Step-up Dosing Research Articles

ABCL-439 Subcutaneous Epcoritamab With Gemcitabine + Oxaliplatin (GemOx) Induced High Response Rates in Patients With Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Ineligible for Autologous Stem Cell Transplant (ASCT)

Patients with R/R DLBCL who fail or are ineligible for ASCT have poor outcomes with standard palliative chemotherapy. Epcoritamab is a subcutaneously administered CD3xCD20 bispecific antibody that demonstrated substantial antitumor activity in R/R DLBCL. Evaluate the safety and efficacy of epcoritamab + GemOx in patients with R/R DLBCL who are ineligible for ASCT in arm 5 of a phase 1/2, open-label trial (EPCORE NHL-2; NCT04663347). Adults with R/R CD20+ DLBCL who failed or were ineligible for ASCT were included. As of December 1, 2021, 27 patients (median age, 71 y) were treated. Patients received subcutaneous epcoritamab (QW, cycle [C] 1-3; Q2W, C4-9; Q4W, C≥10) and GemOx (Q2W, C1-4) until disease progression or unacceptable toxicity (28 d/C). Step-up dosing and prophylactic corticosteroids were required. Of the 27 patients (epcoritamab 24 mg, n=3; 48 mg, n=24), most were stage IV (56%), primary refractory (56%), and/or refractory to last therapy (70%). Median number of prior therapies was 2 (range, 1-13), and median follow-up was 6.0 mo (range, 1.0-11.1), with treatment ongoing in 16 patients (59%). The most common treatment-emergent AEs were CRS (70%), thrombocytopenia (70%), neutropenia (56%), anemia (52%), and infections (52%). CRS events were all grade (G) 1-2, with most cases in C1; all cases resolved. One patient had ICANS (G3). Six patients (22%) had G5 AEs: unrelated to epcoritamab by the investigator in 4 patients; epcoritamab contribution could not be ruled out in 2 patients. The overall response rate for the 25 efficacy-evaluable patients was 92% by PET-CT; 60% had a complete metabolic response (CMR), and 32% had a partial metabolic response (PMR). At data cutoff, the longest duration of response was 6.9 mo. All 3 patients with prior CAR T remained on treatment and in response (2 had CMR and 1 had PMR). In this R/R population with high unmet need, no unexpected safety findings were observed for epcoritamab + GemOx. These initial data are encouraging and warrant further clinical evaluation. This study was funded by Genmab A/S and AbbVie.

IBCL-249 Mosunetuzumab Monotherapy Is an Effective and Well-Tolerated Treatment Option for Patients With Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Who Have Received ≥2 Prior Lines of Therapy: Pivotal Results From a Phase I/II Study

In a Phase I/II study (NCT02500407), escalating doses of the CD20xCD3 bispecific antibody mosunetuzumab were active and well-tolerated in patients with R/R FL and ≥2 prior therapies. Report pivotal Phase II expansion results. All patients had R/R FL (Grade 1-3a) and ≥2 prior therapies, including an anti (a)-CD20 therapy and alkylating agent, and an ECOG PS of ≤1. Mosunetuzumab was given intravenously in 21-day cycles with C1 step-up dosing for CRS mitigation (C1D1: 1mg; C1D8: 2mg; C1D15 and C2D1: 60mg; D1 of C3+: 30mg). Hospitalization was not mandatory. Mosunetuzumab was continued for 8 (CR by C8) or 17 cycles (PR/SD by C8). The primary endpoint was CR rate (best response) by Independent Review. As of March 15, 2021, 90 patients had been enrolled (median age: 60 years; median number of prior therapies: 3); 68.9% were refractory to their last therapy, 78.9% to any prior aCD20 therapy, and 53.3% to any prior aCD20 therapy and alkylating agent (double refractory). 52.2% had POD24. Median follow-up was 12.9 months. ORR (CR/PR) and CR rates in all patients were 78.9% and 57.8%, respectively. Rates were comparable in POD24 (83% and 55%, respectively) and double-refractory patients (69% and 48%). At cut-off, 12-month event-free rates after first response were 65.4% in responders and 80.1% in complete responders. Median PFS was 17.9 months. CRS (44.4% by ASTCT 2019 criteria) occurred primarily in C1 and was predominantly Grade 1-2 (42.2%). Grade 3-4 CRS occurred in 2 patients. No Grade 5 (fatal) CRS events occurred. All CRS events resolved. Other AEs (≥20%) were fatigue (36.7%), headache (31.1%), neutropenia and pyrexia (28.9% each), hypophosphatemia (22.2%), and pruritus (21.1%). Grade 3-4 AEs (≥5%) were neutropenia (26.6%), hypophosphatemia (13.3%), hyperglycemia and anemia (7.8% each), and elevated ALT (5.6%). Grade 5 AEs were malignant neoplasm progression and unexplained death (both events mosunetuzumab unrelated). AEs leading to mosunetuzumab discontinuation occurred in 4 patients (4.4%). Mosunetuzumab induces high CR rates and durable remissions in patients with R/R FL and ≥2 prior therapies. Mosunetuzumab has favorable safety, allowing administration without mandatory hospitalization.

649TiP A phase I/Ib study evaluating the safety, pharmacokinetics, and preliminary efficacy of LP-118 in subjects with relapsed or refractory haematological malignancies

Newave Pharmaceutical is developing an investigational compound LP-118, a next generation selective B-cell lymphoma 2 (BCL-2) inhibitor with tuned B-cell lymphoma extra-large (BCL-XL) activity to improve antitumor efficacy and reduce risk for thrombocytopenia. Clinical development of LP-118 includes targeting of relapsed or refractory hematological malignancies. BCL-2 and BCL-XL are important anti-apoptotic proteins in the intrinsic apoptotic pathway and are involved in the pathophysiology of many hematologic malignancies, including Non-Hodgkin’s Lymphoma (NHL), Richter transformation (RT), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), etc. (Valentin, Grabow et al. 2018). Considering that concern about acquired resistance to venetoclax (the first FDA-approved BCL-2 selective inhibitor indicated for the treatment of AML has been an obstacle in the treatment of AML patients, a promising strategy for overcoming BCL-2 acquired resistance mutation is urgently needed (Tahir, Smith et al. 2017) The inhibitory effect of LP-118 on the targets BCL-2 and BCL-XL is carefully adjusted to be between that of navitoclax and venetoclax with the aim of minimizing BCL-XL on-target platelet toxicity while retaining and improving antitumor efficacy. Newave Pharmaceutical, Inc. intends to conduct the first in human study of LP-118 in hematologic malignancies with a primary focus on relapsed or refractory NHL, RT, MM, T-PLL, AML, ALL, MDS, MDS/MPN, and MF. Phase Ia dose-escalation will begin with Group 1 until DLT is observed and MTD is established, or until an RP2D or OBD is established. Once the MTD, RP2D, or OBD is established for Group 1, the phase Ia dose escalation can proceed for Group 2 (hight risk). Group 1 relapsed/refractory: low risk tumor lysis CLL/SLL; MF, MDS/MPN, CMML-2, MPN-BP, MDS, AML; NHL, RT, MM, T-PLL; ALL A classic “3+3” design will be used in this study. The safe starting dose of LP-118 calculated from non-clinical toxicity studies is 50 mg/d. To mitigate risk of TLS, an accelerated step-up dosing schedule of LP-118 will be used to reach the target dose for each cohort. NCT04771572. Newave Pharmaceutical Inc.

