ALBERT

Description: Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after

Description: BACKGROUND: Historically, causes of death for patients dying with active acute myeloid leukemia (AML) and those in remission have differed. However, it is unknown how changes in therapies and advances in supportive care have impacted death patterns and whether these differ for patients with active disease or those in morphologic remission (with or without measurable residual disease [MRD]) at the time of death. Here, we investigated the cause of death (COD) in AML patients and studied whether these differed for patients in morphologic remission with or without evidence of MRD. PATIENTS AND METHODS:We used an institutional database of adults with newly-diagnosed AML treated with intensive induction chemotherapy from 2006-2017 with either "7+3" (N=140) or cladribine, cytarabine, mitoxantrone and G-CSF ("CLAG-M", N=198). Primary COD, time of death (TOD) and clinical variables were abstracted from chart review. Disease status at TOD was determined by the patient's last bone marrow aspirate/biopsy (BMA) prior to death, unless complete blood count or autopsy clearly showed AML. Complete remission (CR), CR with incomplete hematologic recovery (CRi), and relapse were defined per 2017 ELN criteria. MRD was determined by multiparameter flow cytometry (MFC) and cytogenetics on all BMA. All patients treated on clinical studies gave informed consent in accordance with the Declaration of Helsinki and were treated on Institutional Review Board-approved protocols. RESULTS: Characteristics of the 338 patients are shown in Table 1. With a median follow-up of 928 days, 187/338 (55%) patients died, 2 of which were excluded from subsequent analysis due to incomplete data. The remaining 185 patients were categorized into 3 groups based on disease status at TOD: remission (CR/CRi and MRD negative), MRD (CR/CRi and MRD positive), and relapse. There were 59 (32%) patients in remission, 13 of which had treatment following their last BMA; this treatment consisted of consolidation chemotherapy or transplant in 11/13 patients. There were 17 (9%) MRD patients and in 6/17 the response to last cycle of treatment was unknown. 109 (59%) of patients were in relapse at TOD, and 24/109 were without BMA assessment following last treatment. 36/59 (61%) remission patients underwent hematopoietic cell transplantation, compared to 5/17 (29%) and 42/109 (39%) in the MRD and relapse groups, respectively. Overall, the median survival from the start of initial induction treatment to death was 327 days, with 85/185 (45%) of patients dying within 60 days of their last treatment. Median time between last cycle of treatment and death was 136 days for the remission group, compared to 53 days in MRD and 50 days in relapse groups. Finally, we examined how COD varied by disease status at time of death (Table 2). Of patients dying with morphologic AML (N=109), AML was the most common COD (45%) followed by infection (33%), other (9%), and unknown (7%). For remission patients (N=59), infection was the predominant COD (56%) followed by unknown (17%) and transplant-related complications (12%). In MRD positive patients (N=17), AML was the COD in 1 patient (6%), infection occurred in 6 (35%), with unknown (29%) or other causes (18%) accounting for the remaining deaths. Notably, only 9 (5%) of patients underwent autopsy and of the 50 patients dying with AML as primary cause, the majority (32/50, 64%) died while on hospice and thus AML as primary cause was presumptive. CONCLUSIONS: In our cohort, the majority of deaths occurred within one year of starting induction chemotherapy, and most occurred in patients in active relapse. Only a minor subset of patients dying in morphologic remission had MRD, and COD of patients in the MRD group more closely reflected that of patients in remission. A substantial proportion of deaths occurred within 60 days of treatment, demonstrating that active treatment represents a particularly vulnerable period for patients regardless of disease status. Infection accounted for a substantial proportion of deaths for patients in all disease categories, and is likely undercounted in our study given the high proportion of relapse patients dying on hospice. Thus, despite advances in treatment, infection represents the most common cause of death in AML, highlighting the need for advances in diagnosis and treatment of infections to improve overall outcomes. Disclosures Halpern: Novartis: Other; Bayer: Other; Jazz Pharmaceuticals: Other; Imago BioSciences: Other; Tolero Pharmaceuticals: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Godwin:Pfizer Inc.: Research Funding; Immunogen Inc.: Research Funding.

