Preliminary Evidence Of Clinical Activity Research Articles

Abstract B041: A phase 1 study of DS-8201a in combination with olaparib in HER2-expressing malignancies (CTEP #10355): Results of module 1 dose escalation

Abstract Background: DS-8201a is a HER2-targeting antibody drug conjugate with a topoisomerase 1 (top1) inhibitor payload. Preclinical evidence suggests that inhibiting PARP can potentiate top1 inhibitor-induced DNA damage and cytotoxicity. However, the clinical activity of combined top1-inhibiting chemotherapy and PARP inhibition has been limited by toxicity. We hypothesized that targeted delivery of a top1 inhibitor via DS-8201a may reduce systemic toxicity while maintaining synergistic cytotoxic activity in combination with olaparib. This combination is being investigated in the ongoing phase 1 trial CTEP #10355 (NCT04585958) in patients (pts) with advanced solid tumors expressing HER2. We present the safety analysis of pts enrolled to Module 1 (Mod 1) of dose escalation (continuous olaparib). Preliminary efficacy results are explored. Methods: Accrual was limited to pts ≥18 years old with advanced or recurrent solid tumors expressing HER2, defined as HER2 IHC ≥1+ (local testing allowed) or amplification of ERBB2 by NGS or ISH. In Mod 1, pts received DS-8201a IV once every 3 weeks and olaparib twice daily (BID) continuously in a 3+3 dose escalation design. Dose Level 1 (DL1) of Mod 1 evaluated DS-8201a dosed at 4.4mg/kg with olaparib 100mg BID Days 1-21. Dose Level 2 (DL2) of Mod 1 evaluated DS-8201a dosed at 5.4mg/kg with olaparib 100mg BID Days 1-21. The primary objective was to evaluate the safety and tolerability of combined DS-8201a + olaparib as graded by CTCAE v5. Secondary objectives include assessment of clinical activity as measured by objective response rate (ORR), clinical benefit rate (CBR; partial response [PR] + complete response [CR] + stable disease [SD] ≥6 months [mo]), median progression-free survival (PFS), and duration of response (DOR). Results: As of 30-Nov-2022, 10 pts were treated in Mod 1, with median age of 62.5 years. 10% were Asian, 10% were African American, and 80% were white. 40% had endometrial cancer and 60% had ovarian cancer. 6 of 7 pts treated on DL1 were DLT-evaluable, of which 1 patient experienced a DLT of Grade (G) 4 neutropenia. All 3 pts in DL2 were DLT-evaluable, and each experienced a DLT (2 pts with G4 febrile neutropenia, 1 pt with G4 neutropenia). Most common TRAEs in Mod 1 included: ANC decrease (60% G4, 20% G3, 20% G1/2), platelet count decrease (20% G4, 20% G3, 40% G1/2), and anemia (70% G3, 20% G1/2). All Mod 1 pts required dose holds, dose reductions, and/or discontinuation of olaparib. Of the 10 pts in Mod 1, 40% achieved a RECIST response (1 CR, 3 PR). 40% had SD lasting ≥6 mo, for a CBR of 80%. Median PFS is estimated at 7.4 mo (95% CI 4.7mo-not reached), with 7 patients alive and progression-free at 6 mo. Conclusion: Continuous dosing of olaparib in combination with DS-8201a yielded an unacceptable safety profile and dose escalation in Mod 1 was not continued. An alternative dosing schedule was initiated in Module 2 (Mod 2) evaluating DS-8201a IV every 3 weeks and olaparib BID Days 8-14; accrual to Mod 2 is ongoing. There is preliminary evidence of clinical activity of this combination. Citation Format: Elizabeth K. Lee, Andrea E. Wahner Hendrickson, Gerardo Colon-Otero, Cheryl A. Pickett, Niya Xiong, Su-Chun Cheng, Madeline Polak, Hannah Sawyer, Martin Hayes, Ursula A. Matulonis, Geoffrey I. Shapiro, Panagiotis A. Konstantinopoulos. A phase 1 study of DS-8201a in combination with olaparib in HER2-expressing malignancies (CTEP #10355): Results of module 1 dose escalation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B041.

