Abstract: Background: Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that is currently being evaluated as a targeted therapy for the treatment of t(11;14) relapsed/refractory multiple myeloma (RRMM). The combination of Ven with daratumumab (D) and dexamethasone (d) has shown promising efficacy with a tolerable safety profile in the phase 1/2 study (NCT03314181). VenDd is hypothesized to have increased anti-myeloma activity based upon complementary mechanisms of pro-apoptotic effects on tumor cells as well as potentially enhanced T-cell activation and clonal expansion, which has been shown to be associated with achieving deep sustained response to D-based therapy in MM. Results presented herein describe the immunomodulatory effects observed upon VenDd treatment in t(11;14) RRMM patients, including effects on the T-cell repertoire. Methods: Peripheral blood samples from t(11;14) RRMM patients (n=18) treated with VenDd (NCT03314181) were collected at day 1 of cycles 1-5 to characterize effects on B-, T-, and NK-cell populations by multicolor flow cytometry. TCRβ sequencing (ImmunoSEQ, Adaptive Biotechnologies) was also conducted on peripheral blood samples collected from t(11;14) RRMM patients (n=31) treated with VenDd at day 1 of cycles 1, 3, 5, and 9 to assess changes in T-cell clonality, defined as the extent of mono- or oligoclonal expansion by Simpson clonality index, and T-cell richness, defined as the number of clones with unique TCRβ rearrangements after computationally down-sampling to a common number of T-cells. Results: Consistent with previous findings with Ven, rapid and sustained depletion of B-cells (CD19+/CD5-) was observed in patients treated with VenDd (median absolute count: 115 cells/ml at baseline vs 13 cells/ml at C2D1 (89% decrease), p & lt;0.0001; vs 4 cells/ml at C5D1 (97% decrease), p & lt;0.01). Significant reduction in NK cells (CD16+/CD56+) was also observed upon VenDd treatment (median absolute count: 179 cells/ml at baseline vs 30 cells/ml at C2D1 (83% decrease), p & lt;0.0001; vs 16 cells/ml at C5D1 (91% decrease), p & lt;0.01), which is consistent with previous results with D-containing regimens. Within the circulating T-cell population, a significant and sustained decrease in CD4+ T-cells (median absolute count: 421 cells/ml at baseline vs 251 cells/ml at C2D1 (40% reduction), p & lt;0.0001; vs 211 cells/ml at C5D1 (50% reduction), p & lt;0.01) was observed, with naïve and central memory CD4+ T-cells being more sensitive than effector memory T-cells (median absolute count: 61 cells/ml at baseline vs 34 cells/ml (45% reduction) at C3D1, p & lt;0.01; 162 cells/ml at baseline vs 79 cells/ml (51% reduction) at C3D1, p & lt;0.001; 151 cells/ml at baseline vs 120 cells/ml (21% reduction) at C3D1, p & lt;0.01; respectively). A rapid and sustained decrease in immunosuppressive regulatory T-cells (CD4+/CD25 hi/CD127 dim) was observed in VenDd treated patients (median absolute count: 42 cells/ml at baseline vs 18 cells/ml at C2D1 (56% reduction), p & lt;0.0001; vs 15 cells/ml at C5D1 (63% reduction), p & lt;0.01). In contrast to the CD4+ T-cell subsets, a transient decrease in CD8+ T-cells was observed at C2D1 (median absolute count: 333 cells/ml at baseline vs 259 cells/ml at C2D1 (22% reduction), p & lt;0.001) with levels returning to near-baseline by C3D1, including effector memory CD8+ T-cells. TCR-sequencing revealed a significant increase in T-cell clonality upon treatment with VenDd (Figure 1A). A significant decrease in T-cell richness was observed (Figure 1B), indicating a focusing of the T-cell repertoire. The observed increases in T-cell clonality upon VenDd treatment were due to expansion of both newly detected clones and clones that were present at baseline (Figure 1C). Finally, the immunomodulatory effects of VenDd described herein were consistent between the Ven dose cohorts (400 and 800mg). Conclusions: Treatment of t(11;14) RRMM patients with VenDd resulted in selective depletion of B-cells, NK-cells, and immunosuppressive regulatory T-cells, but not CD8+ T-cell subsets. Increased T-cell clonality indicates focusing of the T-cell repertoire and generation of an adaptive anti-myeloma immune response