Description: BACKGROUND. SEL24/MEN1703 is a first-in-class, orally available, dual PIM/FLT3 kinase inhibitor investigated in unselected AML patients in the First-in-Human, Dose Escalation (DE) and Cohort Expansion (CE) DIAMOND trial (clinicaltrials.gov identifier: NCT03008187). The study has completed the DE part showing an acceptable safety profile up to the recommended dose (RD), with initial evidence of single agent efficacy1. Preclinical studies conducted in vitro - using a panel of 26 AML cell lines harboring different genetic alterations - and in vivo - in xenograft mouse model bearing MOLM-16 cell line - showed a direct correlation between the activity of SEL24/MEN1703 and the inhibition of S6 phosphorylation (pS6) protein, a downstream target of PIM/FLT3 signaling pathway. AIM. To assess the degree of target engagement and its preliminary correlation with the anti-leukemic effect of SEL24/MEN1703 in samples collected from patients enrolled in the DE part of DIAMOND trial. METHODS. S6 phosphorylation has been longitudinally monitored in the DIAMOND study through an optimized assay for multiparametric analysis of phospho-protein activation. The assay allows a quantitative assessment of pS6 at single cell level among blast cells as well as the identification of blast subpopulations in both peripheral blood (PB) and bone marrow (BM). Blast counts were monitored to assess whether the target engagement did translate into blast count reduction. RESULTS. Two cohorts of patients, treated at 100 mg (one dose level below RD) and 125 mg (RD) were analyzed, for a total of n=9 evaluable patients on PB and n=7 on BM. At screening we observed a heterogeneous positivity for pS6 marker in blast cells (range: 1%-53 %) both in PB and in BM, consistent with the unselected AML patient population recruited in the trial. Overall, 7/9 PB and 4/7 BM samples showed pS6 inhibition in blast cells at the end of the Cycle 1 in comparison with screening (range: 70%-94% and 26%-76% in PB and BM, respectively) (Figure 1). In the cohort treated at 100 mg such strong pathway inhibition did not correlate with blast count reduction. Interestingly, in samples from a patient treated at 125 mg who harbored the highest burden of pS6+ blast cells (〉25%), a correlation between pathway inhibition and blast count reduction was observed suggesting that a higher burden of blasts with activated pS6 might be more sensitive to the inhibition of the pathway (Figure 1). CONCLUSIONS. The longitudinal PD assessment through the modulation of pS6 activation by flow cytometry confirmed that meaningful target engagement was achieved, both in PB and BM, in patients treated with SEL24/MEN1703 at 100 and 125 mg. Preliminary data suggest that the FLT3/PIM pathway inhibition might be associated with blast count reduction, particularly in case of high baseline activation of pS6. Longitudinal monitoring of PD will be continued in the CE part of DIAMOND trial. REFERENCES. 1. Solomon et al, EHA 2020 Disclosures Tomirotti: Menarini Ricerche: Current Employment. Bellarosa:Menarini Ricerche: Current Employment. Walter:Genentech: Consultancy; Selvita: Research Funding; StemLine: Research Funding; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy; Arog: Research Funding; Argenx: Consultancy; Aptevo: Consultancy, Research Funding; Amphivena: Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Macrogenics: Research Funding; Kite: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Brzózka:Ryvu Therapeutics: Current Employment. Baldini:Menarini Ricerche: Current Employment. Salerno:Menarini Richerce: Current Employment. Binaschi:Menarini Ricerche: Current Employment. Laurent:Menarini Ricerche: Current Employment. Pellacani:Menarini Ricerche: Current Employment.