Teclistamab in Relapsed or Refractory Multiple Myeloma

BackgroundTeclistamab is a T-cell–redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma.MethodsIn this phase 1–2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better).ResultsAmong 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell–associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2).ConclusionsTeclistamab resulted in a high rate of deep and durable response in patients with triple-class–exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.)

Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study

Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies. We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group performance status of 0-1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing. Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8-23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred. Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies. F Hoffmann-La Roche and Genentech.

Feasibility of therapeutic drug monitoring of sorafenib in patients with liver or thyroid cancer

IntroductionSorafenib is a tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, thyroid carcinoma, and desmoid fibromatosis. As high inter-individual variability exists in exposure, there is a scientific rationale to pursue therapeutic drug monitoring (TDM). We investigated the feasibility of TDM in patients on sorafenib and tried to identify sub-groups in whom pharmacokinetically (PK) guided-dosing might be of added value. MethodsWe included patients who started on sorafenib (between October 2017 and June 2020) at the recommended dose of 400 mg BID or with a step-up dosing schedule. Plasma trough levels (Ctrough) were measured at pre-specified time-points. Increasing the dose was advised if Ctrough was below the target of 3750 ng/mL and toxicity was manageable. ResultsA total of 150 samples from 36 patients were collected. Thirty patients (83 %) had a Ctrough below the prespecified target concentration at a certain time point during treatment. Toxicity from sorafenib hampered dosing according to target Ctrough in almost half of the patients. In 11 patients, dosing was adjusted based on Ctrough. In three patients, this resulted in an adequate Ctrough without additional toxicity four weeks after the dose increase. In the remaining eight patients, dose adjustment based on Ctrough did not result in a Ctrough above the target or caused excessive toxicity. ConclusionsTDM for sorafenib is not of added value in daily clinical practice. In most cases, toxicity restricts the possibility of dose escalations.

P1210: IMMUNE CORRELATES OF RESPONSE TO GLOFITAMAB: BIOMARKER FINDINGS FROM A PIVOTAL PHASE II EXPANSION STUDY IN PATIENTS WITH RELAPSED OR REFRACTORY (R/R) DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

Background: Glofitamab is a T-cell-engaging bispecific antibody with a novel 2:1 configuration that confers bivalency for CD20 (B cells) and monovalency for CD3 (T cells). In an ongoing Phase I/II study (NCT03075696), glofitamab demonstrated durable complete responses (CR) and a favorable safety profile in patients (pts) with R/R B-cell lymphomas (Phase I dose-escalation part; Hutchings, et al. 2021) and in pts with R/R DLBCL (pivotal Phase II expansion). Aims: To evaluate tumor and peripheral blood (PB) biomarkers associated with clinical response to glofitamab in the pivotal Phase II expansion. Methods: Pts with DLBCL (DLBCL, NOS, HGBCL, PMBCL, or trFL; n=107) and ≥2 prior therapies received intravenous (IV) obinutuzumab pretreatment (Gpt; 1000mg) 7 days before the first glofitamab dose. IV glofitamab was then given as step-up doses on Day (D) 1 (2.5mg) and D8 (10mg) of Cycle (C) 1 and at the target dose (30mg) on D1 of C2–12 (21-day cycles). Response was assessed by Independent Review Committee (Lugano 2014 criteria). All pts provided informed consent. Baseline (BL) tumor biopsies were assessed by CD20/PAX5 immunohistochemistry (n=64) and CD8/Ki67 immunofluorescence (IF) (n=61). PB biomarkers were evaluated by flow cytometry (n=87) and plasma cytokines by ELISA (n=70). Immune and stromal cell type were inferred from bulk tumor RNAseq samples (n=55) using xCell cell type enrichment analysis. All BL samples were collected prior to Gpt. Results: Analysis of BL tumor biopsies showed all pts were CD20 positive (range: ~35–98% CD20+ PAX5+ B cells) and CD20 levels were not associated with response. A trend towards higher CD8 counts was observed in pts with CR (by IF in total CD8 and CD8+Ki67- T cells). Gene expression analysis showed that responders had higher tumor microenvironment abundance enrichment scores, including higher CD4+ and CD8+ T-cell subsets scores (Figure). PB immune profiling revealed a positive association of BL counts of B cells (p<0.01), CD4 T cells (p=0.02), and CD4 effector memory (EM) cells (p=0.03) with response. There were no significant differences in BL counts of CD8 subsets, regulatory T cells, natural killer cells or monocytes. In pts with progressive disease (PD), there was a trend towards higher expression of the checkpoint marker PD1 on CD8 cells (p=0.05). Pts with CR had lower levels of IL-6 and C-reactive protein (CRP) at BL (test for association with CR: p=0.1 and p=0.01, respectively). Early on-treatment changes in PB were associated with response to glofitamab: induction of IL-6, IFNγ, IL-10, and TNFα in the 6 hours after the first glofitamab dose was strongest in pts with CR (IL-6, IFNγ, IL-10: 6- to 16-fold induction; TNFα: 1.5-fold induction). Transient margination of CD4 and CD8 T cells was strongest in pts with CR. Additional analyses, including ctDNA, are ongoing and updated data will be presented. Image:Summary/Conclusion: Biomarker results from the expansion cohort in pts with R/R DLBCL were consistent with those from the dose-escalation (Broeske et al. 2021), including comparable BL tumor CD20 expression across response categories, a trend towards higher BL tumor CD8 levels in pts with CR, and lower BL IL-6 and CRP in pts with CR. T-cell margination was strongest in pts with CR. Several novel response-associated biomarkers were identified in PB including higher BL B cell, CD4, and CD4 EM counts in responders and higher PD1 expression on CD8 in pts with PD. These data suggest a model where the clinical activity of glofitamab may be dependent upon immune contexture in the tumor and PB at the start of treatment.

S183: NOVEL COMBINATION IMMUNOTHERAPY FOR THE TREATMENT OF RELAPSED/REFRACTORY MULTIPLE MYELOMA: UPDATED PHASE 1B RESULTS FOR TALQUETAMAB (A GPRC5D X CD3 BISPECIFIC ANTIBODY) IN COMBINATION WITH DARATUMUMAB