Initial Results from a Phase 1 Dose-Escalation Study of WVT078, a BCMA×CD3 Bispecific Antibody, in Combination with WHG626, a Gamma-Secretase (GS) Inhibitor, in Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: WVT078, a potent anti-B-cell maturation antigen (BCMA)×anti-CD3 bispecific antibody (BsAb), is being investigated as a single-agent and in combination with a GS inhibitor (GSI), WHG626 (AL102), in patients (pts) with relapsed and/or refractory (r/r) multiple myeloma (MM). Single-agent WVT078 showed an acceptable safety profile in the ongoing first-in-human study with active dose range of 48-250 µg/kg (Raab, Leukemia 2023). Membrane BCMA expressed on surface of MM cells is cleaved by GS. This results in shedding of its extracellular domain (ECD) as soluble BCMA (sBCMA), which may bind to and interfere with activity of BCMA-targeting agents such as WVT078. By preventing this shedding, GSIs are postulated to increase clinical benefit of BCMA-targeting agents. WVT078 combined with WHG626 was shown to enhance anti-myeloma activity of WVT078 in vitro preclinically (Raab, Leukemia 2023), supporting rationale for this combination in r/r MM. Methods: The combination of WVT078 and WHG626 is being investigated as part of above-mentioned phase 1 study (NCT04123418) in pts with MM who are r/r to ≥2 standard-of-care regimens, including an immunomodulatory drug, proteasome inhibitor, and anti-CD38 agent (if available). Pts who received prior BCMA chimeric antigen receptor T-cell therapy or BCMA antibody-drug conjugates therapy are included; pts with prior BCMA×CD3 BsAb treatment are excluded. Primary objectives were to evaluate safety and tolerability and to determine recommended dose for expansion of WVT078 in combination with WHG626. Secondary objectives were to assess preliminary anti-tumor activity and characterize pharmacokinetics (PK) and immunogenicity. Key exploratory objectives included evaluation of sBCMA and characterization of immune-cell activation phenotypes. Dose escalation was guided by Bayesian Logistic Regression Model, and International Myeloma Working Group criteria were used to assess disease response. Flow cytometry was used to study pharmacodynamic (PD) effects on immunophenotype of immune cells. Immunoassay-based platform (Meso Scale Discovery) was used for assessing cytokine production and enzyme-linked immunosorbent assay for quantifying serum sBCMA levels. Results: As of April 29, 2023, a total of 23 pts (median age, 64 years) with r/r MM were treated in dose escalation with intravenous WVT078 at 12-48 µg/kg once weekly, combined with oral WHG626 at 2-4 mg once daily, given 2 days on and 5 days off. Eighteen pts (78.3%) discontinued treatment due to progressive disease (n=15), adverse event (AE), guardian decision and physician decision (n=1 each). Most frequent (≥20%) treatment-related AEs across all doses in the combination were cytokine release syndrome (65.2%; Grade ≥3, n=1), pyrexia (39.1%), diarrhea (34.8%), decreased appetite (26.1%), hypophosphatemia, nausea and neutropenia (21.7% each); 5 pts experienced dose-limiting toxicities (pneumonia, neutropenia, ALT/AST/lipase increase, platelet count decrease, sepsis and shoulder pain). The safety profile is consistent with WVT078 and WHG626 as single agents. A maximum tolerated dose was not reached. The overall response rate (partial response or better; ORR) and overall complete response (CR) rate (stringent CR+CR) across all dose levels tested were 39.1% (n=9; 90% CI, 22.2, 58.3) and 13.0% (n=3; 90% CI, 3.7, 30.4), respectively; ORR at two highest dose levels combined was 57.1% (n=8/14; 90% CI, 32.5, 79.4). PK total (AUC) and maximal (Cmax) exposure to WVT078 in serum increased approximately proportionally to dose in Cycle 1. Evidence of T-cell engagement with WVT078 was demonstrated by upregulated peripheral T-cell proliferation and activation markers. WHG626 decreased serum sBCMA levels by 10% within first 24 hours of treatment prior to WVT078 dosing. WHG626 enhanced WVT078-mediated increases in serum inflammatory cytokine levels, and upregulated T-cell activation phenotype in bone marrow in a dose-dependent manner.Based on preliminary data, cytokine and clinical effects were observed at lower WVT078 doses with WVT078+WHG626 than with WVT078 alone. Conclusions: WVT078 combined with WHG626 has an acceptable safety profile and shows preliminary evidence of clinical activity at highest doses tested. PD biomarker analysis supports postulated mechanism of action of WHG626 combined with WVT078. This is the first clinical report on combination of BCMAxCD3 BsAb and GSI in r/r MM.

Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody.

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.

Abstract PD13-07: PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC trial

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) provide significant clinical benefit in patients with HR+/HER2- metastatic breast cancer (MBC) and have become a standard of care treatment. Prior insights from tumor profiling and preclinical analyses suggest that AKT1 activation can induce CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may be an effective therapeutic strategy and conducted a clinical trial to evaluate both doublet (ET+AKTi) and triplet (ET+AKTIi+CDK 4/6i) therapy in the ≥ 2nd line MBC setting. Methods: TAKTIC is an open-label phase Ib clinical trial (clinicaltrials.gov NCT03959891) evaluating the combination of the AKT inhibitor ipatasertib (ipat) with fulvestrant (Arm A), an aromatase inhibitor (Arm B), or the triplet combination (Arm C) with fulvestrant + palbociclib (palbo). The primary objective is to evaluate the safety (NCI CTCAE 5.0) and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Secondary objectives include clinical efficacy, as determined by objective response rate (RECIST v1.1), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an updated interim analysis from all study arms. Results: The trial completed accrual with 77 pts enrolled from June 2019 – February 2022, including 19 on Arm A, 16 on Arm B, and 42 on Arm C. Median age was 62 (range 32-88) and 65/77 pts (84%) received prior CDK4/6i (median no. of prior lines = 3, range 1-13). 56/77 pts (73%) had measurable disease at baseline and 50/77 pts (65%) had visceral metastases in the liver/lung (68% Arm A, 44% Arm B, 71% Arm C). Pts enrolled on Arms A and B received ipat at 400mg in combination with fulvestrant or an aromatase inhibitor, respectively. In Arm C, 27/42 pts enrolled into the dose escalation phase and received ipat + palbo at varying doses in combination with fulvestrant. Two DLTs were observed in the 300mg ipat + 125mg palbo cohort (grade 4 neutropenia ≥ 7 days). ET+400mg ipat + 100mg palbo was determined to be the recommended phase 2 dose (R2PD), and the remaining 15/42 pts on Arm C were treated at this dose level in the expansion phase. Treatment was well tolerated in all arms. Grade 3 and 4 toxicities included neutropenia (39/77, 50.6%), leukopenia (15/77, 19.5%), diarrhea (11/77, 14/3%), transaminitis (7/77, 9.1%), lymphopenia (6/77, 7.8%), rash (6/77, 7.8%), and thrombocytopenia (3/77, 3.9%). As of 6/28/2022, 16/77 pts remain on treatment. The median treatment duration for all pts is estimated at 6 months (range 0.5-39). Among the 56 pts with measurable disease, 11 had partial response (PR) and 32 had stable disease (SD) as the best response. CBR, defined as percentage of pts who achieved PR or SD > 6 months, was 48% across the study (53% Arm A, 31% Arm B, 57% Arm C). The median PFS was 5.5 months (95% confidence interval [CI]: 3.8 – 7.4) and the median OS was 24.5 months (95% CI: 17.1 – 33.9). Conclusions: The combination of ipat with endocrine therapy +/- palbo is well tolerated in heavily pre-treated pts, with preliminary evidence of clinical activity. This trial demonstrates how molecular insights related to CDK4/6i resistance inform potential therapy combinations. Further studies are needed to evaluate AKTi-based combinations in pts with HR+ MBC. Citation Format: Seth A. Wander, Jennifer C. Keenan, Andrzej Niemierko, Dejan Juric, Laura M. Spring, Jeffrey Supko, Neelima Vidula, Steven J. Isakoff, Lianne Ryan, Sarah Padden, Elizabeth Fisher, Amber Newton, Beverly Moy, Leif Ellisen, Douglas S. Micalizzi, Aditya Bardia. PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-07.