Description: Introduction: CRS is a potentially life-threatening toxicity observed following T cell-redirecting therapies. CRS is associated with elevated cytokines, including IL6, IFNγ, TNFα, IL2 and GM-CSF. Glucocorticosteroids (GC) and the IL6 receptor blocking antibody tocilizumab (TCZ) can reduce CRS severity; however, CRS may still occur and limit the therapeutic window of novel immunotherapeutic agents. Disruption of cytokine signaling via Janus kinase (JAK) pathway interference may represent a complementary approach to blocking CRS. Ruxolitinib (RUX), an oral JAK1/2 inhibitor approved for the treatment of myelofibrosis and polycythemia vera, interferes with signaling of several cytokines, including IFNγ and IL6, via blockade of the JAK/STAT pathway. We hypothesized that RUX may reduce the frequency and severity of CRS in R/R AML patients (pts) undergoing treatment with flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule. Methods: Relapse/refractory (including primary induction failure, early relapse and late relapse) AML pts were included in this study. RUX pts were treated at a single site, Washington University, St. Louis, MO. RUX was dosed at 10 mg or 20mg BID days -1 through 14. Comparator (non-RUX) pts (n=23) were treated at other clinical sites. FLZ was administered at 500 ng/kg/day continuously in 28-day cycles following multi-step lead-in dosing in week 1 of cycle 1. CRS was graded per Lee criteria1. Results: As of July 1st, 2020, 10 R/R AML pts, median age 65 (range 40-82) years, have been enrolled and treated in the RUX cohort (6 at 10mg, 4 at 20 mg of RUX). All pts had non-favorable risk by ELN 2017 criteria (8 adverse and 2 intermediate); 1 (10.0%) pt had secondary AML; pt characteristics in the RUX and non-RUX cohorts were balanced, except for median baseline BM blasts which was higher in non-RUX pts: 15% (range 5-72) vs (40% (range 7-84), RUX and non-RUX pts respectively. Cytokine analysis showed statistically significant (p

Description: Introduction. Approximately 40% of patients (pts) with newly diagnosed AML either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission (CR1 6 months), the probability of response for PIF/ER pts is particularly poor (~12%) with median expected overall survival of ~3.5 month and no approved therapy for this specific population. We have recently shown that increased immune infiltration of the tumor microenvironment (TME) is associated with induction failure and poor prognosis; conversely, an infiltrated TME predisposes for immunotherapy response1. We provide an update of the first-in-human study of flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule currently in clinical development for PIF/ER AML pts. Methods. In this phase of the study, PIF is defined as being refractory to induction with: ≥1 high-intensity cytarabine-based chemotherapy (CTx) cycles, or ≥2 but ≤4 Bcl-2 inhibitor-based combinations, or gemtuzumab ozogamicin only. ER is defined as relapse following CR1 〈 6 months. Pts who receive up to one prior salvage attempt are included. Pts whose AML recurred following HSCT are excluded. The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day administered as a continuous infusion in 28-day cycles following a step-up ('priming') lead-in dose during Cycle 1 Week 1. Disease status is assessed by modified IWG criteria. Duration of response is measured from initial response to relapse or death. Results. As of July 1, 2020, 38 PIF/ER (as defined above) AML patients have been treated at the RP2D (median age 63yrs [range 28-81]; 31.6% [12] pts female). Most pts (63.2%, 24/38) were PIF and the large majority (94.7%, 36/38) had non-favorable risk by ELN 2017 criteria (25 pts adverse, 11 pts intermediate); 34.2% (13/38) had secondary AML. For ER pts, median duration of CR1 was 2.9 months (range: 0.7-4.0 months). Cytokine release syndrome (CRS) was the most frequently reported treatment related adverse event (TRAE), with all pts experiencing mild-to-moderate (grade ≤ 2) CRS. No grade ≥ 3 CRS events have been reported in this cohort. Most CRS events (51.5%) occurred in the first week of treatment during step-up dosing. The incidence of CRS progressively decreased during dosing at RP2D (34.8% in week 2, 4.5% in week 3, and 6.1% in week 4), allowing outpatient treatment in most cases. Neurologic AEs have been infrequent, with the most prominent event being grade 1 or grade 2 headache in 23.7% (9/38) treated at the RP2D. Two pts experienced grade 3 confusion of short duration (1-2 days) that was fully reversible. Over half (57.9%) of pts had evidence of antileukemic activity (reduction in blast count) with a median decrease of 92.7% in BM blasts (Fig. 1). The overall complete response rate (CRR,