Background: Talquetamab (tal; JNJ-64407564) is a first-in-class, bispecific IgG4 antibody that binds both to G protein-coupled receptor family C group 5 member D (GPRC5D), a receptor highly expressed on malignant plasma cells but with limited expression in healthy tissue, and CD3 to mediate T-cell–activated lysis of GPRC5D+ multiple myeloma (MM) cells. Daratumumab (dara) is an anti-CD38 mAb with direct on-tumor and immunomodulatory actions. Initial clinical results from the phase 1b multicohort TRIMM-2 study identified the recommended phase 2 doses (RP2Ds) of tal as 400 μg/kg weekly or 800 μg/kg Q2W and support the combination of tal + dara for the treatment of RRMM, with manageable safety, no overlapping toxicities, and promising efficacy. Aims: Here we report updated results for both RP2Ds of tal + dara in TRIMM-2 with additional patients (pts) and longer follow-up. Methods: Eligible MM pts (aged ≥18 years) had received ≥3 prior lines of therapy (LOT; including a PI and IMiD) or were double refractory to a PI and an IMiD, and could not have received anti-CD38 therapy within 90 days. Pts received dara SC 1800 mg per approved schedule and tal (400 μg/kg weekly or 800 μg/kg Q2W) with step-up dosing. The primary objectives were to identify the RP2D(s) of tal for combination therapy and evaluate safety of the combination. AEs were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Responses were assessed by IMWG criteria. Results: At data cutoff (Jan 13, 2022, N=46), median follow-up was 4.0 months (range 0.4-16.3), median age was 65 years (range 47-81), and 48% were female. Pts received a median of 5 prior LOT (range 2-16); 83% were triple-class exposed, 61% penta-drug exposed, 37% anti-BCMA non–CAR-T exposed, and 4% anti-BCMA CAR-T exposed. 96% of pts had ≥1 AE (gr 3/4: 67%). The most frequently reported AEs (≥30% across tal + dara cohorts) were CRS (65%; all gr 1/2; median time to onset: 2 days; median duration: 2 days), dysgeusia (57%), thrombocytopenia (35%; gr 3/4: 20%), anemia (39%; gr 3/4: 20%), and dry mouth (44%). Infections occurred in 50% of pts (gr 3/4: 13%). Skin disorders were reported in 72% of pts (gr 3/4: 11%): skin exfoliation in 26% (all gr 1/2) and nail disorders in 11% (all gr 1/2). Two ICANS events were reported in the 800 Q2W group (both gr 1 and resolved within 1 day). 3 pts discontinued due to AEs. Response rates were consistent across both RP2Ds supporting their equivalence (Table). Median time to first response across dosing cohorts was 0.95 months (range 0.9-9.7); median duration of response was not reached. Upregulation of CD38+/CD8+ T cells and proinflammatory cytokines was observed with tal + dara, supporting potential synergy of the combination in pts with prior anti-CD38 exposure. Updated results will be presented. Image:Summary/Conclusion: Longer follow-up with additional patients shows comparable efficacy and safety across both RP2Ds, with no new safety signals, strengthening the benefit-risk profile of tal + dara as a novel immunotherapy-based approach for heavily pretreated pts with RRMM.

S180: RG6234, A NOVEL GPRC5D T-CELL ENGAGING BISPECIFIC ANTIBODY, INDUCES RAPID RESPONSES IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA: PRELIMINARY RESULTS FROM A FIRST-IN-HUMAN TRIAL

Background: Patients (pts) with relapsed/refractory multiple myeloma (RRMM) are in need of effective treatment options. RG6234 is a T-cell engaging bispecific antibody targeting GPRC5D with a novel 2:1 format. NCT04557150 is an ongoing first-in-human Phase 1 trial. We present initial results from the dose-escalation part using intravenous (IV) administration. Aims: To characterize the safety of RG6234 and to identify a recommended Phase 2 dose (RP2D), and to characterize the pharmacokinetics, pharmacodynamics, and preliminary clinical activity. Methods: Eligible pts with RRMM received RG6234 in escalating weekly step-up doses followed by a q2w regimen at a peak ‘target dose’ for up to 1 year. A mCRM model was used for overdose control. Adverse events (AEs) were graded per CTCAE v5.0 and cytokine release syndrome (CRS) per ASTCT criteria (Lee et al. 2019). Response was assessed by the investigator according to IMWG criteria. All pts provided informed consent. Results: As of January 31, 2022, 41 pts had received RG6234 IV (0.006mg to 10mg). Median age was 63 years (range: 27 to 78) and 61% had R-ISS stage II or III at study entry. High-risk cytogenetics (t(4;14), t(14;16), del(17p), 1q21 gain) were present in 17/29 (58%) evaluable cases. Median number of prior therapies was 5 (range: 2 to 15). Pts were triple-class refractory in 67% of cases and penta-class refractory in 36%. Six pts (14.6%) had prior BCMA-directed therapy. CRS occurred in 85.4% of pts (G1 56.1%, G2 24.4%, G3 2.4%). CRS was generally confined to the first cycle, with a median time to onset of 4.2 hours (range: 0 to 64.2), and 14 pts (34%) requiring tocilizumab. Three pts (7.3%) experienced CNS toxicity related to RG6234 (G1 and G3 headache; G1 confusion). G3/4 neutropenia, thrombocytopenia, and anemia occurred in 9.8%, 19.5%, and 12.2% of pts, respectively. Infections were reported in 46.3% of pts (≥G3 14.6%). One patient died of an E. coli sepsis not considered related to RG6234. AEs probably related to target expression included skin-related AEs in 66% of pts (G3 7.3%), dysgeusia/ageusia (36.6%, all G1/2), dry mouth (36.6%, all G1/2), dysphagia (17.1%, all G1/2), and nail changes (12.2%, all G1/2). No discontinuations due to RG6234-related AEs occurred. The maximum tolerated dose (MTD) was not reached. Within the tested target-dose range, RG6234 serum exposure generally showed a dose-proportional increase, with a preliminary IV terminal T½ of ～5 days (mean value, n=22). At the predicted active-dose range (>0.162mg), RG6234 induced profound and rapid reductions in serum free light chains (FLC) and sBCMA. After the first treatment cycle, 93% of evaluable pts (14/15) had <1% of multiple myeloma cells in bone marrow based on flow cytometry. Overall response rate in 34 efficacy evaluable pts across all doses was 68%, and 50% achieved a VGPR or better response, including 2/6 BCMA pre-treated pts. Responses occurred rapidly, with a median time to first response of 1.3 months (95% CI: 1.1, 1.6). Median follow-up was 3.5 months (range: 0.03 to 11.7). Treatment was ongoing for 58.5% of pts at the time of the data cut. Duration of response was not mature. Response was ongoing in 18/23 (78.3%) responding pts, with a longest duration of response of 10 months. Summary/Conclusion: RG6234, a novel T-cell engaging bispecific antibody targeting GPRC5D, demonstrates compelling clinical activity with manageable safety in heavily pretreated pts with RRMM. Dose escalation via IV and subcutaneous routes continues, and data will be updated.

P1126: MOSUNETUZUMAB IS EFFICACIOUS AND WELL TOLERATED IN PATIENTS AGED &lt;65 AND ≥65 YEARS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA AND ≥2 PRIOR THERAPIES: SUBGROUP ANALYSIS OF A PIVOTAL PHASE II STUDY