First-in-Maintenance Therapy for Localized High-Grade Osteosarcoma: An Open-Label Phase I/II Trial of the Anti-PD-L1 Antibody ZKAB001.

We investigated the safety and preliminary efficacy of anti-PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis. This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3. Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2-86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population. Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma.

451O Preliminary evidence of clinical activity from phase I and Ib trials of the CLK/DYRK inhibitor cirtuvivint (CIRT) in subjects with advanced solid tumors

CIRT is a potent, selective pan CLK/DYRK inhibitor that modulates alternative splicing. CIRT is being evaluated in two ongoing phase I studies, a first in human (FIH) and combination trial. Preliminary data from these studies are presented.

Randomized phase 2 study evaluating efficacy and safety of inupadenant in combination with chemotherapy in adults with metastatic non–small cell lung cancer (mNSCLC) who progressed on immunotherapy.

TPS9158 Background: In cancer, the accumulation of adenosine in the tumor microenvironment (TME) mediates immune suppression mainly via the high affinity A2A receptor (A2AR), causing dysregulation of innate and adaptative immune cell subsets and dampening the antitumor immune response. This results in increased tumor cell survival and immune escape (Blay 1997; Merighi 2003; Muller-Haegele 2014). Therefore, inhibiting A2AR could reverse immunosuppression and re-establish immune surveillance in the tumor microenvironment. Inupadenant is an antagonist of the A2AR with potent inhibition of A2AR even at the high concentrations of adenosine present in the tumor microenvironment. Ongoing clinical studies have established inupadenant as a molecule with a favorable safety profile with preliminary evidence of clinical activity in multiple tumor types, including durable PRs in patients who have exhausted standard treatment options (Buisseret 2021). The standard treatment for patients without a driving mutation who progress on first-line IO is a platinum-based doublet chemotherapy regimen. Carboplatin plus Pemetrexed (C+P) is the preferred chemotherapy in nonsquamous mNSCLC. Study A2A-005 will evaluate the efficacy of inupadenant in combination with C+P as a second-line therapy in adult patients with nonsquamous mNSCLC (post-IO). A successful outcome from study A2A-005 will help address a high unmet need for this patient population and could lead to new therapeutic options. Methods: This is a 2-part study. The first part is an open label dose-finding part to determine the safety and recommended Phase 2 dose (RP2D) of inupadenant in combination with C+P (N = 40). In Part 2, 150 patients will be randomized 1:1 to inupadenant or placebo, both in combination with C+P. Tumor response will be determined according to RECIST 1.1 criteria and safety findings will be reviewed by the Safety Review Committee (for Part 1) and the Data Monitoring Committee (for Part 2). Key eligibility criteria include 1) mNSCLC of nonsquamous pathology, 2) have received only 1 line of anti-PD-(L)1 therapy in the metastatic setting, without concomitant chemotherapy, and have progressed (IO/IO combination therapy is allowed), 3) have measurable disease as defined by RECIST v1.1 criteria and 4) Eastern Cooperative Oncology Group status ≤1. Primary endpoints are RP2D (for Part 1) and PFS (for Part 2). Secondary endpoints include change in tumor size, ORR, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers for association with clinical benefit. The study will be conducted in approximately 11 countries in North America and Europe. Clinical trial information: EudraCT 2021-005487-22.

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial.

Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation. This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II. Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.

Abstract P1-18-22: AKT inhibition in combination with endocrine therapy and a CDK4/6 inhibitor (CDK4/6i) in patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) and prior CDK4/6i exposure: A translational investigation

Abstract Background: The cyclin-dependent kinase 4/6 inhibitors, with endocrine therapy (ET), have become the standard of care for patients with HR+/HER2- MBC. Prior insight from tumor biopsies and preclinical analyses suggest that AKT1 activation can provoke CDK4/6i resistance, highlighting a potential therapeutic role for AKT inhibition (AKTi) in this setting. However, combinatorial inhibition can be associated with significant toxicity and identification of the optimal biological dose is often challenging. In this translational co-clinical study, we evaluated escalating doses of AKTi combination with CDK 4/6i in parallel patient-derived pre-clinical models as well as a phase 1b clinical trial. Methods: In an open-label phase Ib dose-escalation clinical trial (TAKTIC, NCT03959891), we evaluated the safety, tolerability and efficacy of escalating doses of the AKT1 inhibitor ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) for patients with HR+/HER2- MBC. Inclusion criteria include unresectable or metastatic disease, at least 1 prior therapy for MBC including any CDK4/6i, and up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). In addition, response to escalating doses of ipat and palbo (with fulv) were explored in vitro via an ATP-based viability assay in tumor cell lines derived from circulating tumor cells (CTC) isolated from patients with endocrine-refractory HR+ MBC. Results: In the dose-escalation portion of the phase 1b clinical trial, 23 patients received the triplet combination of ipat, palbo, and fulv (median number of prior lines = 4.3, range 1-7; 100% with prior CDK4/6i): 3 pts received ipat at 200mg + 125mg palbo, 15 pts received 300mg + 125mg palbo, and 5 pts received 400mg + 100mg palbo, all with fulv (500 mg). Among the 23 patients, 20 patients (86.9%) had disease control (4 partial response and 16 stable disease) as the best response, per RECIST. Grade 3/4 toxicities included neutropenia (n=20), lymphopenia (n=3), diarrhea (n=3), thrombocytopenia (n=2), transaminitis (n=2), and rash (n=2). Two DLTs were observed in the 300mg ipat + 125mg palbo cohort (grade 4 neutropenia ≥ 7 days), but none at 400mg + 100mg palbo. The combination of ipat and palbo demonstrated an additive effect in vitro, with increased sensitivity to lower doses of palbo in the presence of ipat. Based on the totality of data, 400mg ipat + 100mg palbo + fulv 500 mg was selected as the recommended phase II dose (RP2D) in the post-CDK4/6i setting. Conclusions: The triplet combination of endocrine therapy with AKTi and lower dose CDK4/6i appears to be well tolerated in heavily pre-treated pts, with preliminary evidence of clinical activity. Further study is needed to evaluate biomarkers associated with higher AKTi benefit in order to guide rational development of combination therapy for patients with HR+/HER2- MBC in the post-CDK4/6i setting. Overall, this translational study demonstrates how insight into the molecular mechanisms of CDK4/6i resistance and combinatorial modeling can be leveraged to develop actionable therapeutic regimens for patients with MBC. Citation Format: Seth A. Wander, Douglas S. Micalizzi, Taronish Dubash, Dejan Juric, Laura M. Spring, Neelima Vidula, Jennifer Keenan, Maureen Beeler, Elene Viscosi, Dante Che, Elizabeth L. Fisher, Rachel A. Hepp, Beverly Moy, Steven J. Isakoff, Leif W. Ellisen, Jeffrey G. Supko, Shyamala Maheswaran, Daniel A. Haber, Aditya Bardia. AKT inhibition in combination with endocrine therapy and a CDK4/6 inhibitor (CDK4/6i) in patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) and prior CDK4/6i exposure: A translational investigation [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-22.

Safety and Preliminary Antitumor Activity of the Anti-PD-1 Monoclonal Antibody REGN2810 Alone or in Combination with REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Patients with B-Lymphoid Malignancies

Safety and Preliminary Antitumor Activity of the Anti-PD-1 Monoclonal Antibody REGN2810 Alone or in Combination with REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Patients with B-Lymphoid Malignancies

PSMA targeted armored chimeric antigen receptor (CAR) T-cells in patients with advanced mCRPC: A phase I experience.

2534 Background: CART-PSMA-TGFβRDN cells are autologous T cells engineered via lentiviral transduction to express a dominant negative form of TGFβRII (TGFβRDN) and a chimeric antigen receptor (CAR) with specificity to prostate specific membrane antigen (PSMA). The TGFβRDN renders CAR T cells resistant to TGFβ-mediated immunosuppression. CART-PSMA-02 is a multi-center, open-label, Phase 1 study evaluating the safety and feasibility of dosing patients with metastatic castration resistant prostate cancer (mCRPC) with CART-PSMA-TGFβRDN (NCT04227275). Methods: This is a 3+3 dose escalation study to determine the recommended phase 2 dose and schedule of CART-PSMA-TGFβRDN cells following lymphodepleting chemotherapy with cyclophosphamide and fludarabine. Single and fractionated doses are being evaluated. A cohort expansion will enroll patients to further explore the safety of the selected dose and schedule. Results: As of January 2021, 6 patients (pts) have been treated. Two pts were treated in the first dose level (1-3 x107 transduced T cells (TDN)). Four pts were treated in the second dose level (1-3 x 108 TDN with fractionated dosing). AEs occurring in ≥50 % of pts included cytokine release syndrome (CRS), anemia, thrombocytopenia, increased creatinine, nausea, fatigue, pyrexia and dehydration. No DLTs occurred in the 1st dose level. Four pts in the 2nd dose level developed CRS (3 Gr 1 and 1 Gr 2). One pt developed rapid G2 CRS that progressed to Gr 5 encephalopathy and Gr 5 multi-organ failure. Ferritin levels peaked at 56,974 ng/ml (baseline 2,903 ng/mL) despite aggressive immunosuppressive therapy including tocilizumab, dexamtheasone and anakinra. The post infusion cytokine profile indicated elevations in IL-1RA, TNF-alpha, VEGF, IL-10, MIP-1b, IFN-gamma, GM-CSF and notably lower levels of IL6 compared to published reports of CD19 CART-mediated CRS. Autopsy findings were consistent with HLH/MAS, confirming overactivity of the monocyte/macrophage compartment. Based on these observations, a modified immune toxicity management strategy that includes prophylactic anakinra (an IL1R antagonist) was instituted. Preliminary evidence of clinical activity of CART-PSMA-TGFβRDN was noted in the 2nd dose level. Two of 3 pts with 1 month follow-up demonstrated PSA decreases from baseline (1 with >95% decrease, 1 with >50% decrease). Both pts had stable disease per RECIST v1.1. A third pt with only 1 week follow-up had a 40% PSA decrease. Additional data analyses from all infused patients are ongoing and data from pts managed with modified immune toxicity management will be presented. Conclusions: Initial data indicates a unique immune toxicity profile and the potential for anti-tumor activity in mCRPC pts treated with CART-PSMA-TGFβRDN. Modified immune toxicity management could lead to identification of a manageable safety profile and therapeutically active dose. Clinical trial information: NCT04227275.

A phase 1 study of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor in Chinese patients with advanced breast cancer

BackgroundDalpiciclib (SHR6390) is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of dalpiciclib in patients with advanced breast cancer (ABC).MethodsIn this open-label, phase 1 study, Chinese patients who had failed standard therapy were enrolled to receive oral dalpiciclib in 3 + 3 dose-escalation pattern at doses of 25–175 mg. Eligible patients were given a single-dose of dalpiciclib in week 1, followed by once daily continuous doses for 3 weeks, and 1 week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8–10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics.ResultsBetween Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. Dalpiciclib 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose-limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50–175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8–77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4–97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1–not reached).ConclusionsDalpiciclib showed acceptable safety profile and dose-dependent plasma exposure in Chinese patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation.Trial registrationClinicalTrials.gov identifier: NCT02684266. Registered Feb 17, 2016.

Dostarlimab in the treatment of recurrent or primary advanced endometrial cancer.

Immune checkpoint inhibitors have demonstrated significant clinical activity across various tumor subtypes; however, their utility in gynecologic malignancies has thus far proven modest. Since the identification of a molecular subclassification system for endometrial cancer (EC), research in immune checkpoint inhibitor therapies has been focusing on certain subgroups predictive for response, particularly microsatellite instability hypermutated/DNA mismatch repair-deficient subtype. Dostarlimab, a PD-1 inhibitor, has demonstrated preliminary evidence of clinical activity and acceptable safety profile in patients with across recurrent EC, particularly microsatellite instability-hypermutated/DNA mismatch repair-deficient EC. This review outlines existing data for the efficacy and safety of dostarlimab in recurrent or advanced-stage EC.

536MO A phase I, first-in-human, safety, pharmacokinetic, and pharmacodynamic study of oral dubermatinib (TP-0903) in patients with advanced solid tumours

AXL is upregulated in many solid tumors and may drive resistance to targeted cancer therapeutics, traditional chemotherapies, and immuno-oncology agents. Dubermatinib is a novel, orally administered small molecule AXL kinase inhibitor affecting mesenchymal-epithelial transition while targeting oncogenesis and chemoresistance. Ph I enrolled 45 pts with advanced solid tumors across 9 dose levels (1.5-37mg/m2) and 50mg flat dose. The RPh2D was determined as 50mg dubermatinib QD 21/28 days based on dose-proportionate drug accumulation including metabolites, and thrombocytopenia. Five expansion cohorts enrolled 1) dubermatinib plus IO with progression after response (n=19); 2) dubermatinib plus EGFR inhibitor in EGFR+ NSCLC with progression after response (n=18); 3) KRAS+ CRC (n=47); 4) platinum refractory/resistant ovarian cancer (n=22); 5) BRAFmut/wt melanoma (n=13). In 125 patients receiving at least one 50mg dose the most frequently observed Gr3/4 AEs were anemia, diarrhea (7/5.6%); hyponatremia, dyspnea (5/4.0%); vomiting, ascites, fatigue, incr alkphos, decr potassium, PE (3/2.4%). PK values for plasma dubermatinib and active metabolites rose incrementally with dose (t½ 12-20hrs). Day 1 Cmax and AUC0-24 (50mg) were 14.8 ng/mL and 160.9 ng*hr/mL, respectively. Increases were observed at Day 21. Clinical activity included 4 PRs: 2 NSCLC (1 pt 37mg/m2 dubermatinib+TKI, 1 pt 50mg dubermatinib+nivolumab), 1 melanoma pt. 9mg/m2 and 1 cholangiocarcinoma pt. 50mg, both single agent dubermatinib. Dose reduction rate at RP2D was <10% with overall CBR observed in 18.4% (23/125) of pts including 4 PRs and SD>4 months in heavily pretreated patients. PD evaluation of pre, post-treatment tumor biopsies and PBMCs correlated with drug activity (dose dependent sAXL reduction and GAS6 increase on treatment Day 8). Changes in immune cell infiltration, activity of antigen presenting cells and polarization of macrophages will be presented. Dubermatinib at 50mg orally once daily was tolerated, with evidence of AXL engagement in surrogate tissues and preliminary evidence of clinical activity. Combination studies with TKIs and IO agents are being analyzed.

A phase I study of SHR6390, a cyclin-dependent kinase 4/6 inhibitor in patients with advanced breast cancer (ABC).

1095 Background: SHR6390 is a novel inhibitor of cyclin-dependent kinase 4/6 (CDK 4/6). This study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of SHR6390 in patients (pts) with advanced breast cancer (ABC). Methods: In this open-label, single-arm phase I study, pts who had failed standard therapy were enrolled to receive oral SHR6390 in 3 + 3 dose-escalation pattern at doses of 25−175 mg. Eligible pts were given a single-dose of SHR6390 in week 1, followed by once daily continuous doses for three weeks, and one week off in 28-day cycle. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8−10 pts. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics. Results: Between Apr 15, 2016 and Dec 21, 2018, 40 pts were enrolled. All pts were diagnosed of hormone receptor positive and HER2-negative ABC. 45.0% of pts had at least three prior chemotherapies and 55.0% had at least two prior endocrine therapies. SHR6390 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 pts, respectively. No dose limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade ≥3 were observed in 22 (55.0%) of 40 pts, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50−175 mg, median time to peak concentration was 2.5−4.0 h, and mean terminal half-life was 40.3−51.4 h with single-dose SHR6390. Following multiple dosing, steady state SHR6390 was observed on day 8. The steady state areas under the concentration and peak concentration increased slightly greater than the increase rate of dose, with steady state Cmax at day 21 of 41.1, 53.4, 87.0, 115.0, 126.0, and 155.0 ng/mL in 50, 75, 100, 125, 150, and 175 mg cohorts, respectively. The disease control rate was 62.5% (25/40, 95% CI 45.8% to 77.3%). Two pts (5%, one in 125 mg, one in 150 mg cohort) achieved partial response, with responses lasting 169 and 356+ days, respectively. Conclusions: SHR6390 showed acceptable safety profile and dose-dependent plasma exposure in pts with ABC. The recommended phase II dose was 150 mg. Preliminary evidence of clinical activity was observed, warranted further study. Clinical trial information: NCT02684266 .

Results from an international phase 2 study of the anti‐CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B‐lineage acute lymphoblastic leukemia

In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti-CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy. This international, multicenter, phase 2 study enrolled children with relapsed/refractory B-cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21-day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations. Thirty-two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment-related serious adverse event, including capillary leak syndrome (CLS; n=6), hemolytic uremic syndrome (HUS; n=4), and treatment-related death (n=1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS. Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted.

Abstract A072: Preliminary results of ASTX660, a novel non-peptidomimetic cIAP1/2 and XIAP antagonist, in 107 patients with solid tumors or lymphoma

Abstract Background: ASTX660 is an oral, novel nonpeptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first-in-human phase 1–2 study in patients (pts) with advanced solid tumors or lymphoma (ClinicalTrials.gov NCT02503423). In the ongoing phase 2, ASTX660 has demonstrated preliminary evidence of clinical activity in the relapsed/refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) cohorts (Mehta et al, presented at the EHA Conference 2019, abs PS1073). Here, we report overall efficacy and safety data from the solid tumors (head and neck squamous cell carcinoma [HNSCC]; cervical carcinoma and other solid tumors) and lymphoma (diffuse large B-cell lymphoma [DLBCL], PTCL, CTCL,) phase 2 cohorts. Methods: Pts received treatment with ASTX660 orally at the RP2D 180mg/day on days 1 to 7, and 15 to 22 in a 28-day cycle. In the first stage 14 evaluable pts were enrolled in each of the 6 phase 2 cohorts with the option to expand the cohort if activity was observed. The primary endpoint was response rate as assessed by the investigator according to the Lugano criteria (DLBCL and PTCL), Global Assessment (CTCL), or RECIST 1.1 (solid tumors). Adverse events (AEs) were assessed per CTCAE V4.03. Results: As of June 4, 2019, a total of 107 pts have received ASTX660 in the solid tumors and lymphoma phase 2 cohorts (HNSCC n=14; DLBCL n=16; PTCL n=26; CTCL n=23; cervical carcinoma n=14; other solid tumors n= 14). Median age (range) was 61 (23-84) years and median number (range) of prior anticancer regimens was 3 (0-12). Among all pts, the most common related AEs of any grade (≥ 10%) were rash (35%), lipase elevation (34%), amylase elevation (29%), diarrhea (14%), fatigue (14%), AST elevation (13%), nausea (13%), and anemia (11%). Related AEs ≥ Grade 3 occurring in ≥ 5% of pts were rash (18%), lipase elevation (16%) and amylase elevation (9%). As of 4 June 2019, 86 pts (80%) discontinued study treatment: 64 (60%) due to progressive disease, 13 (12%) due to AE, 4 (4%) due to death, 4 (4%) due to withdrawal by participant and 1 (1%) for investigator’s decision. At the time of analysis, the ORR was 36% in the PTCL cohort and 15% in the CTCL cohort. One PR was reported in a pt with metastatic melanoma after 12 cycles of treatment. No objective responses were reported in the HNSCC, DLBCL or cervical cohorts. Accrual in the PTCL and CTCL continues; updated efficacy and safety data will be presented at the meeting. Conclusion: In the phase 2 part of the study ASTX660 monotherapy has demonstrated a manageable safety profile and encouraging activity in PTCL and CTCL warranting cohort expansion. Future plans include evaluation of ASXT660 both as mono- or combination therapy in selected malignancies. Citation Format: Antoine Hollebecque, Sarit Assouline, Felipe Samaniego, Benoit You, Francine Foss, Anca Prica, Sarah W. Gordon, Marc Webster, Martin JS. Dyer, Dima El-Sharkawi, Geoffrey I. Shapiro, Lisa Nabell, Sarah P. Blagden, John Lister, Susanna V. Ulahannan, Yijun Sun, Danna Chan, Roberta Ferraldeschi, Monica Mita. Preliminary results of ASTX660, a novel non-peptidomimetic cIAP1/2 and XIAP antagonist, in 107 patients with solid tumors or lymphoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A072. doi:10.1158/1535-7163.TARG-19-A072

Abstract CT238: TAS-120 in patients with advanced solid tumors bearing FGF/FGFR aberrations: A Phase I study

Abstract Background TAS-120, an oral, highly selective, irreversible FGFR1-4 tyrosine kinase inhibitor, inhibits both mutant and wild-type FGFR1-4 isoforms and has demonstrated activity against cell lines and human xenografts of tumors bearing FGFR aberrations. Safety and antitumor activity of TAS-120 was evaluated in this phase 1 study (NCT02052778) in patients with advanced solid tumors. TAS-120 doses of 8-24 mg once daily continuously (QD) or 8-200 mg Monday-Wednesday-Friday were evaluated for safety in the dose-escalation phase. Continuous TAS-120 20 mg QD was determined to be the maximum tolerated dose (MTD). Results in patients with cholangiocarcinoma (CCA) bearing FGFR2 rearrangements have been presented; here we report data in patients with tumors other than CCA. Methods Patients aged ≥18 years with advanced solid tumors with or without FGF amplifications or FGFR aberrations (including rearrangements/gene fusions, mutations, or amplifications) were treated with escalating doses of TAS-120 during the dose-escalation phase. An expansion phase using doses of 20 mg QD was initiated. FGF/FGFR status was assessed locally or at a designated laboratory. The primary endpoints in the dose-escalation phase were to investigate the safety and to determine the MTD. Objective response rate (ORR) assessed per RECIST 1.1 was the primary endpoint in the expansion phase, and the secondary endpoints were safety, duration of response, progression-free survival, and overall survival. Results A total of 134 patients with advanced solid tumors were treated in the dose escalation or expansion phases. Tumor types included primary CNS tumors (n=24), urothelial carcinoma (UC; n=21), breast cancer (BC; n=17), colorectal cancer (n=15), gastroesophageal cancer (GC; n=9), and other tumor types. Aberrations in FGFR1, FGFR2, FGFR3, and FGFR4 genes were observed, including amplifications, mutations, and rearrangements, as well as amplifications of FGF ligand genes. Hyperphosphatemia, an on-target, mechanism-based adverse effect of TAS-120, was the most common adverse event. Partial responses were observed in patients with BC (both HER2+ and triple-negative), UC, primary CNS tumors, and GC. Safety and efficacy details will be presented at the time of the congress. Conclusions Continuous oral TAS-120 doses up to 20 mg QD were safe and showed preliminary evidence of clinical activity in selected patients with several tumor types bearing various FGF/FGFR aberrations. Results will determine which tumor types move into further clinical development. Citation Format: Funda Meric-Bernstam, Lipika Goyal, Ben Tran, Ignacio Matos, Hendrik-Tobias Arkenau, Helen He, Jerry Huang, Rastislav Bahleda. TAS-120 in patients with advanced solid tumors bearing FGF/FGFR aberrations: A Phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT238.

Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours

BackgroundThis phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulin-liposomal formulation (eribulin-LF) in patients with advanced solid tumours.MethodsEligible patients with ECOG PS 0–1 were treated with eribulin-LF either on day 1 every 21 days (Schedule 1), or on days 1 and 15 every 28 days (Schedule 2). Doses ranged from 1.0 to 3.5 mg/m2, with dose escalation in a 3 + 3 design. The dose-expansion phase evaluated eribulin-LF in select tumour types. Primary objectives: maximum tolerated dose (MTD) and the recommended dose/schedule of eribulin-LF.ResultsTotally, 58 patients were enroled (median age = 62 years). The MTD was 1.4 mg/m2 (Schedule 1) or 1.5 mg/m2 (Schedule 2), the latter dose selected for the dose-expansion phase. Dose-limiting toxicity (DLTs) in Schedule 1: hypophosphatemia and increased transaminase levels. DLTs in Schedule 2: stomatitis, increased alanine aminotransferase, neutropenia and febrile neutropenia. The pharmacokinetic profile of eribulin-LF showed a similar half-life to that of eribulin (~30 h), but with a 5-fold greater maximum serum concentration and a 40-fold greater area-under-the-curve. Eribulin-LF demonstrated clinical activity with approximately 10% of patients in both schedules achieving partial responses.ConclusionsEribulin-LF was well tolerated with a favourable pharmacokinetic profile. Preliminary evidence of clinical activity in solid tumours was observed.

REGN5458, a Bispecific BCMAxCD3 T Cell Engaging Antibody, Demonstrates Robust In Vitro and In Vivo Anti-Tumor Efficacy in Multiple Myeloma Models, Comparable to That of BCMA CAR T Cells

Improving therapies for multiple myeloma (MM) remains a high medical need because of the significant morbidity and mortality of the disease. Targeted immunotherapies represent a promising opportunity to fill this clinical need. B cell maturation antigen (BCMA) is an attractive cell-surface target for MM due to its consistent expression on MM patient malignant plasma cells and expression limited in normal tissue primarily to plasma cells. Redirection of a patient's T cells to recognize tumors by CD3-binding bispecific molecules or through the generation of chimeric antigen receptor (CAR) T cells, has shown preliminary evidence of clinical activity. Bispecific antibodies concurrently engage a tumor antigen on cancer cells and the CD3 signaling machinery on T cells, bringing the tumor cell and T cell into proximity and facilitating T cell activation and tumor cell killing. By contrast, CAR T cell therapy involves re-infusion of the patient's own T cells after ex vivo engineering to express CARs targeting tumor antigens and triggering T cell signaling.Here we describe the generation of REGN5458, a human bispecific antibody that binds to BCMA and CD3. In vitro, REGN5458 efficiently activates T cells and induces polyclonal T cell killing of myeloma cell lines with a range of BCMA cell-surface densities, and also induces cytotoxicity of primary human plasma cells. Similar to gamma-sectretase inhibitors, incubation of myeloma cell lines with REGN5458 increased surface levels of BCMA. In xenogenic studies, after BCMAhigh NCI-H929 and BCMAlow MOLP-8 MM cells were co-implanted with PBMC and grown subcutaneously in immunodeficient NOD/SCID/L2Rgamma-deficient (NSG) mice, REGN5458 doses as low as 0.4 mg/kg significantly suppressed the growth of both tumors. Using aggressive, systemic xenogenic tumor models, in which NSG mice were engrafted with PBMC and intravenously injected with BCMAhigh OPM-2 cells or BCMAlow MOLP-8 cells expressing luciferase, REGN5458 reduced tumor burden and suppressed tumor growth at doses as low as 0.4 mg/kg. In immunocompetent mice genetically engineered to express human CD3, REGN5458 inhibited the growth of syngeneic murine tumors expressing human BCMA at doses as low as 0.04 mg/kg. Finally, as REGN5458 binds to cynomolgus CD3 and BCMA and mediates cytotoxicity of primary cynomolgus plasma cells, the pharmacology of REGN5458 was evaluated in cynomolgus monkeys. REGN5458 administration was well-tolerated, resulting in a mild inflammatory response characterized by transiently increased CRP and serum cytokines. Importantly, REGN5458 treatment led to the depletion of BCMA+ plasma cells in the bone marrow, demonstrating cytotoxic activity in non-human primates.The anti-tumor efficacy of REGN5458 was compared to BCMA-specific CAR T cells using 2nd generation CAR lentiviral constructs containing a single-chain variable fragment binding domain from REGN5458's BCMA binding arm and 4-1BB and CD3z signaling domains. Human PBMC-derived T cells were transduced to express this CAR and expanded. Both REGN5458 and the BCMA CAR T cells demonstrated similar targeted cytotoxicity of myeloma cell lines and primary patient blasts in vitro, and were capable of clearing established systemic OPM-2-luciferase myeloma tumors in NSG mice, but with different kinetics: treatment with REGN5458 resulted in rapid clearance of tumors within 4 days, whereas treatment with BCMA CAR T cells allowed tumors to continue to grow for 10-14 days following injection before rapidly inducing tumor clearance. Thus, REGN5458 exerts its therapeutic effect rapidly after injection, using effector T cells that are already in place. In contrast, BCMA CAR T cells require time to traffic to the tumor site and expand, before exerting anti-tumor effects.Collectively, these data demonstrate the potent pre-clinical anti-tumor activity of REGN5458 that is comparable to that of CAR T cells, and provide a strong rationale for clinical testing of REGN5458 in patients with MM. DisclosuresDilillo:Regeneron Pharmaceuticals: Employment. Olson:Regeneron Pharmaceuticals: Employment. Mohrs:Regeneron Pharmaceuticals: Employment. Meagher:Regeneron Pharmaceuticals: Employment. Bray:Regeneron Pharmaceuticals: Employment. Sineshchekova:Regeneron Pharmaceuticals: Employment. Startz:Regeneron Pharmaceuticals: Employment. Retter:Regeneron Pharmaceuticals: Employment. Godin:Regeneron Pharmaceuticals: Employment. Delfino:Regeneron Pharmaceuticals: Employment. Lin:Regeneron Pharmaceuticals: Employment. Smith:Regeneron Pharmaceuticals: Employment. Thurston:Regeneron Pharmaceuticals: Employment. Kirshner:Regeneron Pharmaceuticals: Employment.