Description: Introduction Immunotherapy offers the promise of a new paradigm for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). CD123, the IL-3 receptor alpha-chain, represents an attractive target for antibody therapies because of its high expression on AML/MDS blasts and leukemic stem cells compared to normal hematopoietic stem and progenitor cells. APVO436, a novel bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule, depleted CD123+ cells in AML patient samples ex vivo (Godwin et al. ASH 2017), reduced leukemia engraftment in a systemic AML xenograft model (Comeau et al. AACR 2018), and transiently reduced peripheral CD123+ cells in non-human primates with minimal cytokine release and in a dose-dependent fashion (Comeau et al. AACR 2019). These data provide a basis for the clinical application of APVO436 as a treatment in AML and MDS. Here, we report preliminary data from a first-in-human dose-escalation study of APVO436 in patients with R/R AML and high-risk MDS. Study Design/Methods This ongoing Phase 1/1b study (ClinicalTrials.gov: NCT03647800) was initiated to determine the safety, immunogenicity, pharmacokinetics, pharmacodynamics, and clinical activity of APVO436 as a single agent. Major inclusion criteria were: R/R AML with no other standard treatment option available, R/R MDS with 〉 5% marrow blasts or any peripheral blasts and failure of a hypomethylating agent, ECOG performance status ≤ 2, life expectancy 〉 2 months, white blood cells ≤ 25,000 cells/mm3, creatinine ≤ 2 x upper limit of normal (ULN), INR and PTT 〈 1.5 x ULN and alanine aminotransferase 〈 3 x ULN. Patients were not restricted from treatment due to cytogenetic or mutational status. Intravenous doses of APVO436 were administered weekly for up to six 28-day cycles (24 doses) with the option to continue dosing for up to 36 total cycles (144 doses). Flat and step dosing regimens were escalated using a safety-driven modified 3 + 3 design. Pre-medication with diphenhydramine, acetaminophen, and dexamethasone was administered starting with dose 1 to mitigate infusion related reactions (IRR) and cytokine release syndrome (CRS). First doses and increasing step doses of APVO436 were infused over 20-24 hours followed by an observation period of 24 hours or more. Bone marrow biopsies were performed every other cycle with responses assessed by European Leukemia Net 2017 criteria for AML or International Working Group (IWG) 2006 criteria for MDS. Results The data cut-off for this interim analysis was July 9, 2020. Twenty-eight patients with primary R/R AML (n=19), therapy-related R/R AML (n=3), or high-risk MDS (n=6) have been enrolled and received a cumulative total of 186 doses. The number of doses received per patient ranged from 1 to 43 (mean of 6.4 doses). Most patients discontinued treatment due to progressive disease; however, blast reduction was achieved in 2 patients, with one patient with MDS maintaining a durable response for 11 cycles before progressing. APVO436 was tolerated across all dose regimens in all cohorts tested. The most common adverse events (AEs), regardless of causality, were edema (32%), diarrhea (29%), febrile neutropenia (29%), fever (25%), hypokalemia (25%), IRR (21%), CRS (18%), chills (18%), and fatigue (18%). AEs ≥ Grade 3 occurring in more than one patient were: febrile neutropenia (25%), anemia (18%), hyperglycemia (14%), decreased platelet count (11%), CRS (11%), IRR (7%), and hypertension (7%). After observing a single dose limiting toxicity (DLT) at a flat dose of 9 µg, step dosing was implemented and no DLTs have been observed thereafter. No treatment-related anti-drug antibodies (ADA) were observed. Transient serum cytokine elevations occurred after several reported IRR and CRS events, with IL-6 most consistently elevated. Conclusions Preliminary results indicate that APVO436 is tolerated in patients with R/R AML and MDS at the doses and schedules tested to date, with a manageable safety profile. Dose escalation continues and the results will be updated for this ongoing study. Disclosures Watts: BMS: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Lin:Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding; Celgene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mateon Therapeutics: Research Funding; Jazz: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding. Wang:Abbvie: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; PTC Therapeutics: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau. Mims:Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Agios: Consultancy; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Cull:Aptevo Therapeutics: Research Funding. Patel:Agios: Consultancy; Celgene: Consultancy, Speakers Bureau; DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria. Shami:Aptevo Therapeutics: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Cogle:Aptevo Therapeutics: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Chenault:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Macpherson:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chunyk:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. McMahan:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gross:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Stromatt:Aptevo Therapeutics: Current equity holder in publicly-traded company.

