Preparing for ASH 2023: Heme-oncology research & abstracts

Our research oncology experts are looking forward to the 65^th American Society of Hematology (ASH) Annual Meeting and Exposition. As we prepare for the data and abstracts to be presented, we’re sharing some spotlights to help support our clients and partners navigate the meeting.

Latest research in heme-oncology to be presented

The upcoming 65^th ASH Meeting will showcase exciting new data from several novel and first-in-class assets and other major updates from pathbreaking clinical trials and preclinical research of the promising therapeutic agents. Some of the noteworthy innovative potential new therapy classes to be featured at ASH will include target protein degraders (TPDs), menin inhibitors, allogeneic CAR T-cell therapies, and trispecific antibodies across hematological malignancies.

Target protein degraders (TPDs):
Recently, TPDs have surfaced as a novel, promising therapeutic modality with a potential to meet the needs of underserved patients in both heme malignancies and solid tumors. TPDs have the potential to aim at the undruggable targets and high-value proteins such as BTK, BCL6, Cereblon, STAT3, etc. In the last few years, advances have been made in conventional PROTACs (Proteolysis-Targeting Chimeras) technology from the pioneers like Arvinas to next-generation degradation platforms such as Biotheryx’s PRODEGY platform and Dialectic’s APTaD platform. Kymera Therapeutics, Nurix Therapeutics, BMS, and AbbVie are the leading companies who have brought protein degraders to preclinical and clinical development phases.

The key abstracts/presentations on TPDs to include:

• BMS will highlight the efficacy and safety outcomes of its early-stage oral cereblon E3 ligase modulators (CELMoD) – iberdomide, golcadomide, and mezigdomide, which may likely emerge as potential new treatment approaches for R/R multiple myeloma. [Abstract#208; #4496; #1013]
• Kymera Therapeutics will feature the updated clinical data from phase 1 study of a STAT3 degrader, KT-333 intravenously dosed weekly in relapsed/refractory patients with lymphomas, leukemias, and solid tumors. The early signs of potent anti-tumor activity of KT-333 seen in acute myeloid leukemia (AML) patient samples can lead to a potential effective strategy for venetoclax-resistant AML. [Abstract#3081]
• Nurix Therapeutics will showcase the latest data for the two BTK degraders- NX-2127 and NX-5948, demonstrating phase 1 results in heavily pre-treated R/R CLL and NHL patients who have acquired resistance to both covalent and non-covalent BTK inhibitors. [Abstract#4463; #4473]
• AbbVie, Dialectic Therapeutics and Remix Therapeutics have disclosed the initial preclinical activity of their pipeline assets- BTK degrader (ABBV-101), BCL-XL degrader (DT-2216), and c-MYB mRNA degrader (REM-422), across lymphoma and leukemia models. [Abstract#1187; #4154; #1425]

Menin inhibitors:
In recent years, menin has emerged as a potentially important target in leukemias and several assets are targeting the menin-KMT2A interaction, thus promoting the differentiation of leukemic immature blasts. Several notable early to late-stage asset candidates are in pipeline such as revumenib, ziftomenib, DSP-5336, DS-1594, JNJ-75276617, and BMF-21, mostly tested in acute leukemia patients with menin–histone-lysine N-methyltransferase 2A (KMT2Ar) and/or nucleophosmin (NPM1)-mutations.

The key abstracts/presentations on menin inhibitors to include:

• Syndax Pharma’s Revumenib is ahead in the race of developing menin inhibitors in AML space, with an expected new drug application (NDA) filing for revumenib in the end of 2023.
  – The follow-up data from the phase 1 portion of revumenib’s phase 1/2 pivotal trial (AUGMENT-101) in R/R KMT2Ar AML will be featured at ASH. [Abstract#2907]
• Sumitomo Pharma will present the preliminary efficacy and safety data from a phase 1/2 study of DSP-5336, reporting the promising early signs of clinical activity in R/R KMT2Ar/NPM1-mut AML patients. [Abstract#2911]
  – Sumitomo aims to initiate the pivotal study of DSP-5336 monotherapy in the first half of 2024, aiming for potential FDA approval in 2026 and potential Japan approval in 2027.
• Biomea Fusion will highlight the phase 1 data from cohort 1 of the COVALENT-101 study of covalent menin inhibitor, BMF-219 investigating R/R AML and acute lymphoblastic leukemia (ALL) patients. [Abstract#2916]
• Kura’s lead product, ziftomenib has as expanded strategy to initiate phase 1 KOMET-008 study evaluating ziftomenib combinations with standard-of-care (SoC) regimens for treating AML The trial design will be presented at ASH 2023. [Abstract#1553]
• Janssen’s menin inhibitor, JNJ-75276617 will have an oral presentation from dose-escalation part of phase 1 study in R/R AML patients harboring KMT2A or NPM1 alterations. Additionally, preclinical efficacy of doublet or triplet combination of JNJ-75276617 with AML-directed therapies such as venetoclax and azacitidine in KMT2A- or NPM1-altered AML models will be reported. [Abstract#57; #4167]
• Daiichi Sankyo will present the preclinical evidence of in vivo effectiveness of DS-1594b in combination with venetoclax in a PDX model of NPM1-mutated AML, thus supporting the phase 1 study of the combination for treatment of R/R AML and ALL patients. [Abstract#4169]

Allogeneic CAR T-cell therapy:
Autologous CAR T-cell therapies have gained significant traction given the profound anti-tumor activity in hard-to-treat hematological malignancies. Apparently, they pose barriers to uptake like multiple logistical issues such as long manufacturing time, the need for bridging therapy in progressing patients, antigen escape, reduced persistence of CAR T-cells, and viability concerns of T-cells in late-lines. The new wave of “off-the-shelf” allogeneic therapies can offer compelling advantages over auto CAR-Ts such as quick availability, shorter vein-to-vein time, bridging therapy sparing, and more. However, efficacy and long-term side effects still need to be validated. Numerous pharma and start-up biotech companies are focusing on developing novel allogeneic and universal CAR-T cell therapies.

The key abstracts/presentations on allogeneic CAR T-cell therapies to include:

• Poseida Therapeutics will showcase the updated efficacy and safety outcomes from a phase 1 study of P-BCMA-ALLO1, a non-viral transposon-generated cell therapy. [Abstract#3479]
• Cellectis will present preliminary results of the phase 1/2a NATHALI-01 trial evaluating UCART20x22, dual CAR-T cells for treatment of patients with R/R NHL. Cellectis will also provide updated results of phase 1 BALLI-01 study investigating CD22-directed allogeneic CAR-T cells, UCART22 in patients with R/R CD22+ B-cell ALL. [Abstract#2110; #4847]
• Wugen will highlight the preliminary efficacy and safety data from the phase 1/2 trial of WU-CART-007, a CD7-directed allogeneic CAR-T cell therapy treating R/R T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (LBL). The FDA has granted fast-track designation for the treatment of R/R T-ALL/LBL. [Abstract#770]
• Adicet Bio’s ADI-001 will report the outcomes of the phase 1 study of dose-dependent cell expansion and persistence of allogeneic CAR γδ T-cell therapy for R/R NHL patients. Based on meaningful clinical data, the company plans to initiate pivotal phase 2 study in post CAR-T LBCL and MCL patients. [Abstract#3478]

Trispecific antibodies (TsAbs):
A novel ‘‘trispecific’’ antibody approach is being explored for hematological malignancies. The trispecific antibodies are engineered to bind to two different antigens/epitopes on tumor cells along with T-cells, potentially enhancing broader antigen coverage, promoting tumor binding, and preventing resistance or relapse via TAA escape to maximize tumor eradication. It is perceived to be more efficacious and potent, with more sustained anti-tumor responses than recently approved bispecifics. Several trispecific antibodies are under pre-clinical or clinical evaluation to treat lymphomas, NHL, PTCL, MM, AML, and ALL. Therapeutic advancements are expected from conventional bispecifics antibodies technology to trispecific platforms, such as Ichnos’ TREAT platform and Harpoon’s TriTAC-Tri-specific T-Cell Activating Construct platform. Janssen, Harpoon, Novartis, Sanofi, and Ichnos are some of the key companies with TsAbs in the pipeline.

The key abstracts/presentations will include:

• Discussion of several promising trispecifics in the pipeline for multiple myeloma
  – Janssen is evaluating JNJ-79635322 (BCMA x GPRC5D x CD3 T-cell redirecting trispecific antibody) in a phase 1 dose-escalating study in R/R MM. The preclinical study demonstrated the potent cytotoxicity in various myeloma cell lines in vitro and anti-tumor activity in murine MM xenograft prevention model and tumor regression models. [Abstract#456]
  – Harpoon will report robust and durable clinical responses with manageable adverse event of HPN217 (BCMA x anti-albumin x CD3 trispecific) in a phase 1 study in R/R MM. MTD was not reached in step dose cohorts. [Abstract#1012]
  – Ichnos will present its trial design for ISB 2001 in R/R MM, the first in-human phase 1 study assessing dose escalation and dose expansion for safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of its first-in-class BCMA x CD38 x CD3 trispecific Earlier, the pre-clinical study showed improved anti-tumor activity compared to other BCMA or CD38-targeted molecules either as a monotherapy or in combination across different MM models. [Abstract#3396]
  – Sanofi’s SAR442257 targeting CD38 x CD28 x CD3 is in phase I clinical development for R/R MM and NHL. Its preclinical efficacy reporting reduction in CD38 levels in MMPC and impaired cytotoxic activity of NK cells in R/R MM patients will be presented. [Abstract#1921]
• Sanofi will present the preclinical data of SAR442257 (CD38 x CD3 x CD28 trispecific antibody) that led to efficient killing of malignant PTCL cell lines along with effective T-cell activation seen as induction of CD25 and CD69 expression on normal T-cells. [Abstract#4384]
• Sanofi will also report SAR442257’s therapeutic potential and preclinical data of exerting its anti-tumor efficacy regardless of CD38 density in AML. [Abstract#4178]
• Novartis will present anti-CD3 x CD19 x CD2 trispecific antibody PIT565’s phase 1 open-label, multi-center study design in heavily treated R/R NHL (including LBCL) and ALL. The study will assess safety, including dose-limiting toxicities and tolerability, and identify the MTD and/or recommended dose (RD), schedule, and route of administration. The prior preclinical studies showed more potent and sustained anti-tumor T-cell responses of PIT565 compared to CD3 bispecifics.
  [Abstract#3099]

Featured key abstracts in DLBCL and myelofibrosis

The conference will focus on the most cutting-edge science in heme-oncology, covering a range of topics on the management of rapidly evolving large B-cell lymphomas (LBCL), diffuse large B-cell lymphoma (DLBCL), and myelofibrosis (MF). Multiple treatment abstracts will provide the key updates on the clinical outcomes of current and emerging modalities including small molecules, antibody drug conjugates (ADCs), CAR-T cell products, bispecific and trispecific therapies, and many novel combinations that can offer effective therapeutic options across diseases especially for underserved patients.

Key abstracts to watch out for: DLBCL
In recent years, the DLBCL therapeutic landscape has witnessed a considerable shift with the advent of approvals of CAR T-cell therapy and bispecific monoclonal antibody (mAb) treatment. This year’s ASH conference will provide a glimpse into the ever-changing treatment landscape of DLBCL across clinical settings of frontline and relapsed/refractory (R/R).

• Frontline DLBCL: Once called invincible, the frontline DLBCL treatment is now opening up to add novel SOCs beyond R-CHOP. Recently, Pola-R-CHP joined the armamentaria of 1L DLBCL management. Among the ASH’s key updates in 1L DLBCL, the promising clinical data from CD20 x CD3 bispecific mAbs – epcoritamab, glofitamab, and mosunetuzumab will be seen, especially in elderly, unfit/frail patients.

The key abstracts/presentations will include:

– Roche will feature the clinical data of its early-phase study of the chemotherapy-free combination of mosunetuzumab and polatuzumab (M-Pola) that demonstrated preliminary efficacy in previously untreated DLBCL in elderly unfit/frail 1L patients. Data of durable responses of the glofitamab and R-CHOP combination will be reported exploring the frontline [Abstract#855, #3085]
– AbbVie/Genmab will report the initial data from arm: 8 of EPCORE NHL-2 study evaluating epcoritamab in combination with R-mini-CHOP in previously untreated patients ineligible for full-dose R-CHOP. [Abstract#4457]

• Relapsed/refractory DLBCL: Treatment options in the R/R setting have been rapidly evolving given the recent approvals of mAbs, ADCs, CAR-Ts, and bispecifics with or without current SoCs. The new compelling data from a few novel key products to be presented at ASH 2023 suggest that these agents are moving to earlier lines that will shift the overall treatment paradigm in 2L and above. One of the focus areas in R/R LBCL at ASH 2023 is in hard-to-treat patients who progressed after or were ineligible for ASCT and/or CAR-T cell therapy.

The key abstracts/presentations will include:

– Roche will showcase the durable CR rates in patients with prior CAR T-cell therapy from the extended follow-up data of glofitamab monotherapy in a subgroup analysis of the pivotal study with prior CAR-T experienced R/R LBCL patients. [Abstract#433]
– AbbVie/Genmab will report the high CMR rates from epcoritamab with gemcitabine and oxaliplatin (GemOx) combination in 2L DLBCL patients who are ineligible for transplant. [Abstract#3092]
– Regeneron will present the final analysis data of odronextamab from pivotal ELM-2 trial testing heavily pretreated DLBCL patients including high-risk patients and patients who have relapsed following CAR-T cell therapy. The company has submitted a biologics license application and received a FDA’s target action date of March 31, 2024. [Abstract#436]
– Merck will report the updated outcomes of the anti-ROR1 ADC candidate, zilovertamab vedotin with clinically meaningful anti-tumor activity from the phase 2 Waveline-004 study evaluating heavily pretreated R/R DLBCL patients who progressed after or are ineligible for transplant and CAR T-cell therapy. [Abstract#1720]

Key abstracts to watch out for: Myelofibrosis (MF)
JAK inhibitor (JAKi) ruxolitinib has been the cornerstone for the treatment of MF for over a decade, along with other JAK inhibitors, fedratinib and pacritinib. Recent approval of momelotinib (JAK1/2 and ACVR1 inhibitor) made a significant addition to the MF treatment guidelines in patients with anemia. However, significant unmet need still exists for second- or third-line patients who progress or are intolerant to JAKi. An effort to move beyond the single agent JAKi is ongoing and ASH 2023 will highlight the latest clinical findings from novel combinations and therapeutic agents such as pelabresib (BET inhibitor), BMS-986158 (BET inhibitor), navitoclax (BCL2 inhibitor), zilurgisertib (ALK2 inhibitor), and TP-3654 (PIM1 kinase inhibitor) across different treatment settings of MF.

The key abstracts/presentations will include:

• GSK will feature momelotinib data showing high SVR, TI, and TSS response rates from a subgroup analysis of the phase 3 SIMPLIFY-2 study in MF patients who required blood transfusions. The data led to its recent approval across MF. [Abstract#3189]
• Morphosys’ lead asset, pelabresib is being evaluated in combination with ruxolitinib in the phase 3 MANIFEST-2 study in frontline JAKi-naïve MF. The company will report the primary analysis outcomes of Pela+Rux, that has shown significant clinical activity and disease-modifying potential without typical treatment-limiting toxicity. [Abstract#628]
• BMS’s BMS-986158 is another emerging BET inhibitor in the pipeline. BMS-986158 in combination with ruxolitinib or fedratinib is a potential treatment for patients with intermediate- or high-risk MF. The updated result from a phase 1/2 CA011-023 study of BMS-986158 combination will be highlighted at ASH; the study showed early and deep SVR by week 12, which continued and deepened at week 24 and beyond. [Abstract#623]
• AbbVie will present the anti-tumor activity data from a phase 3 TRANSFORM-1 study of navitoclax combination with ruxolitinib, leading to durable responses and impressive SVR_35W24 versus ruxolitinib alone in JAKi-naïve MF. [Abstract#620]
• Incyte’s oral presentation will highlight the efficacy and safety outcomes of zilurgisertib, being studied as monotherapy and in combination with ruxolitinib in a phase 1/2 LIMBER-104 study for MF patients with anemia. The study showed reduced hepcidin (which otherwise leads to functional iron deficiency anemia), and improvement in anemia in non-transfusion-dependent MF. [Abstract#624]
• Sumitomo Pharma will present the preliminary data of its pipeline candidate, TP-3654, a PIM1 kinase inhibitor from a phase 1/2 study exploring R/R myelofibrosis that showed cytokine reduction, SVR, and TSS improvement. [Abstract #626]

We look forward to seeing you at ASH and the learnings we will gather following. Please contact us to learn more about our therapeutic area expertise and how we can help support your next innovation.