Background: Advancing age is associated with a decline in immune function and an increase in the incidence of comorbidity (Castellino et al. 2017). Vulnerability to treatment-related toxicities may also increase with age. Mosunetuzumab is a T-cell engaging CD20xCD3 bispecific monoclonal antibody (Ab) that redirects T cells to eliminate malignant B cells. In a pivotal Phase II study (NCT02500407), mosunetuzumab induced deep and durable remissions and had a favorable safety profile in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior therapies (Budde et al. ASH 2021). Aims: In the current study, we evaluated the efficacy and safety of mosunetuzumab in pts aged <65 and ≥65 years (age stratification per ESMO Clinical Practice Guidelines for management of newly diagnosed and R/R FL; Dreyling et al. 2021) in the pivotal Phase II study. Methods: All pts had Grade (Gr) 1–3a FL and ECOG performance status (PS) 0–1, and were R/R to ≥2 prior therapies, including an anti-CD20 Ab and an alkylating agent. Intravenous mosunetuzumab was given in 21-day cycles with Cycle (C) 1 step-up dosing: C1 Day (D) 1: 1mg; C1D8 2mg; C1D15 and C2D1: 60mg; D1 of C3+: 30mg. Pts with a complete response (CR) by C8 completed therapy; pts with a partial response or stable disease continued treatment for up to 17 cycles, unless disease progression or unacceptable toxicity occurred. The primary endpoint was CR (as best response) rate by PET/CT assessed by Independent Review Committee using standard response criteria (Cheson et al. 2007). Cytokine release syndrome (CRS) was graded using ASTCT criteria (Lee et al. 2019). All pts provided informed consent. Results: As of August 27, 2021, 90 pts had received mosunetuzumab; 67% were aged <65 years and 33% were aged ≥65 years. Of 30 pts aged ≥65 years, median age was 71 years (range: 65–90) and 43% had ECOG PS 1 at entry, 53% had FLIPI 3–5, and 70% had Ann Arbor stage III/IV disease. Median number of prior therapies in the older age group was 3 (range: 2–8); 77% were refractory to a prior anti-CD20 Ab and 43% were double-refractory to a prior anti-CD20 Ab and an alkylating agent. Compared with younger pts, those aged ≥65 years had a numerically higher objective response rate (87% [95% CI: 69–96] vs 77% [95% CI: 64–87]) and CR rate (70% [95% CI: 51–85] vs 55% [95% CI: 42–68]). The 18-month event-free rate for duration of response was 54% (95% CI: 31–76) in pts aged ≥65 years and 59% (95% CI: 43–74) in those aged <65 years. The rate of Gr 3–4 adverse events (AEs) was comparable in the older and younger age groups (73% vs 68%, respectively). A lower rate of serious AEs of any Gr was observed in pts aged ≥65 years (37% vs 52%). One patient in each age group discontinued treatment due to mosunetuzumab-related AEs. CRS occurred less frequently in pts aged ≥65 years than in those aged <65 years (30% vs 52%), while CRS events were predominantly low-Gr in both groups (age ≥65 vs <65 years: Gr 1, 20% vs 28%; Gr 2, 7% vs 22%); high-Gr CRS was uncommon (one patient in each group). All CRS events resolved. No cases of aphasia, seizures, encephalopathy or cerebral edema occurred. Rates of serious AEs of infection (any Gr) were comparable in pts aged ≥65 and <65 years (17% vs 22%, respectively). The PK disposition of mosunetuzumab was also comparable in pts aged ≥65 and <65 years. Summary/Conclusion: Mosunetuzumab is efficacious and well tolerated in older and younger pts with R/R FL and ≥2 prior therapies. In older pts (aged ≥65 years), numerically lower rates of CRS and serious AEs were observed.

P1124: MOSUNETUZUMAB RETREATMENT IS EFFECTIVE AND WELL-TOLERATED IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA

Background: The prognosis for heavily pretreated patients (pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) is poor and there is a need for effective treatment options (Batlevi, et al. 2020; Crump, et al. 2017). Mosunetuzumab (M) is a T-cell engaging CD20xCD3 bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells (Sun, et al. 2015; Budde, et al. 2022). Results from a single-arm, Phase I/II study (NCT02500407) of M in pts with R/R aggressive and indolent NHL showed durable complete responses (CR) and a manageable safety profile (Budde, et al. 2022). Specifically, in pts with R/R follicular lymphoma (FL) after ≥2 prior therapies, M demonstrated a 60% CR rate and an 80% objective response rate with a median duration of response (DoR) of 22.8 months (Budde, et al. ASH 2021). Initial M treatment had a fixed duration (8 cycles for pts who achieved CR; 17 cycles for pts with partial response or stable disease after 8 cycles); however, for pts who achieved a CR but had progressive disease (PD) after initial treatment completion, M retreatment could be provided. We report additional data from this ongoing study to describe the M retreatment experience of pts with R/R NHL. Aims: To evaluate the efficacy and safety of M monotherapy (mono) retreatment in pts with R/R NHL from an ongoing Phase I/II study (NCT02500407). Methods: Pts with R/R NHL who achieved CR after initial treatment with intravenous (IV) M mono but subsequently developed PD after treatment completion were eligible for retreatment. Pts were retreated with IV M mono at a previously tested dose and schedule, which included step-up dosing for cytokine release syndrome (CRS) mitigation. All pts provided informed consent. Results: At the clinical cut-off date, March 15, 2021, 12 pts received M retreatment; 6 pts completed retreatment and 6 pts discontinued retreatment (PD, n=5; start of another anti-lymphoma therapy, n=1). M retreatment step-up dose schedules were as follows (Cycle [C] 1, Day [D] 1/C1D8/C1D15/C2D1/C3+D1): 1/2/13.5mg (n=1), 1/2/20mg (n=1), 1/2/27mg (n=1), 1/2/40.5mg (n=1) and 1/2/60/60/30mg (n=8). Median number of M retreatment cycles received was 8.0 (range, 2–13). Overall, 8 pts with R/R FL, 2 pts with R/R diffuse large B-cell lymphoma (DLBCL), 1 pt with R/R transformed FL (trFL) and 1 pt with R/R mantle cell lymphoma (MCL) were included in the analysis. During retreatment, 9 (75.0%) pts had an objective response (6/8 pts with R/R FL; 2/2 pts with R/R DLBCL; 1/1 pt with trFL; and 0/1 pt with MCL; Table). Six/12 pts achieved a CR (4/8 pts with R/R FL, 1/2 pts with R/R DLBCL; 1/1 pt with R/R trFL; and 0/1 pt with MCL). All pts who received M retreatment were included in the safety population and had ≥1 adverse event (AE). The most common any-grade AE and Grade 3–4 AE was hypophosphatemia (n=7, 58.3% [each]; none were serious and all events resolved with or without treatment). Four pts experienced ≥1 serious AE. No Grade 5 events were reported and no pts had an AE that led to treatment discontinuation. Three pts (25.0%) had low-grade CRS (by Lee, 2014; Grade 1, n=2; Grade 2, n=1) and there were no Grade 3–4 CRS events. Image:Summary/Conclusion: Our results show that IV M mono retreatment was efficacious in heavily pretreated pts with R/R NHL who initially achieved a CR with M treatment, but subsequently developed PD. M retreatment had a manageable safety profile, consistent with the initial treatment.

P1234: REAL-WORLD EXPERIENCE OF OUTCOMES WITH GLOFITAMAB SALVAGE THERAPY FOR RELAPSE/REFRACTORY B-CELL LYMPHOMA IN TAIWAN: MINIMAL SAFETY CONCERN WITH HEPATITIS B REACTIVATION