Description: Background: IMGN632 is a CD123-targeting ADC, comprised of a high affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. An ongoing Phase I trial in patients with CD123-positive AML or BPDCN (NCT03386513) has reported encouraging efficacy and manageable tolerability with IMGN632 monotherapy. Preclinical data from AML mouse models demonstrate synergy in combinations with azacitidine and/or venetoclax1,2, supporting the clinical exploration of these combinations. Here we describe the ongoing Phase 1b/2 study actively enrolling patients to determine the safety, tolerability, and preliminary anti-leukemia activity of IMGN632 when administered in combination with azacitidine and/or venetoclax to patients with relapsed and frontline CD123-positive AML, and the single-agent activity of IMGN632 in patients with minimal residual disease (MRD)-positive AML after frontline treatment. M ethods and s tudy d esign : Adult patients with CD123-positive relapsed or refractory (R/R) AML, who are deemed appropriate for experimental therapy, are eligible to enroll as part of the dose escalation phase. Key exclusion criteria for all regimens include active central nervous system disease, and history of sinusoidal obstruction syndrome/venous occlusive disease of the liver. Three different combination regimens are being evaluated: Regimen A, IMGN632 plus azacitidine (632+AZA); Regimen B, IMGN632 plus venetoclax (632+VEN); and Regimen C, IMGN632 plus azacitidine and venetoclax (632+AZA+VEN). For each regimen, a Phase 1b dose escalation cohort in R/R patients will determine the recommended Phase 2 dose (RP2D) of IMGN632 for the specific combination. Escalation will follow a standard 3+3 design, with a starting dose for IMGN632 of 0.015 mg/kg administered intravenously on Day 7 of a 21- (632+VEN) or 28-day cycle (632+AZA, 632+AZA+VEN). Regimens A and B (the doublets) were initially explored to evaluate safety at increasing doses of IMGN632. Escalation of IMGN632 on Regimen C (the triplet) was allowed once the corresponding dose of IMGN632 was evaluated in each doublet combination (Figure). This will be followed by a Phase 2 dose expansion stage to further characterize the safety profile and assess antileukemia activity in frontline or relapsed AML patients, depending on the combination regimen. In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD-positivity to MRD-negativity, in fit and unfit AML subpopulations. NCT04086264 Figure Disclosures Daver: Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet:Incyte: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Stemline: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Montesinos:Celgene, Pfizer, Abbvie: Consultancy; Pfizer, Abbvie, Daiichi Sankyo: Research Funding; Astellas, Novartis, Janssen: Speakers Bureau. Wang:Genentech: Consultancy; PTC Therapeutics: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Stemline: Speakers Bureau; Astellas: Consultancy; Macrogenics: Consultancy. Aribi:Seattle Genetics: Consultancy. DeAngelo:Jazz: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Incyte Corporation: Consultancy; Forty-Seven: Consultancy; Glycomimetics: Research Funding; Autolos: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Takeda: Consultancy. Walter:Pfizer: Consultancy, Research Funding; Macrogenics: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Celgene: Consultancy, Research Funding; StemLine: Research Funding; BioLineRx: Consultancy, Research Funding; Genentech: Consultancy; Seattle Genetics: Research Funding; New Link Genetics: Consultancy; Agios: Consultancy, Research Funding; BiVictriX: Consultancy; Boston Biomedical: Consultancy; Amphivena: Current equity holder in publicly-traded company; Aptevo: Consultancy, Research Funding; Argenx: Consultancy; Arog: Research Funding; Astellas: Consultancy; Daiichi: Consultancy; Race Oncology: Consultancy; Kite: Consultancy; Selvita: Research Funding. Altman:Biosight: Research Funding; PrIME Oncology: Consultancy; France Foundation: Consultancy; PeerView: Consultancy; Fujifilm: Research Funding; Kartos: Research Funding; Celgene: Research Funding; ASH: Consultancy; Bristol-Myers Squibb: Consultancy; Immune Pharma: Consultancy; Janssen: Consultancy; Syros: Consultancy; Novartis: Consultancy; Genentech: Research Funding; Amphivena: Research Funding; Aprea: Research Funding; Amgen: Research Funding; ImmunoGen: Research Funding; Boehringer Ingelheim: Research Funding; Kura: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Other: DSMC; Daiichi Sanko: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cancer Expert Now: Consultancy. Advani:Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Abbvie: Research Funding; Takeda: Research Funding; OBI: Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding. Sloss:ImmunoGen, Inc.: Current Employment. Malcolm:ImmunoGen, Inc.: Current Employment. Zweidler-McKay:ImmunoGen, Inc.: Current Employment. OffLabel Disclosure: Phase 1b/2 trial of experimental therapy

Description: Introduction: Somatic TP53 mutations and deletions of 17p, to which TP53 is mapped, (TP53mut) occur in 8-10% of de novo Acute myeloid leukemia (AML) and in up to 37-46% of patients (pts) with adverse-risk cytogenetics and treatment-related myeloid neoplasms and confer a poor prognosis. In addition to its well-characterized function as a tumor suppressor, emerging evidence implicates mutant TP53 in activating genes involved in immune response and inflammation such as chemokines, cytokines and extracellular matrix modulators. An analysis of The Cancer Genome Atlas (TCGA) transcriptomic data showed that TP53 mutations, in 30 diverse cancer types, correlated with increased leukocyte infiltration into tumors with higher proportions of PD-L1-expressing CD8+ T cells and increased expression of T-cell effector genes and interferon (IFN)-γ-related genes. We recently characterized tumor microenvironmental (TME) immune gene sets that capture elements of both type I- and IFN-γ-driven biology and stratify AML into immune-infiltrated and immune-depleted subtypes. Our immune classifier predicted survival in patients receiving cytarabine-based induction and immunotherapy with flotetuzumab (FLZ), an investigational CD123×CD3 bispecific DART® molecule. We hypothesized that TP53-mutated AML represents immune-infiltrated AML that would be particularly responsive to FLZ. Methods: Fifteen TP53mut AML pts have been treated with FLZ on clinical trial CP-MGD006-01 (NCT#02152956). Disease status was assessed by modified International Working Group (IWG) criteria. Specifically, overall response rate (ORR), collectively complete response, defined as 50% decrease or decrease to 5-25% BM blasts. Microenvironmental RNAs were profiled using the PanCancer IO 360™ gene expression panel on the nCounter® platform. Baseline formalin-fixed paraffin embedded BM samples were evaluated for PD-L1, FoxP3, CD8 and CD3 expression by immunohistochemistry (IHC). Slides were stained using a Leica BondRx autostainer. Fluorescence was imaged using a Polaris Vectra 3 and analyzed using inForm software. A density-based clustering algorithm developed and run in QuPath was used to quantify T-cell 'hotspots". Results: Baseline (BL) BM samples for immune gene expression profiling were available in 13 pts with TP53mut (median age 61yrs [range 27-81]; 46.7% [7] pts female); among these, 77% (10/13) had high or intermediate immune infiltration in the TME compared with pts with 33% (10/30) TP53-WT AML (pt characteristics in the TP53-WT AML cohort were balanced) (Fig. 1A). IHC analysis confirmed high CD8+ T-cell, regulatory T cell (Treg) and PD-L1+ cell infiltration in TP53mut BL BM samples (Fig. 1B). ORR was 60% (9/15), with 47% (7/15) achieving complete response. In the TP53mut subgroup, the reduction of BM blasts relative to baseline averaged 51.2% (Fig. 1C). Time on treatment and time to death and/or censoring are summarized in Fig. 1D, including three pts who proceeded to receive allogeneic hematopoietic stem cell transplantation (HSCT). In pts who achieved a complete remission (CR, CRi), median OS was 10.3 months. Furthermore, the tumor inflammation signature (TIS), inflammatory chemokine, Treg and IFN-γ gene expression scores were significantly higher at baseline in pts with complete remission compared with non-responders (Fig. 1E), highlighting the association between response to T-cell engagers and a T cell-infiltrated TME. Conclusion: TP53 mutated AML is associated with immune infiltration in the TME and FLZ immunotherapy demonstrated activity in pts with TP53 alterations. This suggests that FLZ immunotherapy may alleviate the negative prognostic immunological impact of TP53 mutation. Figure 1 Disclosures Lai: Abbvie: Consultancy; Agios: Consultancy; Macrogenics: Consultancy; Astellas: Speakers Bureau; Jazz: Speakers Bureau. Church:NanoString Technologies, Inc.: Current Employment. Advani:Novartis: Consultancy, Other: advisory board; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; OBI: Research Funding; Takeda: Research Funding. Wieduwilt:Macrogeneics: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Merck: Research Funding; Leadiant: Research Funding; Amgen: Research Funding. Arellano:Hanmi: Research Funding; Cephalon Oncology: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Uy:Pfizer: Consultancy; Agios: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria. Ravandi:Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Foster:Bellicum Pharmaceuticals: Research Funding; Daiichi Sankyo: Consultancy; Macrogenics: Consultancy, Research Funding. Stiff:Atara: Research Funding; Delta-Fly: Research Funding; Kite, a Gilead Company: Research Funding; Amgen: Research Funding; Unum: Research Funding; Gamida Cell: Research Funding; Macrogenics: Research Funding. Emadi:NewLink Genetics: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; Jazz Pharmaceuticals: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Tran:MacroGenics: Current Employment. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Guo:Macrogenics: Current Employment. Gojo:Genentech: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Amphivena: Research Funding; Amgen: Research Funding; Merck: Research Funding. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Davidson-Moncada:Macrogenics: Current Employment. Rutella:MacroGenics, Inc.: Research Funding; NanoString Technologies, Inc.: Research Funding; Kura Oncology: Research Funding.

Description: The histone-lysine-N-methyltransferase 2A (KMT2A) gene (formerly known as mixed-lineage leukemia (MLL)) plays an essential role in regulating gene expression including homeobox (HOX) and MEIS1 genes. In 5-10% of AML cases, specific KMT2A gene perturbations can occur which result in an aggressive and poor prognostic group of blood cancers. The KMT2A complex also appears to play a central role in the epigenetic dysregulation in AMLs with co-mutations such as NPM1, IDH1/2, EZH2, and DNMT3A. Therefore, there is strong rationale for targeting these AML subsets which may be exquisitely sensitive to inhibition of the menin-KMT2A chromatin complex. KO-539 is a novel, once daily, oral investigational drug candidate targeting the menin-KMT2A protein-protein interaction. KOMET-001 (NCT04067336) is an ongoing Phase 1/2A open-label study evaluating KO-539 in adult patients (pts) with relapsed and/or refractory AML agnostic to oncogenic mutational type. The Phase 1 dose-escalation objectives are to assess safety and tolerability, characterize the pharmacokinetics (PK), and determine a recommended Phase 2 dose. The Phase 2A dose expansion portion will assess anti-leukemic activity, PK, safety and tolerability in select genetic subtypes of AML. Preclinically, the drug is shown to be highly protein bound (〉99%) across animal species. Using physiologically-based PK (PBPK) modeling, the estimated human efficacious dose was estimated to be 600 mg po qd. As of data cutoff on August 10, 2020, 6 pts with relapsed and/or refractory AML have been enrolled in the trial. Dose escalation began with single pt cohorts at 50 mg po qd in 28 day cycles and has proceeded through to 200 mg dosing cohorts. An expansion of 3 pts at 200 mg was initiated to better characterize the PK and exposure of KO-539. To date, 3 enrolled pts have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28 day DLT-assessment window. Grade 3 (G3) or higher drug related adverse events have included G3 tumor lysis syndrome (TLS) at 50 mg and a G3 