upon treatment with VenDd. The study is continuing with a randomized, open-label expansion that will further evaluate the safety and efficacy of VenDd in patients with t(11;14) RRMM, including correlative studies between the observed immune modifications and patient outcome. Figure 1 Figure 1. Disclosures Bahlis: Genentech: Consultancy; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kaufman: Fortis Therapeutics: Research Funding; Sutro, Takeda: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Heidelberg Pharma: Research Funding; BMS: Consultancy, Research Funding; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tecnofarma SAS, AbbVie: Honoraria; Amgen: Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Baz: BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding; Merck: Research Funding; GlaxoSmithKline: Consultancy, Honoraria; Oncopeptides: Consultancy. Quach: Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner: Genmab, Genentech, Roche: Research Funding; Janssen, Celgene, Takeda, Oncopeptides, AbbVie: Consultancy, Research Funding. Moreau: Celgene BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Luo: AbbVie: Current Employment, Current equity holder in publicly-traded company. Mantis: AbbVie: Current Employment, Current equity holder in publicly-traded company. Vishwamitra: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Harrison: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that is being investigated as therapy for the treatment of relapsed/refractory multiple myeloma.

Abstract: Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-XL/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-XL without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients & lt;45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population. Significance: In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histologic and genomic subtypes and in those who failed available therapies including stem cell transplant. See related commentary by Larkin and Byrd, p. 1324. This article is highlighted in the In This Issue feature, p. 1307

Abstract: Hepatocellular carcinoma (HCC) is an aggressive neoplasm with poor clinical outcome because most patients present at an advanced stage, at which point curative surgical options, such as tumor excision or liver transplantation, are not feasible. Therefore, the majority of HCC patients require systemic therapy. Nonetheless, the currently approved systemic therapies have limited effects, particularly in patients with advanced and resistant disease. Hence, there is a critical need to identify new molecular targets and effective systemic therapies to improve HCC outcome. The liver is a major target of the growth hormone receptor (GHR) signaling, and accumulating evidence suggests that GHR signaling plays an important role in HCC pathogenesis. We tested the hypothesis that GHR could represent a potential therapeutic target in this aggressive neoplasm. We measured GH levels in 767 HCC patients and 200 healthy controls, and then carried out clinicopathological correlation analyses. Moreover, specific inhibition of GHR was performed in vitro using siRNA and pegvisomant (a small peptide that blocks GHR signaling and is currently approved by the FDA to treat acromegaly) and in vivo , also using pegvisomant. GH was significantly elevated in 49.5% of HCC patients, and these patients had a more aggressive disease and poorer clinical outcome (P & lt;0.0001). Blockade of GHR signaling with siRNA or pegvisomant induced substantial inhibitory cellular effects in vitro. In addition, pegvisomant potentiated the effects of sorafenib (P & lt;0.01) and overcame sorafenib resistance (P & lt;0.0001) in vivo. Mechanistically, pegvisomant decreased the phosphorylation of GHR downstream survival proteins including JAK2, STAT3, STAT5, IRS-1, AKT, ERK, and IGF-IR. In two patients with advanced-stage HCC and high GH who developed sorafenib resistance, pegvisomant caused tumor stability. Our data show that GHR signaling represents a novel “druggable” target, and pegvisomant may function as an effective systemic therapy in HCC. Our findings could also lead to testing GHR inhibition in other aggressive cancers.

Abstract: The pronounced biological influence of the tumor microenvironment on cancer progression and metastasis has gained increased recognition over the past decade, yet most preclinical antineoplastic drug testing is still reliant on conventional 2D cell culture systems. Although monolayer cultures recapitulate some of the phenotypic traits observed clinically, they are limited in their ability to model the full range of microenvironmental cues, such as ones elicited by 3D cell–cell and cell–extracellular matrix interactions. To address these shortcomings, we established an ex vivo 3D Ewing sarcoma model that closely mimics the morphology, growth kinetics, and protein expression profile of human tumors. We observed that Ewing sarcoma cells cultured in porous 3D electrospun poly(ε-caprolactone) scaffolds not only were more resistant to traditional cytotoxic drugs than were cells in 2D monolayer culture but also exhibited remarkable differences in the expression pattern of the insulin-like growth factor-1 receptor/mammalian target of rapamycin pathway. This 3D model of the bone microenvironment may have broad applicability for mechanistic studies of bone sarcomas and exhibits the potential to augment preclinical evaluation of antineoplastic drug candidates for these malignancies.

Abstract: 8020 Background: Infection, a key complication of MM, may be due to patient, disease, or treatment-related factors. Immunotherapies that impact normal immune cells may increase risk of infection. Tal, a bispecific antibody with clinical benefit in pts with RRMM, targets G protein–coupled receptor family C group 5 member D (GPRC5D), a protein of unknown function with significantly higher expression on malignant versus normal plasma cells. We report the infection profile and immune function with tal in the phase (ph) 1/2 MonumenTAL-1 study (NCT03399799/NCT04634552). Methods: Pts had RRMM, were intolerant to/progressed on established therapies (ph 1), or had ≥3 prior lines of therapy (ph 2; ≥1 proteasome inhibitor/immunomodulatory drug/anti-CD38 antibody). Subcutaneous tal was given at 0.4 mg/kg QW or 0.8 mg/kg Q2W. Infections (graded by CTCAE v4.03) were treated per local guidelines. B-cell subpopulations and IgG levels were assessed from whole blood and serum samples, respectively. Results: We evaluated 339 pts on tal QW or Q2W, of whom 51 had prior T-cell redirection therapy (pTCRT); infection rates are shown in the table (median follow-up, 15.9, 10.1, and 13.1 mo, respectively). New-onset infections were most prevalent during cycles 1–2. Grade (gr) 3/4 infections observed in 〉 2 pts were pneumonia (3.5%) and UTI (2.1%) on tal QW; pneumonia (2.1%) and COVID-19 (2.1%) on tal Q2W; and pneumonia (5.9%) with pTCRT. Opportunistic infections were observed in 3.5%, 4.1%, and 5.9% of pts, respectively. Less than 1.5% of pts died from infections: COVID-19 pneumonia (n=2) and one each due to septic shock, fungal sepsis, and unknown etiology. Hypogammaglobulinemia rates by IgG values were 64.3% (tal QW), 65.5% (tal Q2W), and 70.6% (pTCRT); IVIg use was 14.7%, 12.4%, and 15.7%, respectively. CD19+ B-cell levels were stable, and there was a trend toward increased non-clonal IgG over time. Conclusions: Roughly 20% of pts had gr 3/4 infections on tal (most frequently cycles 1–2), with low rates of opportunistic infections, discontinuation, and death. Infection rates, particularly rates of fatal infections, appear lower with tal than with BCMA-targeted T-cell–based therapies. A trend toward increased non-clonal IgG suggests potential recovery of humoral immunity accompanies rapid, deep, and durable responses to tal. These results distinguish tal as an important emerging therapy for RRMM. Clinical trial information: NCT03399799 , NCT04634552 . [Table: see text]

Abstract: Introduction: Pediatric acute myeloid leukemia (AML) is a molecularly heterogeneous group of diseases lacking therapy options that would improve overall survival. Venetoclax (VEN) is an oral inhibitor for selective targeting of B-cell lymphoma 2 (BCL2), which is highly expressed in most patients (pts) with AML and has demonstrated promising efficacy in pediatric pts with AML when combined with chemotherapy (CTx) (Karol SE, et al. Lancet Oncol. 