Background: Glofitamab, a T-cell-engaging bispecific antibody (Ab) with a novel 2:1 configuration conferring robust bivalency for CD20 and monovalency for CD3, has recently shown promising activity in its phase I/II trial as a salvage therapy in various major subtypes of B-cell lymphoma. Few studies, however, have described the use of glofitamab in a real-world clinical setting. Aims: We aimed to depict the efficacy and safety profiles of glofitamab as a salvage therapy for patients with diffuse large B-cell lymphoma (DLBCL) and other subtype of B-cell lymphoma in the real-world setting with a special focus on the risk of hepatitis B virus (HBV) reactivation. Methods: The clinical data of patients with DLBCL or other B-cell lymphomas who had received ≥3 lines of prior therapies and received glofitamab salvage therapy in a compassionate use program in Nov. 2020 - Dec. 2021 were retrospectively analyzed. The treatment protocol included obinutuzumab pretreatment 1000mg given 7 days before the first glofitamab dose, followed by step-up dose of glofitamab administration: 2.5mg on Day 1 and 10mg on Day 8 of cycle 1, and then 30mg on Day 1 of cycle 2-12 (21-day cycles). Results: As of the end of 2021, 26 patients from two medical centers in Taiwan, 11(43%) of whom were females, were enrolled. Among them, 18 were diagnosed with de novo DLBCL, 3 with transformed large B-cell lymphoma, and 5 with other subtypes of B-cell lymphoma. The median age was 57 years (26-75). Among the 18 cases with de novo DLBCL, 10(56%) had non-germinal center subtype, and 9(50%), double-hit/triple-hit lymphoma. Extra-nodal lesions were observed in 12(46%) patients, and 7(27%), marrow involvement. Elevated LDH levels occurred in 15 (58%) patients. Median prior therapies were 5 (3–10) with 24(92%) patients having received ≥4 prior therapies. All patients had received prior rituximab therapy, 6(23%), autologous or allogeneic stem cell transplantation (SCT), and 9(35%), polatuzumab salvage. Nineteen (79%) patients were refractory to their most recent regimen. Median cycles of glofitamab treatment were 5 (1-12). With the median follow-up of 9 months, the median overall survival was 6 months. The overall response and complete response rates were 50% and 23%, respectively. The remissions are durable (Figure 1): among 13 responders, 8 are continuing the treatment, 1 finished the planned 12 cycles of therapy, 1 had consolidated autologous SCT in remission status, and 2 passed away because of infections in remission status; only one case had disease relapse after achieving remission. No case has had disease progression after achieving an initial response. Cytokine releasing syndrome (CRS) occurred in 15(58%) patients; most of them occurred in the initial two cycles and were mostly of grade 1/2 severity except two cases (8%) with grade 3 CRS, both resulted from transaminitis. No grade 4/5 CRS, neurological toxicity, or fatal toxicity was observed. In terms of HBV infection, 7 patients were HBs antigen(+) and 6 of them had concurrent prophylactic HBV therapy during glofitamab treatment, whereas 11 patients were anti-HBc antibody(+)/HBs antigen(-) and 2 of them received prophylactic HBV therapy. No HBV reactivation event was observed in this cohort of patients. Image:Summary/Conclusion: In the real-world setting, glofitamab remains an effective salvage treatment for patients with heavily pretreated relapse/refractory DLBCL and B-cell lymphomas. No new safety issues were observed. With optimal prophylaxis, the risk of HBV reactivation would not be of concern during glofitamab treatment.

S184: EVALUATING TECLISTAMAB IN PATIENTS WITH RELAPSED/ REFRACTORY MULTIPLE MYELOMA FOLLOWING EXPOSURE TO OTHER B-CELL MATURATION ANTIGEN (BCMA)-TARGETED AGENTS

Background: Teclistamab (JNJ-64007957) is a T cell redirecting bispecific antibody that targets both B-cell maturation antigen (BCMA) and CD3 receptors to induce T cell mediated cytotoxicity of BCMA-expressing myeloma cells. MajesTEC-1 is an open-label, multicohort, phase 1/2 study evaluating teclistamab in patients (pts) with relapsed/ refractory multiple myeloma (RRMM) previously treated with ≥3 prior lines of therapy (LOT). An overall response rate (ORR) of 62.0% in pts with no prior anti-BCMA treatment (tx) was previously reported in a pooled analysis from phase 1 and phase 2 cohort A at a median follow-up of 7.8 mo. Aims: We report efficacy and safety results of teclistamab from cohort C, which enrolled patients who had prior exposure to anti-BCMA treatment. Methods: Eligible pts (age ≥18 y) had multiple myeloma (MM) per IMWG criteria and were previously treated with ≥3 prior LOT, including a PI, IMiD, anti-CD38 antibody, and anti-BCMA treatment (chimeric antigen receptor T cell therapy [CAR-T] or Ab drug conjugate [ADC]). Pts were enrolled using a Simon’s stage design to receive weekly subcutaneous teclistamab 1.5 mg/kg (step-up doses of 0.06 and 0.3 mg/kg). ORR per IMWG 2016 criteria was the primary endpoint. All AEs were graded per CTCAE v4.03; immune effector cell–associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) were graded per ASTCT guidelines. Results: In cohort C, 38 pts (median age 63.5 y [range 32–82]; 63% male) received teclistamab (median prior LOT 6 [range 3–14]) at the data cutoff date of Sep 7, 2021. Of the 38 patients, 25 (66%) were refractory to an anti-BCMA treatment, and 32 (84%) were refractory to last LOT. Among 25 efficacy-evaluable patients, 16 (64%) received prior ADC, 11 (44%) received prior CAR-T, and 2 pts received both. The ORR was 40% (95% CI, 21–61) at a median follow-up of 6.9 mo (range 0.7–8.7). Complete response or better were observed in 5 pts (20%). In ADC-exposed and CAR-T-exposed pts, the ORR was 38% (95% CI, 15–65) and 45% (95% CI, 17–77), respectively. Responses were rapid in most, with deepening of responses over time in 7 of 25 pts. While the median duration of response was not reached, median time to first response was 1.2 mo (range, 0.2–4.9) and to best response was 2.1 mo (range, 1.1–5.7). No new safety concerns were observed, and the safety profile was comparable with that of BMCA tx-naive pts. Infections were reported in 16 pts (42%; grade 3/4, 26%). Most common AEs (n=38) were CRS (63%; all grade 1/2; median time to CRS onset: 3 d [range, 2–6], duration of CRS: 2 d [range, 1–4]), thrombocytopenia (42%; grade 3/4, 29%), neutropenia (55%; grade 3/4, 50%), lymphopenia (40%; grade 3/4, 37%), and anemia (39%; grade 3/4 29%), Grade 3 ICANS was reported in 1 pt which resolved with supportive care and the pt remained on tx. Anti-teclistamab Abs were not detected in any pts. Baseline BCMA expression levels were comparable with those reported in BCMA tx-naive pts. Updated efficacy and safety results will be presented for 40 pts. Summary/Conclusion: These preliminary results observed with serial targeting of BCMA with teclistamab following ADC or CAR-T tx suggest a promising ORR with early responses that deepen over time. Additionally, a well-tolerated safety profile was observed in patients treated with anti-BCMA tx.

