory endpoint. The ORR by PET-CT assessment was higher than the CT-based rate (52·1% vs 43·7%, respectively), and the complete remission rate by PET-CT assessment was nearly double that by CT (26·9% vs 14·3%).
Analyses of gene mutation frequencies were generally consistent with historical findings in PTCL13,19,26; TET2 and RHOA mutations were common, particularly in patients with AITL, whereas EZH2 and EZH1 mutations were rare in this cohort. Numerical trends of differences in clinical response by mutational status were observed in TET2 and RHOA (appendix p 15). It is unclear whether these observations are true genetic biomarkers of a vulnerability to valemetostat, or whether the higher response is merely correlated with the TFH phenotype. Given that pathological subtypes of PTCL are being elucidated in light of molecular pathogenesis,27 genetic analyses using a comprehensive gene panel with a particular focus on PTCL molecular biology would result in a further refinement of genetic determinants to valemetostat response.
The mean concentration values of total and unbound valemetostat and total CALZ-1809a were generally higher for the ATLL cohort than the PTCL cohort. However, it should be noted that the interpretation of these results may be limited due to the ATLL cohort’s small sample size (N = 22) and large PK variability.
Valemetostat had an acceptable safety profile in patients with R/R PTCL or ATLL. TEAEs were generally manageable and infrequently required treatment discontinuation (PTCL, 9·8%; ATLL, 9·1%). Acknowledging the limitations of cross-trial comparisons and the absence of a comparator arm, the rates of discontinuing therapy for TEAEs appeared lower than with other monotherapies, including belinostat, romidepsin, and pralatrexate, which were associated with adverse event discontinuation rates of 19%, 19%, and 23%, respectively, in their phase 2 trials.7,14,24 Cytopenias were the most commonly reported TEAEs during valemetostat therapy. Thrombocytopenia was the most frequent TEAE, which occurred during the first treatment cycle and typically recovered with or without dose modification or supportive therapies.
The limitations of this study were that it was non-randomised without a comparator arm and that the number of patients with certain PTCL subtypes was limited. Given the positive results of this VALENTINE-PTCL01 study, valemetostat was approved in Japan for the treatment of R/R PTCL.28 This study provides rationale to further explore valemetostat treatment for patients with R/R PTCL in a confirmatory randomised trial.
Supplementary Material
Research in context.
Evidence before this study
We searched PubMed using the terms “EZH”, “relapsed”, “refractory”, and “T-cell lymphoma” to find research published in any language between January 1, 2000, and November 15, 2023. The search returned no results. A similar search was then conducted, omitting “EZH” from the query, which yielded 259 results, including 76 articles reporting outcomes from clinical trials using the PubMed “Clinical Trial” article type filter.
Valemetostat tosylate is a novel and potent dual inhibitor of enhancer of zeste homolog 2 (EZH)2 and EZH1 and is approved in Japan for the treatment of relapsed/refractory (R/R) adult T-cell leukaemia/lymphoma (ATLL), based on results from a single-arm, phase 2 trial demonstrating a 48% objective response rate (ORR) in this patient population. Our phase 2 trial assessed valemetostat monotherapy in patients with R/R peripheral T-cell lymphomas (PTCL), including ATLL.
Added value of this study
There remains a need for tolerable treatment options with a high and durable response for patients with PTCL. To our knowledge, this is the first clinical trial of an EZH inhibitor for treatment of patients with R/R PTCL. Results from our phase 2 trial show an acceptable safety profile, promising ORR, and durable responses with valemetostat monotherapy in patients with R/R PTCL, including ATLL. Cytopenias were common but could usually be managed without discontinuing treatment. Based on the results of this VALENTINE-PTCL01 study, valemetostat was approved in Japan for the treatment of R/R PTCL.
Implications of all available evidence
Valemetostat is the first dual inhibitor of EZH2 and EZH1 under investigation for the treatment of PTCL. Results from a first-in-human phase 1 trial of valemetostat patients with R/R B- and T-cell non-Hodgkin lymphomas are reported by Maruyama et al. in a separate article in this issue. Our study further confirms the safety and clinical activity of valemetostat in R/R PTCL Taken together, these results warrant confirmation in a large, randomised, controlled clinical trial.
Acknowledgements
Daiichi Sankyo was the study sponsor. We thank the patients and families who participated in the trial, all investigators that contributed to patient enrolment, Dr Francine Foss and Dr Pierluigi Porcu for participation in protocol development, and Dr Jose Cabecadas for the central pathology review. The authors received editorial and writing assistance from Declan Grewcock, PhD, and Brian Kaiser of Excerpta Medica, supported by Daiichi Sankyo.
Footnotes
Declarations
Declaration of interests
PLZ has received consulting fees from lncyte, Novartis, BeiGene, and SOBI; honoraria from Takeda, AstraZeneca, MSD, BMS, lncyte, Roche, Gilead, Recordati, Kyowa Kirin, Novartis, BeiGene, Janssen, and SOBI, unrelated to this study. KoI has received manuscript support from Daiichi Sankyo to their institution, related to this work; research funding Chugai, Bristol Myers Squibb, Incyte, Genmab, LOXO Oncology, Daiichi Sankyo, BeiGene, AbbVie, AstraZeneca, Regeneron, Yakult, Chugai, Otsuka, Novartis, Pfizer, MSD, Bayer, Kyowa Kirin, Eisai, Janssen, Ono Pharmaceutical, Gilead, Astellas, and Amgen to their institution, unrelated to this work; consulting fees from AstraZeneca, Ono Pharmaceutical, Mitsubishi Tanabe, Eisai, Chugai, Bristol Myers Squibb, AbbVie, Takeda, Zenyaku, Genmab, Kyowa Kirin, MSD, Carna Biosicences, Novartis, Yakult, Nihon Shinyaku, Novartis, and BeiGene, unrelated to this work; honoraria from AstraZeneca, Ono Pharmaceutical, Eisai, Chugai, Janssen, Symbio, Bristol Myers Squibb, Daiichi Sankyo, Otsuka, AbbVie, Takeda, Eli Lilly, Genmab, Kyowa Kirin, MSD, Astellas, Pfizer, Meiji Seika Pharma, Novartis, Nihon Kayaku, and Gilead, unrelated to this work. NM-S has received research funding from AstraZeneca, Bristol Myers-Squibb, C4 Therapeutics, Celgene, Corvus Pharmaceuticals, Daiichi Sankyo, Dizal Pharmaceuticals, Genetech/Roche, Incyte Corp, Innate Pharmaceuticals, Secura Bio, Verastem, and Yingli Pharmaceuticals, to their institutions, unrelated to this work; consulting fees from Astra Zeneca, Kyowa Hakka Kirin, Karyopharm, Ono Pharmaceuticals, Secura Bios, Daiichi Sankyo, Genentech, and Janssen, unrelated to this work; participated on a Data Safety Monitoring Board or Advisory Board for Daiichi Sankyo, unrelated to this work. SKB received manuscript support from Daiichi Sankyo, related to this work; consulting fees and honoraria from Acrotech, Kyowa Kirin, and Seagen, unrelated to this work; participated on a Data Safety Monitoring Board or Advisory Board for Janssen, unrelated to this work. KeI has received manuscript support from Daiichi Sankyo, related to this work; research funding from Ono Pharmaceutical and Kyowa Kirin to their institutions, unrelated to this work; honoraria from Kyowa Kirin, Takeda, Chugai Pharmaceutical, Celgene, Bristol Myers Squibb, Daiichi Sankyo, Ono Pharmaceutical, Astellas, Eizai, Pfizer, Otsuka, Sanofi, CSL Behring, AbbVie, Yakult, Janssen Pharmaceutical, and Nippon Shinyaku, unrelated to this work; participated on Data Safety Monitoring Board or Advisory Board for Meiji Seika Pharma and Daiichi Sankyo, unrelated to this work; received materials from Ono Pharmaceutical to their institution, unrelated to this work. SK has received support from Daiichi Sankyo, related to this work; research funding from Chugai, Kyowa Kirin, and Janssen, unrelated to this work; honoraria from Daiichi-Sankyo, Chugai, Kyowa Kirin, and Janssen, unrelated to this work. EB receive research funding from Amgen and BMS, to their institution, unrelated to this work; honoraria from Novartis, Kite/Gilead, Roche, Takeda, Janssen, and AbbVie, unrelated to this work; support for attending meetings and/or travel from Roche and Kite/Gilead, unrelated to this work; participated on Data Safety Monitoring Board or Advisory Board from Novartis, Kite/Gilead, Roche, Incyte, ADC Therapeutics, and AbbVie, unrelated to this work. KC received consulting fees from Roche, Takeda, Celgene, and AbbVie, unrelated to this work; honoraria from Roche and Takeda, unrelated to this work; support for attending meetings and/or travel from Roche, Takeda, and BMS, to their institution; participated on Data Safety Monitoring Board or Advisory Board for Daiichi Sankyo, unrelated to this work. GG received honoraria from Ideogen and Takeda, unrelated to this work; support for attending meetings and/or travel from Roche, Kite-Gilead, Sandoz, BeiGene, and Janssen, unrelated to this work; participated on Data Safety Monitoring Board or Advisory Board for AbbVie, Roche, Takeda, Kite-Gilead, Italfarmaco, Ideogen, and Genmab, unrelated to this work. EJ received research funding from Celgene, Merck, Pharmacyclics, and Hoffman-LaRoche, unrelated to this work; honoraria from Merck, Daiichi, BMS, and Bayer, unrelated to this work; have patents planned, issued, or pending with UpToDate, unrelated to this work. TF has received research funding from ADCT, AstraZeneca, BMS, Corvus, Daiichi, Genmab, Kymera, Merck, Seagen, TESSA, Trillium, Alexion, and Portola, unrelated to this work; consulting fees from ADCT, AstraZeneca, BMS, Epizyme, Genmab, Seagen, Pharmacyclics, and Celgene, unrelated to this work; honoraria from Takeda, Seagen, Genmab, Epizyme, ADCT, AstraZeneca, BMS, Pharmacyclics, AbbVie, and Pfizer, unrelated to this work; owns stock in OMI and Genomic Testing Cooperative, unrelated to this work. DE received research funding from Nippon Shinyaku Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Eisai Pharmaceutical Co., Ltd., to their institution, unrelated to this work; honoraria from Eisai Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Co., Ltd., Bristol Myers Squibb, Kyowa Kirin Pharmaceutical Co., Ltd., and Nippon Shinyaku Pharmaceutical Co., Ltd., unrelated to this work. EDD received consulting fees from Takeda, unrelated to this work; honoraria from Takeda and BeiGene, unrelated to this work; funding for attending meetings and/or travel from Takeda, unrelated to this work. JZ received research funding from Secura Bio, Astex, CRSPR, Myeloid Therapeutics, and Daichi Sankyo, unrelated to this work; consulting fees from Seattle genetics, Secura Bio, Kyowa Kirin, and Myeloid Therapeutics, unrelated to this work; honoraria from Kyowa Kirin, unrelated to this work. JJ, SW, TM, AI, and KN are employed with Daiichi Sankyo; TM has received support for attending meetings and/or travel from Daiichi Sankyo, unrelated to this work; TM and YC own stock options in Daiichi Sankyo, unrelated to this work, KN owns stock in Daiichi Sankyo, unrelated to this work. SH received research funding from NIH/NCI Cancer Center, Support Grant P30 CA008748; research funding from ADC Therapeutics, Affimed, Aileron, Celgene, Crispr Therapeutics, Daiichi Sankyo, Forty Seven Inc., Kyowa Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio; honoraria from Abcuro, Inc., Autolus, Auxilus Pharma, Corvus, Cimeio Therapeutics, Daiichi Sankyo, Dren Bio, Kyowa Hakko Kirin, March, Bio, ONO Pharmaceuticals, SecuraBio, Shore line, Biosciences, Inc., Takeda, Tubulis and Yingli Pharma Limited. All other authors declare no competing interests.
Data sharing
Anonymised individual participant data from completed studies and applicable supporting clinical study documents are available upon request at https://vivli.org/. Data sharing access is provided through the Vivli data sharing portal (https://vivli.org/ourmember/daiichi-sankyo/) after approval of a research proposal and signed data agreement. If clinical study data and supporting documents are provided pursuant to company policies and procedures, Daiichi Sankyo will continue to protect the privacy of the company and clinical study participants.
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Associated Data
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Supplementary Materials
Data Availability Statement
Anonymised individual participant data from completed studies and applicable supporting clinical study documents are available upon request at https://vivli.org/. Data sharing access is provided through the Vivli data sharing portal (https://vivli.org/ourmember/daiichi-sankyo/) after approval of a research proposal and signed data agreement. If clinical study data and supporting documents are provided pursuant to company policies and procedures, Daiichi Sankyo will continue to protect the privacy of the company and clinical study participants.