2020;21:551-560). Here, we present safety, efficacy, and preliminary genomic results from pediatric pts with relapsed/refractory (R/R) AML receiving VEN + CTx. Methods: This phase 1 open-label, 2-part, multicenter study (NCT03236857) enrolled pts & lt;25 years with R/R malignancies; here we report on R/R AML. During VEN monotherapy (monoTx), 10 pts received a weight- or age-adjusted adult-equivalent oral daily dose of 800 mg VEN after a 3-day ramp-up to mitigate tumor lysis syndrome risk. Standard of care CTx could be added after 21 days of VEN monoTx at the discretion of the treating physicians. In cohort expansion, 26 pts were enrolled with standard of care CTx allowed after VEN ramp-up. Primary and secondary endpoints included safety and preliminary efficacy of VEN monoTx and VEN + CTx. In addition, exploratory biomarker analyses were performed. For genomic analyses, whole exome sequencing was performed on pretreatment blood or bone marrow samples, and highly recurrent genetic alterations across various functional classifications in AML were analyzed. Previously documented gene fusion data were acquired through site-reported cytogenetic entries at screening. RNA sequencing was performed on pretreatment blood or bone marrow samples and BCL2 family expression was assessed. Results: As of June 2020, 36 pts with R/R AML were enrolled and received VEN monoTx (n=3) and VEN + CTx (n=33: VEN + decitabine [VEN-DEC, n=5], azacitidine [VEN-AZA, n=19] , or low- [VEN-LDAC, n=1] or high-dose cytarabine [VEN-HDAC, n=8] ) (Table). The primary reason for VEN discontinuation was progressive disease (n=19); median duration of VEN therapy was 3.1 months (range 0.2-9.3). All pts experienced adverse events (AEs); 3 pts (n=1 VEN-DEC, n=2 VEN-AZA) had fatal AEs considered unrelated to VEN. The most common grade 3/4 AEs were febrile neutropenia (58%) and hypokalemia (33%). The overall objective response rate (ORR) was 25% (9/36); median duration of response was 0.8 month (95% CI, 0.5, 3.6). The best ORR was seen with VEN-HDAC (4/8, 50%) with 1 complete response (CR), 1 CR without platelet recovery, 1 CR with incomplete marrow recovery (CRi), and 1 partial response (PR); 2 pts achieved minimal residual disease negativity and 2 pts proceeded to transplant. The ORR with VEN-AZA was 26% (5/19), with 3 CR/CRi and 2 PR. No responses were seen with VEN monoTx or VEN + other CTx. The genomic landscape of biomarker-evaluable pts was highly heterogeneous (Figure A). Mutations of genes involved in epigenetic modification (MYH11, IDH2, ASXL1, SETBP1, TET2, and NSD1) and transcription regulation (GATA1, WT1, RUNX1, and CEBPA) were the most common, in 58% and 48% of pts, respectively. Analysis of the recurring mutations found in ≥2 pts revealed that responses to VEN-AZA were seen in pts with IDH2 (1/4), MYH11 (2/6), RUNX1 (1/3), or FLT3 (1/3) mutations, and responses to VEN-HDAC were seen in pts with JAK2 (1/4) or GATA1 (1/3) mutations. Pts with WT1 (3/6) and PTPN11 (3/4) mutations responded to both regimens. Pts with TP53 (n=2) or ETV6 (n=3) mutations and PML-RARA (n=2) or KMT2A rearrangements (n=8) did not respond to any treatment. Gene expression profiling revealed that BCL-xL expression was significantly higher compared with BCL2;MCL1 levels were the highest (Figure B). There was no association between expression of these genes and response. Mutations were seen in BCL2 and MCL1 (n=1 each), but not in BCL-xL. Conclusions: VEN + CTx was well tolerated in pediatric pts with R/R AML, with no unexpected toxicities. Preliminary efficacy was seen in pts receiving VEN-AZA or VEN-HDAC: ORR 26% and 50%, respectively. VEN + CTx resulted in responses in pts harboring mutations across a range of functional classifications; however, some alterations may confer resistance. Due to the limited number of pts harboring each mutation and the overall heterogeneity of the genomic landscape, these findings need to be evaluated in a larger population, and warrant further investigation. Disclosures Karol: AbbVie Inc.: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study. . Bittencourt:Jazz Pharmaceuticals: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy. Morgenstern:EUSA Pharma: Consultancy, Other: travel support; Bayer: Consultancy; Clarity Pharmaceuticals: Consultancy; BMS: Other: Institutional Research Funding; Boehringer Ingelheim: Consultancy; Roche: Consultancy. Macy:Merck: Other: Institutional Research Funding; Pfizer: Other: Institutional Research Funding; Bayer: Other: Institutional Research Funding; AbbVie Inc.: Other: Institutional Research Funding; Roche: Other: Institutional Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company. Khaw:Amgen: Other: Institutional Research Funding; Bristol-Myers Squibb: Other: Institutional Research Funding; AbbVie Inc.: Other: Institutional Research Funding; Novartis: Other: travel, accommodation, expenses; Walter and Eliza Hall Institute of Medical Research.: Patents & Royalties: Recipient of a share in royalty payments . Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Ramsingh:Genentech: Current Employment, Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Unnebrink:AbbVie: Current Employment, Other: may hold stock or other options. Vishwamitra:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Dunbar:Abbvie: Current Employment, Current equity holder in publicly-traded company. Prine:AbbVie: Current Employment, Other: may hold stock or other options. Palenski:AbbVie: Current Employment, Other: may hold stock or other options. Place:Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA approved for some indications. Venetoclax for treatment of pediatric AML is not an approved indication.

Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase with structural similarities to the insulin receptor. ALK is physiologically expressed in neuronal cells at early stages of human development. Thereafter, ALK expression is largely limited to malignant neoplasms including T-cell anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma. It has been previously established that ALK, in the form of chimeric proteins or constitutively activated mutants, plays a central role in the survival of these tumors. Hence, targeting ALK is considered a legitimate and likely successful strategy to eradicate these tumors. Nucleophosmin-ALK-expressing (NPM-ALK+) T-cell ALCL is an aggressive type of cancer. It is one of the most common hematological neoplasms in children as it comprises 40% of the non-Hodgkin lymphomas in this age group. Recently, a selective ALK inhibitor, ASP3026, was developed utilizing an ALK kinase inhibition assay aimed at the chimeric tyrosine kinase echinoderm-microtubule-associated protein-like 4-ALK (EML4-ALK), which is expressed in a subgroup of NSCLC tumors.1 Initial studies showed that not only ASP3026 possesses remarkable inhibitory effects on EML4-ALK but also it overcomes the resistance of EML4-ALK+ NSCLC to crizotinib; a prototype ALK and c-MET inhibitor. ASP3026 is currently being tested in phase I clinical trials that include EML4-ALK+ NSCLC patients. Of important note is that the effects and therapeutic potential of ASP3026 in NPM-ALK+ T-cell ALCL are not known. We systematically analyzed the effects of ASP3026 (ChemieTek, Indianapolis, IN) in NPM-ALK+ T-cell ALCL using in vitro and in vivo experimental approaches. ASP3026 (0.1 to 3.0 µM; 24 and 72 h) induced a concentration- and time-dependent decrease in the viability and proliferation of NPM-ALK+ T-cell ALCL cell lines including Karpas 299, SU-DHL-1, SUP-M2, SR-786, and DEL. In contrast, these negative effects were not observed in normal human T lymphocytes. Furthermore, ASP3026 reduced anchorage-independent colony formation of NPM-ALK+ T-cell ALCL cells. The effects of ASP3026 could be explained, at least in part, by successful induction of apoptotic cell death in these cells. At the biochemical level, ASP3026 decreased significantly the levels of pNPM-ALK and the activated/phosphorylated form of its interacting oncogenic protein type I insulin-like growth factor receptor (pIGF-IR). We are performing additional experiments to further characterize the biochemical effects of ASP3026 in NPM-ALK+ T-cell ALCL cells. To further evaluate the therapeutic potential of ASP3026, we utilized an in vivo systemic lymphoma model developed in our laboratory. Briefly, Karpas 299 cells (1 × 106 cells per mouse), engineered to simultaneously express humanized firefly luciferase and GFP, were injected intravenously in CB-17 SCID mice (Taconic; female; 6-8 weeks old). Systemic lymphoma tumors, detected by using IVIS whole body imaging system after intraperitoneal injection of D-lucifern, were established at approximately 3 weeks after lymphoma cell injections.Thereafter, vehicle or ASP3026 (30 mg/kg/day) was administered daily to the mice (10 mice per group) through oral gavage. Also, standard CHOP combination chemotherapy was used in another group. Treatment with ASP3026 for only 2 weeks was associated with complete lymphoma eradication, which persisted with the daily administration of ASP3026 and until study termination at 6-8 weeks from treatment initiation. In contrast, cessation of ASP3026 after 2 weeks of treatment was associated with lymphoma relapse. Although CHOP initially eradicated the lymphoma, most of the CHOP-treated mice developed significant toxicity and relapsed at 4 weeks after treatment. Importantly, vehicle- and CHOP-treated mice had inferior overall survival compared with mice treated with ASP3026. Taken together, our results provide strong evidence that ASP3026 could represent a novel approach to efficiently treat NPM-ALK+ T-cell ALCL. 1Kuromitsu S, et al. Mol. Cancer Ther. 2011;10[Supp. 1]: A227 DV and SKG equally contributed to this work Citation Format: Deeksha Vishwamitra, Suraj Konnath George, Roxsan Manshouri, Ping Shi, Hesham M. Amin. In vitro and in vivo antitumor activity of the selective ALK inhibitor ASP3026 against NPM-ALK+ T-cell anaplastic large-cell lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A80.

Abstract: 8015 Background: G protein-coupled receptor family C group 5 member D (GPRC5D), which has limited expression in normal human tissue but is highly expressed on malignant plasma cells, is a promising target for multiple myeloma (MM) immunotherapy. Talquetamab (JNJ-64407564) is a first-in-class, bispecific IgG4 antibody that binds to both GPRC5D and CD3 receptors, mediating T-cell–activated lysis of GPRC5D+ MM cells. Here we report updated results with additional patients (pts) and longer follow-up from MonumenTAL-1, a phase 1 trial of talquetamab in RRMM (NCT03399799). Methods: Eligible pts had RRMM or were intolerant to standard therapies; prior B-cell maturation antigen-directed therapies were permitted. The primary objectives were to identify the recommended phase 2 doses (RP2Ds) (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Collective safety, efficacy, PK, and PD data supported 2 RP2Ds for talquetamab: 405 μg/kg SC QW (n = 30) and 800 μg/kg SC Q2W (n = 44). Step-up dosing was used to mitigate against severe cytokine release syndrome (CRS); required premedications were limited to step-up doses and the first full dose of talquetamab. Adverse events (AEs) were graded by CTCAE v4.03 with CRS events graded per Lee et al 2014 criteria. Investigators assessed responses per International Myeloma Working Group criteria. Results: As of Jan 17, 2022, pts in the 405 μg/kg/800 μg/kg groups, respectively, received a median of 6 /5 prior lines of therapy, 100%/98% were triple-class (TC) exposed, 77%/75% were TC refractory. Median follow-up (range) was 11.7 (1.0–21.2)/4.2 (0.7–13.7) months. Most AEs were grade 1 or 2. The most common AEs were cytopenias and CRS. Cytopenias (including neutropenia [67%/36%; grade 3/4: 53%/23%]) were reversible, mostly confined to step-up and cycle 1–2 doses, and generally resolved within 1 week. Infections occurred in 47%/34% (grade 3/4: 7%/9%) of pts. CRS (77%/80%; grade 3: 3%/0%) mostly occurred during step-up dosing. Skin-related and nail disorder AEs occurred in 83%/75% of pts (most commonly skin exfoliation: 37%/39% [all grade 1 and 2] ). Dysgeusia (63%/57%) was generally mild and managed with dose adjustments. The overall response rates in response-evaluable pts were 70% (21/30 pts)/64% (28/44 pts); very good partial response or better rate: 57%/52%; median time to first confirmed response (range): 0.9 (0.2–3.8)/1.2 (0.3–6.8) months. Median duration of response will be reported. No pts died due to drug-related AEs. The PK and PD profiles of both RP2Ds appear comparable. Conclusions: These data show that both RP2Ds of talquetamab have comparable safety, efficacy, and pharmacokinetic profiles and confirm talquetamab as a novel, first-in-class therapy with highly promising efficacy in a heavily pretreated RRMM pt population. Clinical trial information: NCT03399799.