P366: BLINATUMOMAB ADDED TO PREPHASE AND CONSOLIDATION THERAPY IN NEWLY DIAGNOSED PRECURSOR B-ALL IN ADULTS. A PHASE II HOVON TRIAL

Background: The bispecific antibody blinatumomab (blina) is approved for patients(pts) with relapsed/refractory precursor B-cell ALL (ALL). It has also shown to be highly effective in MRD+ pts in first line treatment. TABLE - Pt characteristics Total, N(%) 71(100%) Age(y), median(range) 53(18-70) Age (y), N(%) ≤40 22(31%) 40-60 29(41%) >60 20(28%) BM blasts (%), N(%) ≤50% 4(6%) >50% 62(87%) Unknown 5(7%) Karyotype, N(%) Ph+ 26/71(37%) KMT2A 2/67(3%) Complex 23/67(34%) Hypodiploidy 5/67(7%) Aims: To evaluate whether blina added in upfront therapy to prephase and after consolidation (cons)-1 would increase MRD negativity measured by qPCR or flowcytometry at a cut-off of <10-4 (primary endpoint). Secondary endpoints included CR, EFS, OS, adverse events and treatment-related mortality. Methods: Pts, 18-70 years(y) old, with newly diagnosed CD19+ ALL (incl. Ph+), were included. Treatment was based on a pediatric inspired protocol (HOVON 70, Rijneveld et al., 2011) with reduced doses of anthracyclines, MTX, etoposide and PEG-ASP for pts ≥40y old. Prephase consisted of 10 days steroids, from day 5 combined with 14 days blina in the standard step-up dosing schedule. After cons-1 and after intensification 2, two 4-week blina courses were added irrespective of MRD. The protocol was amended twice due to toxicity. First, in 2018 the first PEG-ASP administration was omitted. Second, in 2021 doxorubicin, dexamethasone and PEG-ASP were reduced during intensification 1. Rituximab (if CD20+), prophylactic ITs and imatinib (if Ph+) were standard. AlloHSCT was offered to intermediate and high-risk pts. Trial was registered with ClinicalTrials.gov, identifier NCT03541083. Results: Seventy-one pts were enrolled. Pt characteristics are presented (Table). Fifteen pts discontinued treatment before blina cons-1 due to refractory disease (n=8), toxicity (n=7) or death (n=2). In the total study population, 55/71 pts (77%) achieved CR after (blina) cons-1. Among pts still on treatment after cons-1, 55/56 (98%) pts achieved CR, 50/55 (91%) reached MRD negativity. After prephase, CR was already reached in 63% and MRD negativity in 53%. Blina related AEs in prephase were as expected (83% of pts had ≥1 AE and 10% had ≥1 SAE (hepatotoxicity 3 pts, pain lymph node 1, CRS 1, pneumonia 1, renal insufficiency 1)). CRS was observed in 35% of pts, 32% of whom experienced grade 3 and no grade ≥4. During prephase 5 pts discontinued blina; during blina cons-1, 4 pts stopped blina. With a median follow-up of 17,6 months, the estimated 2-y EFS was 64% standard error (SE) ± 7% (≤60y 71% SE ± 9% and >60y 47% SE ± 12%). Overall, 14 (20%) pts died. OS after 2y was 73% SE ± 7% (≤60y 82% SE ± 8% and >60y 52% SE ± 14%) (Figure 1). For pts with Ph+ ALL, 2-y EFS was 88% SE ± 6%and OS also 88% SE ± 7%. For Ph- ALL, 2-y EFS and OS were 53% SE ± 9% and 68% SE ± 9%, resp. Among pts who reached CR on protocol (n=60), 5 (8%) had relapse, 6 (10%) died and 6 (10%) discontinued treatment due to toxicity. Until now, 22 pts proceeded to alloHSCT and 11 with maintenance. Image:Summary/Conclusion: Blina can safely be added to prephase of an intensified pediatric schedule for newly diagnosed ALL up to 70y of age, albeit with dose reductions for PEG-ASP, doxorubicin and dexamethasone. The combination increases CR and MRD negativity rate. The early addition of blina resulted in very early achievement of MRD negativity with 53% after prephase and 91% after blina cons-1. Further reductions of chemotherapy should be explored (especially for Ph+) if these results are maintained with longer follow-up.

S173: T-CELL ACTIVATION AND MYELOMA CELL KILLING CONFIRM THE MODE OF ACTION OF RG6234, A NOVEL GPRC5D T-CELL ENGAGING BISPECIFIC ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA

Background: RG6234 is a novel T-cell engaging bispecific antibody targeting G protein-coupled receptor 5D (GPRC5D) with a unique 2:1 format. GPRC5D is highly expressed on multiple myeloma (MM) cells and concurrent binding of RG6234 to GPRC5D and CD3 on T cells results in immunological synapse formation and potent T-cell directed tumor cell killing. An ongoing Phase 1 dose-escalation study (NCT04557150) is investigating the safety, clinical activity, pharmacodynamics (PD), and pharmacokinetics of RG6234 monotherapy in patients (pts) with relapsed/refractory MM (RRMM). Clinical activity was observed during dose escalation, and the safety profile was manageable (Riley et al. EHA 2022). Aims: Here, we present preliminary clinical biomarker data highlighting PD effects after intravenous (IV) administration that confirm the mechanism of action and high potency of RG6234. Methods: Exploratory biomarker analyses included data from pts treated with RG6234 doses ranging from 0.006mg to 4.8mg in dose escalation. RG6234 was administered as an IV infusion under a step-up dosing regimen, reaching the target dose not later than 2 weeks after the priming dose. Peripheral biomarkers were evaluated using whole blood flow cytometry (n=28), plasma cytokine Protein Simple ELLA (n=33), and plasma sBCMA Protein Simple ELLA (n=26). MM cells were assessed at baseline and on-treatment by bone marrow (BM) aspirate flow cytometry and by BM biopsy CD138/CD8 immunohistochemistry. Informed consent was obtained from participating pts. The clinical cut-off date for the current analysis was January 31, 2022. Results: PD changes were observed in peripheral blood at all tested doses. Cytokines (IFNg, TNFa, CXCL10, IL6, IL10, IL2, IL8) and sCD25 peaked at 4 to 24 hours (h) following the first administration, while cytokine peak magnitudes decreased at subsequent administrations. Cytokine release was followed by transient reduction of circulating T cells at 4 h after infusion, with partial recovery of peripheral T-cell counts by Day 8 after first administration. Elevation of sCD25 and IFNg in plasma (~3.2 and 33 median fold change from baseline, respectively) together with increase in T-cell proliferation (~4 median fold increase of Ki67+CD8+ T-cells) within 72 h post first infusion indicated T-cell activation. Analysis of a limited number of paired baseline and on-treatment BM biopsies (n=13) revealed that the density of CD8+ tumor-infiltrating T cells increased upon treatment in responders, indicating T-cell recruitment towards the tumor. RG6234 induced rapid depletion of MM cells, as demonstrated by a decrease of sBCMA in the plasma of responding pts already 8 days after the first administration (median 33.5% reduction from baseline in responding pts; n=15). Moreover, at the end of Cycle 1, the majority of pts (14/15) had <1% of MM cells in BM based on flow cytometry readout. GPRC5D expression was detected at baseline in all pts with evaluable bone marrow aspirate and >20 detectable MM cells (n=16). Updated exploratory biomarker data will be presented. Summary/Conclusion: Cytokine release, T-cell activation, BM infiltration, and MM cell depletion are early PD changes seen after treatment with RG6234 and precede clinical responses. These PD changes indicate that RG6234 leads to T-cell engagement in the BM of pts with RRMM and clearly demonstrate rapid and effective T-cell mediated anti-MM activity.