embolic event at 100 mg. KO-539 has been well tolerated with no dose interruptions or discontinuations due to drug related adverse events. There were no treatment-related deaths, and two pts discontinued treatment due to disease progression. Peak drug concentrations were attained between 2-3 hours after daily oral dosing with an elimination half-life of greater than 24 hours. KO-539 has demonstrated evidence of biologic activity in pts in the first 3 dose levels treated to date. The 50 mg pt with a KMT2A-r and the 200 mg pt with a p53 mutation and PICALM-AF10 fusion exhibited evidence of tumor lysis syndrome and markedly decreased hydroxyurea requirements with blood count stabilization, respectively. A third pt (100 mg dose level) with SETD2 and RUNX1 co-mutations achieved a complete remission with confirmed negative MRD by flow cytometry after two cycles of therapy and continues on treatment. The biologic activity of KO-539 at lower doses may be explained by inhibition of the CYP3A4 enzyme by concomitantly administered azole antifungals. KO-539 is metabolized into at least two metabolites with comparable activity to KO-539; total drug concentrations (i.e., KO-539 plus active metabolites) exhibited a dose-dependent increase. Although KO-539 is a CYP3A4 substrate, preclinical data suggest both KO-539 and its metabolites act as inhibitors, potentially providing an advantage in overcoming drug resistance attributable to CYP3A4 metabolism by bone marrow stroma. The physiology of the bone marrow sinusoids also allows both unbound and protein-bound drug to reach the sites of leukemic involvement. The high level of protein binding may therefore provide an opportunity for organ-specific targeted action while possibly limiting off target effects. The potential advantage associated with the CYP3A4 inhibitory characteristics of KO-539 to overcome drug-resistance in the bone marrow stroma also continues to be investigated. In conclusion, the early biologic activity of KO-539 in relapsed AML is encouraging, and its unique PK characteristics may be advantageous for clinical benefit. In addition to the above, any updated safety, PK, and efficacy data will be presented at the time of the conference. Disclosures Wang: Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy. Altman:BioSight: Other: No payment but was reimbursed for travel , Research Funding; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Kartos: Research Funding; Fujifilm: Research Funding; France Foundation: Consultancy; PrIME Oncology: Consultancy; Novartis: Consultancy; Theradex: Other: Advisory Board; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Janssen: Consultancy; ASH: Consultancy; Amphivena: Research Funding; Immune Pharmaceuticals: Consultancy; Syros: Consultancy; Amgen: Research Funding; ImmunoGen: Research Funding; Genentech: Research Funding; Aprea: Research Funding; AbbVie: Other: advisory board, Research Funding; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Cancer Expert Now: Consultancy; PeerView: Consultancy. Pettit:PharmaEssentia: Other: advisory board; Kura Oncology: Other: advisory board; CTI Biopharma: Other: advisory board. Walter:Kite: Consultancy; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; Macrogenics: Research Funding; New Link Genetics: Consultancy; Selvita: Research Funding; Seattle Genetics: Research Funding; StemLine: Research Funding; Agios: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Genentech: Consultancy; Arog: Research Funding; Argenx: Consultancy; Amphivena: Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding. Fenaux:Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Burrows:Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Tomkinson:Kura Oncology: Current Employment. Martell:Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Fathi:Daiichi Sankyo: Consultancy; Amphivena: Consultancy, Honoraria; Astellas: Consultancy; Celgene: Consultancy, Research Funding; PTC Therapeutics: Consultancy; TrovaGene: Consultancy; Takeda: Consultancy; Kura: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Novartis: Consultancy; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria.