Dasatinib vs. imatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: the DASCERN randomized study

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Phase 1/2 Study Investigating CC-90011, a Potent, Selective, and Reversible Oral Inhibitor of Lysine-Specific Demethylase 1 (LSD1), Plus Concurrent Venetoclax (VEN) and Azacitidine (AZA) in Patients with Acute Myeloid Leukemia (AML)

Abstract Background AML may be initiated by cytogenetic alterations or mutations in genes encoding epigenetic regulators. Epigenetic dysregulation influences the transformation of hematopoietic stem cells or their downstream progenitors into self-renewing leukemic stem cells (LSCs), which contribute to AML pathogenesis and tumor growth. Residual chemoresistant LSCs are implicated in relapsed and/or refractory (R/R) AML, a life-threatening disease with limited treatment options. The epigenetic eraser LSD1 demethylates histone lysine residues to alter gene expression, is essential for hematopoiesis, and is often overexpressed in LSCs in AML. CC-90011 is a potent, selective, and reversible oral inhibitor of LSD1 that has shown antitumor effects in solid-tumor and AML cell-line models. CC-90011 monotherapy had a favorable safety profile and showed evidence of antitumor activity in patients with advanced solid tumors and R/R non-Hodgkin lymphoma (Hollebecque et al. ESMO TAT 2021. Abstract 7O). CC-90011 combined with etoposide plus carboplatin or cisplatin was well tolerated in patients with extensive-stage small cell lung cancer (Ponce at al. ELCC 2021. Abstract 50P). VEN plus AZA has emerged as standard therapy for elderly patients with AML. Adding CC-90011 to VEN and AZA may inhibit the aberrant LSD1 activity associated with AML pathogenesis and LSC propagation, increase sensitization to VEN and AZA, and produce deeper and more durable responses than VEN plus AZA alone. Study Design and Methods CC-90011-AML-002 (NCT04748848) is a phase 1/2, open-label, multicenter study to evaluate the safety, tolerability, and preliminary efficacy of CC-90011 plus concurrent VEN and AZA in adult patients with R/R AML or in patients with newly diagnosed AML (ndAML) who are ≥ 75 years of age or are 18-74 years of age and ineligible for intensive induction chemotherapy. The study has 2 dose-escalation parts in patients with R/R AML (part 1) or ndAML (part 2), and a randomized dose-expansion part in patients with ndAML (part 3). Part 3 will use a 2:1 randomized design with Bayesian informative prior to calculate the posterior probability that the complete remission (CR) rate in the treatment arm is higher than in the control arm. Enrolled patients must have a projected life expectancy of ≥ 12 weeks, ECOG performance status of 0-2, white blood cell count ≤ 25 × 10 9/L, and adequate organ function. Patients will be excluded if they are candidates for FLT3 inhibitor therapy or have suspected or proven acute promyelocytic leukemia, favorable-risk cytogenetics, or central nervous system involvement. In parts 1 and 2, patients will receive CC-90011 20, 40, or 60 mg plus VEN and AZA (3-6 patients per treatment arm). In part 3, patients will receive VEN plus AZA with or without CC-90011 administered at the recommended phase 2 dose (RP2D) determined in part 2 (approximately 64 and 32 patients, respectively), with an interim analysis for futility once 50% of patients have been randomized and completed 3 treatment cycles. In all parts, CC-90011 will be administered orally on days 1, 8, and 15 of each 28-day cycle, AZA 75 mg/m 2 will be administered intravenously or subcutaneously on days 1-7 of each cycle, and oral VEN 400 mg will be administered on days 1-28 of each cycle, with a dose ramp-up on days 1 and 2 of cycle 1. VEN will be given ≥ 6 hours after CC-90011 to minimize drug-drug interactions. For clinical outcome evaluation, patients should be treated for ≥ 3 cycles but can discontinue sooner due to disease progression, unacceptable adverse events, intercurrent illness, or investigator's decision. Primary objectives are to evaluate the safety and tolerability of CC-90011 plus VEN and AZA, and to determine the maximum tolerated dose and/or RP2D of CC-90011. Secondary objectives are to assess the preliminary efficacy of CC-90011 plus VEN and AZA in parts 1-3, and to evaluate the minimal residual disease (MRD) response and conversion rates by multicolor flow cytometry and/or next-generation sequencing in parts 2 and 3. Preliminary efficacy will be determined using CR rate, rate of CR with partial or incomplete hematologic recovery, overall response rate, and duration of response in parts 1-3, and event-free and overall survival in part 3. Because CC-90011 is expected to target LSCs, its addition to VEN plus AZA is predicted to increase the depth and durability of response by MRD evaluation compared with control, rather than increase remission rates. Figure 1 Figure 1. Disclosures DiNardo: AbbVie: Consultancy, Research Funding; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; GSK: Consultancy; Astex: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee; AbbVie Inc: Other: Independent review committee. Mawad: Abbvie: Speakers Bureau. Kremyanskaya: Protagonist Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Constellation: Research Funding; Astellas: Research Funding; Bristol Myers Squibb: Research Funding; Chimerix: Research Funding; Astex: Research Funding. Blachly: AstraZeneca: Consultancy, Honoraria; KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Other: Independent review committee; AbbVie: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Other: Independent review committee; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Youn: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Garzon: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Martin-Regueira: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Watts: Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Rafael Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding

Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study

Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (≥median; p = .0051), line of therapy (first line; p = .0138), and age (>65 years; p = .0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond

AML-432 Overall Survival (OS) by IDH2 Mutant Allele (R140 or R172) in Patients With Late-Stage, Mutant-IDH2 Relapsed/Refractory Acute Myeloid Leukemia (AML) Treated With Enasidenib or Conventional Care Regimens (CCR) in the Randomized, Open-Label, Phase 3 IDHENTIFY Trial

Context : IDH2 mutations (mIDH2) occur in ~8%-19% of patients with AML, typically as R140Q (~75%) or R172K (~25%) point mutations, which have distinct functional effects and prognostic relevance. In the phase 3 IDHENTIFY trial, enasidenib did not significantly improve OS vs CCR in older patients with mIDH2 relapsed/refractory AML, but a trend for improved OS with enasidenib was detected in patients with IDH2-R172. Objective : Investigate molecular profiles and OS in mIDH2 variant subgroups (R140/R172). Methods : IDHENTIFY (NCT02577406) enrolled patients aged ≥60 years who had received 2-3 prior AML-directed therapies. Patients were randomized 1:1 to enasidenib 100-mg/day or CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care). Co-occurring mutations were identified by targeted NGS of BMMC DNA. Total 2-hydroxyglutarate was determined by LC/MS. Results : Of 319 patients enrolled, 88 (28%; 43 enasidenib, 45 CCR) had mIDH2-R172 and 229 (72%; 115 enasidenib, 114 CCR) had mIDH2-R140. Median baseline 2-hydroxyglutarate level and IDH2 VAF were similar between arms and mIDH2 subgroups. Patients with mIDH2-R172 had fewer baseline mutations (median 4 [range 2-8]) than those with mIDH2-R140 (5 [1-11]) (P<0.0001). Common co-mutations were SRSF2 and RUNX1 in the R140 cohort (59% each) and DNMT3A in the R172 cohort (57%). Compared with R172, R140 was enriched with SRSF2, FLT3 (-ITD/-TKD), NPM1, RUNX1, and JAK2, whereas DNMT3A and TP53 were more common with R172. In Cox multivariate analysis including mIDH2 variant, DNMT3A status, and number of baseline mutations, mIDH2-R172 was significantly correlated with improved OS (P=0.04 vs R140) in the enasidenib arm, and number of baseline mutations was significantly (P<0.01) associated with OS in the CCR arm. Median OS in the R172 subgroup was 14.6 months with enasidenib vs 7.8 months with CCR (HR, 0.59 [95%CI 0.35-0.98]; P=0.039); 1-year survival rates were 62% and 30%. In the R140 subgroup, median OS was 5.7 months in both arms (0.93 [0.70-1.24]; P=0.61), and 1-year survival rates were 29% and 25% with enasidenib and CCR. Conclusions: Mutational burden and co-mutational profiles differed between patients with mIDH2-R140 and mIDH2-R172 relapsed/refractory AML. In the R172 subgroup, median OS and 1-year survival rate with enasidenib were approximately double those with CCR

Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial

Background: Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy. Methods: This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m2 per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing. Findings: Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71–78). 50 (74%; 95% CI 61–84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20–55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0–11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [19%] of 32 in the azacitidine-only group), neutropenia (25 [37%] vs eight [25%]), anaemia (13 [19%] vs seven [22%]), and febrile neutropenia (11 [16%] vs five [16%]). Serious treatment-related adverse events were reported in 29 (43%) patients in the combination group and 14 (44%) patients in the azacitidine-only group; serious treatment-related adverse events occurring in more than 5% of patients in either group were febrile neutropenia (nine [13%] in the combination group vs five [16%] in the azacitidine-only group), differentiation syndrome (seven [10%] vs none), and pneumonia (three [4%] vs two [6%]). No treatment-related deaths were reported. Interpretation: Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia

Dasatinib with intensive chemotherapy in de novo paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (CA180-372/COG AALL1122):a single-arm, multicentre, phase 2 trial

BACKGROUND: The outcome of children with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia significantly improved with the combination of imatinib and intensive chemotherapy. We aimed to investigate the efficacy of dasatinib, a second-generation ABL-class inhibitor, with intensive chemotherapy in children with newly diagnosed Ph-positive acute lymphoblastic leukaemia.METHODS: CA180-372/COG AALL1122 was a joint Children's Oncology Group (COG) and European intergroup study of post-induction treatment of Ph-positive acute lymphoblastic leukaemia (EsPhALL) open-label, single-arm, phase 2 study. Eligible patients (aged &gt;1 year to &lt;18 years) with newly diagnosed Ph-positive acute lymphoblastic leukaemia and performance status of at least 60% received EsPhALL chemotherapy plus dasatinib 60 mg/m2 orally once daily from day 15 of induction. Patients with minimal residual disease of at least 0·05% after induction 1B or who were positive for minimal residual disease after the three consolidation blocks were classified as high risk and allocated to receive haematopoietic stem-cell transplantation (HSCT) in first complete remission. The remaining patients were considered standard risk and received chemotherapy plus dasatinib for 2 years. The primary endpoint was the 3-year event-free survival of dasatinib plus chemotherapy compared with external historical controls. The trial was considered positive if one of the following conditions was met: superiority over chemotherapy alone in the AIEOP-BFM 2000 high-risk group; or non-inferiority (with a margin of -5%) or superiority to imatinib plus chemotherapy in the EsPhALL 2010 cohort. All participants who received at least one dose of dasatinib were included in the safety and efficacy analyses. This trial was registered with ClinicalTrials.gov, NCT01460160, and recruitment is closed.FINDINGS: Between March 13, 2012, and May 27, 2014, 109 patients were enrolled at 69 sites (including 51 COG sites in the USA, Canada, and Australia, and 18 EsPhALL sites in Italy and the UK). Three patients were ineligible and did not receive dasatinib. 106 patients were treated and included in analyses (49 [46%] female and 57 [54%] male; 85 [80%] White, 13 [12%] Black or African American, five [5%] Asian, and three [3%] other races; 24 [23%] Hispanic or Latino ethnicity). All 106 treated patients reached complete remission; 87 (82%) were classified as standard risk and 19 (18%) met HSCT criteria and were classified as high risk, but only 15 (14%) received HSCT in first complete remission. The 3-year event-free survival of dasatinib plus chemotherapy was superior to chemotherapy alone (65·5% [90% Clopper-Pearson CI 57·7 to 73·7] vs 49·2% [38·0 to 60·4]; p=0·032), and was non-inferior to imatinib plus chemotherapy (59·1% [51·8 to 66·2], 90% CI of the treatment difference: -3·3 to 17·2), but not superior to imatinib plus chemotherapy (65·5% vs 59·1%; p=0·27). The most frequent grade 3-5 adverse events were febrile neutropenia (n=93) and bacteraemia (n=21). Nine remission deaths occurred, which were due to infections (n=5), transplantation-related (n=2), due to cardiac arrest (n=1), or had an unknown cause (n=1). No dasatinib-related deaths occurred.INTERPRETATION: Dasatinib plus EsPhALL chemotherapy is safe and active in paediatric Ph-positive acute lymphoblastic leukaemia. 3-year event-free survival was similar to that of previous Ph-positive acute lymphoblastic leukaemia trials despite the limited use of HSCT in first complete remission.FUNDING: Bristol Myers Squibb.</p