P1214: SUBCUTANEOUS EPCORITAMAB + R-CHOP FOR FIRST-LINE TREATMENT OF PATIENTS WITH HIGH-RISK DIFFUSE LARGE B-CELL LYMPHOMA: PHASE 1/2 UPDATE

Background: Patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) with high/poor risk according to the revised International Prognostic Index (IPI) who are treated with immunochemotherapy (IC) have a 4-y survival rate of 55% (Sehn et al, Blood 2007). Epcoritamab is a subcutaneously administered, well-tolerated, bispecific antibody with single-agent antitumor activity in relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL). As its mechanism of action and safety profile are distinct from IC, epcoritamab is well suited for use in combination therapy and in earlier lines of therapy. The suboptimal prognosis of high-risk pts may be improved with the addition of a novel agent to standard IC. Aims: To present updated results of epcoritamab + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in previously untreated pts with DLBCL and IPI 3–5 (EPCORE NHL-2 arm 1; NCT04663347). Methods: Adult pts with previously untreated CD20+ DLBCL (IPI ≥3) received subcutaneously administered epcoritamab (every wk, cycles 1–4; every 3 wk, cycles 5–6) + R-CHOP for 6 cycles of 21 d, followed by epcoritamab monotherapy (every 4 wk, in cycles of 28 d, up to 1 y). Corticosteroid prophylaxis and step-up dosing of epcoritamab were required in cycle 1 to mitigate CRS. PET-CT with contrast was used to assess response per Lugano 2014 criteria. Informed consent was obtained. Results: As of the data cutoff date of December 1, 2021, 33 pts had received epcoritamab + R-CHOP (epcoritamab 24 mg, n=4; 48 mg, n=29). Median age was 66 y (range, 19–82); median time from diagnosis to first dose of epcoritamab was 25 d (range, 5–70). At least 24% of pts had double- or triple-hit DLBCL; all had IPI ≥3. Median number of total cycles initiated was 5 (range, 1–13), and median follow-up was 3 mo (0–9.7). Among the 33 pts enrolled, 31 (94%) remained on treatment. The most common treatment-emergent adverse events (TEAEs) were neutropenia (48%; febrile neutropenia in 9% of all pts), CRS (45%), infections (42%), anemia (39%), injection-site reactions (36%), nausea (33%), constipation (30%), and pyrexia (30%). No pts discontinued epcoritamab due to TEAEs. AEs of special interest were CRS (24% grade [G] 1, 18% G2, 3% G3; resolved) and ICANS (3% G2; resolved); tumor lysis syndrome was observed in 1 pt (3% G3). Most CRS events were associated with the first full dose. Median time to resolution of CRS events was 2 d (range, 1–11); 4 pts with CRS were treated with tocilizumab. Epcoritamab was not discontinued or delayed due to CRS. There were no fatal TEAEs. Individual pt response profiles are shown in Figure 1. For efficacy-evaluable pts, irrespective of whether they had yet completed 6 cycles of therapy, the overall response rate (ORR) was 96% (24/25). Among the 10 pts who completed 6 cycles of R-CHOP and had a subsequent response assessment, the ORR and complete metabolic response (CMR) rate were 100% and 90%, respectively. These 10 pts remained in response as of the data cutoff date. The longest duration of response was 7.1+ mo and ongoing. Image:Summary/Conclusion: Epcoritamab is the first subcutaneously administered bispecific antibody to be evaluated in combination with standard IC in pts with previously untreated DLBCL. These results show that epcoritamab + R-CHOP has a manageable safety profile. CRS events were observed to be mostly of low grade and were not associated with treatment discontinuation. Rates of overall response and CMR were high, and no relapses were reported as of the data cutoff date. Updated data will be presented at the meeting.

Abstract 5588: PD-1 blockade synergizes with IMiDs to enhance bispecific T cell engager immune responses to Vk*MYChCRBN multiple myeloma by preventing T cell exhaustion

Abstract Bispecific T cell engagers (TCE) are novel immunotherapies for cancer that redirect a synthetic immune response against tumors. Early clinical trial data show that BCMA-targeting TCEs are highly effective immunotherapies for treating relapsed and refractory multiple myeloma (MM). Thus, it is important to define combinatorial approaches that increase the efficacy and durability of TCE. We recently investigated a murine anti-BCMA TCE in the immunocompetent IMiD-sensitive Vk*MYChCRBN model of MM. Our data show that anti-BCMA TCE was safe and efficacious in most mice, but failed in those with high-tumor burden, consistent with clinical reports of TCE in leukemia. We tested the combination of anti-BCMA TCE and IMiDs to provide an additive anti-tumor effect and stimulatory cytokines, such as IL-2 in the tumor environment. This combination expanded cytolytic T cells and improved activity even in IMiD-resistant high-tumor burden cases. Yet, survival was only marginally extended due to T cell exhaustion. We hypothesized that blockade of the inhibitory immune checkpoint PD-1 would synergize with TCE and IMiDs to potentiate the response directed by the TCE by reinvigorating exhausted T cells. We evaluated the efficacy of the triple therapy combination in Vk*MYChCRBN: the anti-BCMA TCE, pomalidomide, and anti-PD1. Checkpoint blockade alone, or in combination with TCE did not improve tumor control or survival compared to control treatments. The triple combination proved most effective at controlling tumor growth, inducing a complete response after 2 weeks of treatment, and was curative in 40% of the mice. Longitudinal analysis of the immune response showed that the addition of anti-PD1 to TCE-IMiDs rescued T cell expansion at tumor sites and sustained expression of activation markers after repeated doses. Longitudinal analysis of blood and bone marrow (BM) cytokines showed the typical profile associated with cytokine release syndrome (CRS) during T cell immunotherapy. Of note, we observed IL-2, IFN-γ, and GM-CSF production was sustained in the BM tumor environment in the triple combination. We suspect that these cytokines, especially IL-2, are key to sustaining non-exhausted effector T cell proliferation in response to TCE therapy. Expectedly, we observed toxicity with the elevated cytokine release in the triple combination. that we anticipate could be controlled with step-up dosing or CRS mitigation treatment. We conclude that combination of PD1 blockade, IMiDs and TCE provides superior efficacy in the immunocompetent preclinical model of MM, Vk*MYChCRBN, while increasing inflammatory pathways that can lead to CRS. Finally, as we found this combination to be curative in some mice, we will investigate whether this combination immunotherapy also enhanced an endogenous anti-tumor immune response leading to protective immunosurveillance. Citation Format: Erin W. Meermeier, Seth J. Welsh, Meaghen Sharik, Megan T. Du, Chang-Xin Shi, Bryant Chau, Feng Wang, Matthew Wheeler, Natalie Bezman, Pavel Strop, P. Leif Bergsagel, Marta Chesi. PD-1 blockade synergizes with IMiDs to enhance bispecific T cell engager immune responses to Vk*MYChCRBN multiple myeloma by preventing T cell exhaustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5588.

Abstract ND03: AMX-818: Next generation conditionally active, masked T-cell engager for the treatment of HER2-expressing solid tumors

Abstract T Cell Engagers (TCEs) are a highly potent, cancer killing modality that redirect T cell cytotoxicity against tumors that express a selected tumor-associated antigen, or TAA, bypassing the requirements for T cell recognition of tumor specific MHC/peptides. In addition to their induction of direct cytotoxicity, their potency is amplified by cytokine driven actions downstream of T cell activation that enhance the anti-tumor immune response. Because of this two-fold mechanism of action, TCEs have demonstrated clinical activity in patients with “cold” tumors that are not responsive to other immune therapies such as checkpoint inhibitors. While a razor-thin therapeutic index (TI) has been observed in hematologic malignancies for TCEs like blinatumomab, and similarly with CAR-Ts, developing solid tumor T-cell-directed therapies has been hampered by on-target off-tumor toxicities including cytokine release syndrome (CRS), other toxicities, and other challenges related to immunogenicity. Attempts to circumvent CRS include step-up dosing, prophylactic steroids, complex molecular designs, have had limited success. Unmasked TCEs targeting HER2 have been unable to achieve a therapeutic index in the clinic due to dose limiting CRS toxicities at doses below 1 ug/kg. To address this challenge, we have engineered conditionally-activated T cell engagers or XPATs (XTENylated Protease Activated T Cell Engagers), that exploit the intrinsically high protease activity in tumors relative to healthy tissues. XPATs utilize our universal protease-releasable masking technology (Pro-XTEN) to provide preferential unmasking and activation in tumors, thereby mitigating off-tumor toxicities. Several key features of the technology have clinical validation including half-life extension, protease-driven unmasking and low immunogenicity, as over 200 patients have been treated with XTENylated products. AMX-818 is a conditionally active, masked T cell engager targeting HER2. AMX-818 is comprised of a tandem scFv core with a HER2-binding domain and a proprietary low affinity CD3 binding domain with each domain masked by a protease-releasable XTEN polymer that works by spatial/steric shielding of the active domains. AMX-818 is designed to overcome the on-target, off-tumor toxicities associated with existing TCEs by mitigating toxicity against healthy tissues that express the target antigen. Extensive in vitro and in vivo preclinical testing demonstrate the potential for AMX-818 to drive anti-tumor activity similar to an unmasked TCE, yet significantly expand the safety margin in NHPs. In vitro, proteolytically-unmasked AMX-818 demonstrates potent cytotoxicity against tumor lines with EC50s in the single-digit pM range. AMX-818 reduces target-directed T cell cytotoxicity and T cell activation by up to 4 orders of magnitude, while singly-masked variants of AMX-818 show intermediate activity relative to unmasked HER2 T cell engager. Only minimal complete unmasking of AMX-818 is required to generate potent cytotoxicity. In the established HER2-high (BT-474) and HER2-low (HT-55) xenograft models, AMX-818 induced protease-dependent tumor regressions comparable to the unmasked (active) TCE while remaining stable in circulation. In vivo, preferential cleavage of XPATs were demonstrated in patient-derived xenograft tumors relative to healthy organs (average of 24% unmasked TCE was observed in tumors). In NHPs, AMX-818 demonstrated a wide safety margin (MTD of AMX-818 = 42mg/kg vs MTD of fully unmasked HER2 TCE = 0.2mg/kg/day), supported by its protease stability in circulation and a maximum tolerated Cmax that was &amp;gt;400-fold higher than that of its active form (unmasked HER2 TCE). No CRS or systemic T cell activation was observed even at 50 mg/kg, supportive of minimal CRS risk for XPATs, whereas the unmasked form induced lethal CRS at &amp;gt; 0.3 mg/kg/day. Only 1-3% of the singly-cleaved XPAT metabolites were detected in plasma from NHPs treated with high doses of AMX-818 (25 &amp; 42 mg/kg), while the fully unmasked TCE form was undetectable. In vitro studies in which AMX-818 was incubated for 7-days at 37°C in plasma from healthy and diseased NHPs and humans, (conditions which over-represent the accumulation of metabolites in vivo) demonstrate that AMX-818 is stable in plasma with comparable amounts of fully unmasked TCE generated between species. The similar rates of cleavage between species and the strong safety margin observed with AMX-818 in NHPs predict limited systemic accumulation of active TCE in human patients. In a repeat-dose GLP toxicology study, the highest dose evaluated (6 mg/kg) was the NOAEL, suggesting that HER2-XPAT has a wide TI based on predicted human PK and predicted efficacious exposures. The collective data demonstrate a significant decrease in toxicity with AMX-818 compared to its potent, fully unmasked TCE counterpart. Together with the data supporting stability of AMX-818 in plasma and healthy tissue and its preferential cleavage in tumors, the nonclinical data package supports further evaluation in a planned clinical trial. AMX-818 represents a promising solution to widen the TI for TCE activity in HER2-high and HER2-low expressing tumors. Citation Format: Bryan Irving. AMX-818: Next generation conditionally active, masked T-cell engager for the treatment of HER2-expressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND03.

Abstract CT503: A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies

Abstract Background: The over-expression of CD73 has been linked to many cancers. NZV930, an investigational, CD73-targeting monoclonal antibody (mAb), forms bidentate structures with the CD73 dimer, shutting down the catalytic activity of cell surface and soluble CD73. Taminadenant is an investigational A2AR antagonist and spartalizumab is an anti-PD-1 mAb. Preclinical studies provide compelling antitumor activity when combining CD73, A2AR, and PD-1 blockade. Methods: This first-in-human study (NCT03549000) comprised dose-escalation and dose-expansion parts. Here, we present the dose-escalation results of the four treatment (tx) arms: NZV930 single agent (SA; 60-1000 mg Q2W), NZV930 (200-600 mg Q2W) + spartalizumab (400 mg Q4W) or taminadenant (80-240 mg Q2W), or in combination with spartalizumab (400 mg Q4W) + taminadenant (80-240 mg BID). Eligible pts had selected malignancies, and disease progression following standard therapy. Primary objectives included assessing safety and tolerability and determining the recommended dose for expansion (RDE) of NZV930 SA and its combinations. Secondary objectives were to determine efficacy, characterize the pharmacokinetics (PKs) of NZV930 SA and its combinations, and assess the immunogenicity of spartalizumab and NZV930. Biomarker tumor samples were obtained at screening, C2D1, and C4D1. Results: As of June 10, 2021, 105 pts were enrolled for dose escalation, including pts with CRC (n=63), ovarian cancer (n=15), pancreatic cancer (n=11), NSCLC (n=8), TNBC (n=5), RCC (n=2), and prostate cancer (n=1). Most pts (81%) had been treated with ≥3 lines of prior therapy. In total, 98 pts discontinued, mainly due to disease progression (72%); six were ongoing. At least one tx-related adverse event (TRAE) was reported by 89 pts (85%); these were mostly grade 1-2. A triad of headache, fever, and nausea/emesis was observed after the first infusion of NZV930. Most common TRAEs (≥30%) were headache (67%), nausea and vomiting (32% each), and pyrexia (30%). At least one grade ≥3 TRAE was reported in 15 pts (14%); headache (4%) was most common, accounting for 4/7 DLTs (all grade ≥3). There were no tx-related deaths. Overall, no responses were reported; 12 pts (11%) had stable disease and 69 pts (66%) had progressive disease. NZV930 has good PK properties, with target-mediated drug disposition at lower doses, which normalize to typical IgG-like PKs at higher doses. Biomarker data confirm CD73 target engagement in plasma. Adenosine pathway modulation in tumors and plasma was seen post-NZV930 tx. Conclusions: NZV930 reduced adenosine levels in plasma and tumors. The RDE of NZV930 SA or in combination with spartalizumab and/or taminadenant is 600 mg Q2W with a step-up dosing regimen. NZV930 SA and its combinations exhibited a tolerable safety profile in multiple advanced solid tumors and showed good PK properties. Citation Format: Siqing Fu, Udai Banerji, Philippe L. Bedard, Aitana Calvo Ferrándiz, Alberto Chiappori, Jayesh Desai, Rahima Jamal, Desamparados Roda Perez, Noboru Yamamoto, Erica Vieira, Gabrielle Wong, Kulandayan K. Subramanian, Shunguang Wang, Britta Mueller, Javier A. Otero, Si-Lin Koo. A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT503.

Efficacy and safety of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): Updated results from MonumenTAL-1.

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.