Burgués, Juan Miguel Bergua

Abstract Background and Significance Diffuse large B-cell lymphoma (DLBCL) and other LBCLs account for 35–40% of non-Hodgkin lymphoma cases in North America, Europe, and East Asia. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line treatment for DLBCL, achieving cure rates in approximately 60–70% of patients. However, 30–40% of patients will relapse or become refractory (R/R) to treatment, facing poor prognosis. Patients with high International Prognostic Index (IPI) scores (3–5) and those with IPI 1–2 who have bulky disease and/or very high lactate dehydrogenase (LDH) are recognized as high-risk (HR) subsets with suboptimal outcomes (Maurer et al, ASH 2023, #4512). Novel combination strategies are an area of focus for improving efficacy in this population. GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin [COO]) and immunomodulatory activity. In the Phase 1b study CC-220-DLBCL-001, GOLCA in combination with R-CHOP demonstrated a predictable and manageable safety profile with high rates of durable responses, irrespective of COO, in previously untreated aggressive B-cell lymphomas (BCL), including promising activity in HR patients (Amzallag et al, ASH 2024, #579). The median relative dose intensity for GOLCA and CHO components was high (97–99%), indicating uncompromised delivery of curative standard-of-care treatment and combinability. GOLCA ± rituximab has also shown encouraging efficacy and safety in patients with R/R DLBCL (Bachy et al, ICML, #148). These findings support the further study of GOLCA + R-CHOP combination in the Phase 3 setting. Study Design and Methods GOLSEEK-1 (NCT06356129) is a randomized, double-blind, placebo-controlled, Phase 3 study evaluating GOLCA + R-CHOP versus placebo + R-CHOP in patients with previously untreated HR LBCL. Approximately 850 patients with previously untreated LBCL will be randomized 1:1 to either GOLCA + R-CHOP or placebo + R-CHOP. Eligible patients include those with histologically confirmed LBCL per WHO 2022 criteria—including DLBCL (not otherwise specified [NOS], ABC/GCB), high-grade BCL with MYC and BCL2 rearrangements or NOS, T-cell/histiocyte–rich LBCL, or Epstein Barr Virus-positive DLBCL. HR status is defined by IPI ≥3, or IPI 1–2 with HR features: LDH >1.3× upper limit of normal and/or bulky disease (≥7 cm lesion). All patients must have measurable disease as defined by Lugano criteria. Key exclusion criteria are other lymphoma subtypes such as primary mediastinal LBCL; primary cutaneous DLBCL-leg type, grade 3b follicular lymphoma (FL); transformed indolent lymphoma; anaplastic lymphoma kinase (ALK) positive LBCL; primary effusion lymphoma; and Burkitt lymphoma and known or suspected central nervous system involvement. Randomization will be stratified by IPI score (HR 1–2 and 3 vs 4–5) and bulky disease status (≥7 cm vs <7 cm). After a screening period of ≤4 weeks, patients will receive either GOLCA (0.4 mg) or placebo orally once daily for 7 consecutive days in each of 6 cycles, combined with R-CHOP every 21 days. The primary endpoint is progression-free survival (PFS) by investigator assessment per Lugano Response Criteria. Key secondary endpoints include PFS in non–high-grade BCL, event-free survival, independently assessed complete metabolic response, undetectable minimal residual disease by PhasED-Seq (defined as undetectable circulating tumor DNA levels at end of treatment), and overall survival. Patients will be followed up for up to approximately 67 months after beginning treatment. This study is currently recruiting at 309 sites in 36 countries , across the United States, Europe, Latin America, and East Asia. Acknowledgement BMS Artificial Intelligence was used to revise existing text with human author oversight.

Introduction Age correlates with survival in patients (pts) with DLBCL, which has a median age at diagnosis of 67 y. Recent therapeutic advances, including bispecifics and cell therapy, have promising efficacy, but safety and accessibility continue to be limited for older pts. The randomized, global, phase 3 ECHELON-3 study (NCT04404283) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with brentuximab vedotin (BV) + lenalidomide (Len) + rituximab (R; BV+Len+R) vs placebo+Len+R in pts with R/R DLBCL after ≥ 2 prior systemic therapies who were ineligible for hematopoietic stem cell transplant and/or chimeric antigen receptor (CAR) T-cell therapy. Here, we present safety and efficacy in pts aged ≥65 y. Methods In ECHELON-3, pts were randomized 1:1 to receive BV (1.2 mg/kg) or placebo every 3 weeks (q3w), in combination with R (375 mg/m2) q3w and Len (20 mg) once daily. Granulocyte colony-stimulating factor was required in all cycles. Efficacy was assessed by investigators per Lugano 2014 classification. The primary endpoint was OS, with key secondary endpoints of PFS and ORR. Other secondary endpoints included detailed safety and tolerability. This subgroup analysis comprises pts aged ≥65 y. P values are descriptive. Results A total of 155 pts aged ≥65 y were enrolled from April 2021 to November 2023 and randomized to BV+Len+R (n=79) or placebo+Len+R (n=76). The median age was 75 y (range, 65-89 y); 54% of pts were male, 59% were White, and 19% were Asian. Twenty-three percent and 54% had Ann Arbor stage III and IV disease, respectively, and 64% had high-intermediate or high International Prognostic Index scores (3-5) at enrollment. The most common DLBCL subtype was DLBCL not otherwise specified (58%). Twenty-nine percent of pts had transformed DLBCL. Approximately half (49%) of pts had primary refractory disease, and 81% had disease refractory to their most recent prior line of therapy. Seventy percent of pts had <1% CD30 expression via IHC; 48% of cases had germinal center B-cell origin. Prior CAR-T was reported in 21.9% of pts. At a median follow-up of 16.8 mo (95% CI, 14.3-19.5 mo), median OS was 15.9 mo (95% CI, 11.7 mo-not estimable [NE]) with BV+Len+R vs 8.5 mo (95% CI, 5.5-11.5 mo) with placebo+Len+R (hazard ratio [HR], 0.540; 95% CI, 0.351-0.830; P=.0043). Median PFS was 5.7 mo (95% CI, 4.1-12.7 mo) with BV+Len+R vs 2.8 mo (95% CI, 1.9-4.1 mo) with placebo+Len+R (HR, 0.478; 95% CI, 0.318-0.718; P=.0003). ORR was 70.9% (95% CI, 59.6%-80.6%) with BV+Len+R vs 46.1% (95% CI, 34.5%-57.9%) with placebo+Len+R (P=.0020); complete response (CR) rate was 45.6% vs 19.7%, respectively. Median time to CR was 1.61 mo with both BV+Len+R and placebo+Len+R (range, 1.2-7.3 vs 0.7-4.6 mo, respectively). Median duration of CR was 18.9 mo (95% CI, 12.4 mo-NE) with BV+Len+R vs 5.4 mo (95% CI, 2.8 mo-NE) with placebo+Len+R (HR, 0.416; 95% CI, 0.139-1.250). In total, 154 pts were evaluable for safety analysis (75 pts in placebo+Len+R group). The median number of cycles was 5 (range, 1-34) vs 3 (range, 1-31) in the BV+Len+R and placebo+Len+R groups, respectively. The percentage of pts with any treatment-emergent adverse event (TEAE) was similar between groups (97% with BV+Len+R and 99% with placebo+Len+R); grade ≥3 TEAEs occurred in 89% of pts in the BV+Len+R group and 76% in the placebo+Len+R group. Serious TEAEs and TEAEs leading to death were reported more frequently in the BV+Len+R group (62% and 13%, respectively) than the placebo+Len+R group (47% and 8%, respectively). More pts discontinued study treatment due to TEAEs in the BV+Len+R group than the placebo+Len+R group (20% vs 8%). In total, 39% of pts on BV+Len+R had a peripheral neuropathy event vs 27% of pts on placebo+Len+R; however, the majority of cases were grade 1 (22% and 17%, respectively). Additional information on older pts will be presented. Conclusions BV+Len+R demonstrated a clinically meaningful improvement in all key efficacy outcomes in pts aged ≥65 y, which is consistent with the overall ECHELON-3 population (median age 74 y; 70.5% of pts aged ≥65 y in BV+Len+R group). Differences in some safety endpoints are likely attributable to longer duration of treatment in the BV+Len+R group. No clinically meaningful safety trends in pts aged ≥65 y were identified. These results suggest that BV+Len+R may be an effective treatment option in older pts with R/R DLBCL.

LBA7005 Background: Despite recent advances, there remains a need for novel therapies for pts with R/R DLBCL. BV, an anti-CD30 antibody-drug conjugate, has shown efficacy and safety when combined with lenalidomide (len) and with rituximab (R) in heavily pretreated populations (Bartlett 2022; Ward 2022). The double-blind, global phase 3 ECHELON-3 study (NCT04404283) compared BV with R+len (R2) vs R2 in pts with R/R DLBCL who are ineligible for HSCT or CAR T-cell therapy. Here, we present results from the interim analysis (IA) for overall survival (OS). Methods: Pts with R/R DLBCL received BV+R2 or placebo+R2 (randomized 1:1). Pts received BV (1.2 mg/kg) or placebo q3w, R (375 mg/m2) q3w, and len (20 mg) qd. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (ORR), and complete response (CR) rate. The preplanned IA was performed at 134 OS events with a prespecified efficacy boundary of 2-sided P=0.0232. Results: 230 pts were randomized: 112 to BV+R2 and 118 to R2; all but 2 pts (both in R2 arm) received ≥1 dose of study drug. Median age was 71 yrs (range, 21-89), 56.5% were male, and 10.9% had an ECOG of 2. Median prior lines of therapy was 3 (range, 2-8); 29% had prior CAR T-cell therapy and 68% were CD30- (<1% CD30 tumor expression). At median follow-up of 16.4 months (mos) (range, 0.1-31.5) (cut-off: January 22, 2024), median OS was 13.8 mos (95% CI: 10.3-18.8) with BV+R2 vs 8.5 mos (95% CI: 5.4-11.7) with R2 (HR 0.629; 95% CI: 0.445-0.891; P=0.0085); OS benefit was consistent across key subgroups. Median PFS was 4.2 mos (95% CI: 2.9-7.1) with BV+R2 vs 2.6 mos (95% CI: 1.4-3.1) with R2 (HR 0.527; 95% CI: 0.380-0.729; P<0.0001). ORR was 64.3% (95% CI: 54.7-73.1) with BV+R2 vs 41.5% with R2 (95% CI: 32.5-51.0; P=0.0006); CR rate was 40.2% vs 18.6%, respectively. In CD30+ vs CD30- subgroups, ORR/CR was 72.2%/38.9% vs 60.5%/40.8% with BV+R2, respectively, and 50.0%/26.3% vs 37.5%/15.0% with R2, respectively. Efficacy analysis including cell of origin will be presented. The safety profile of BV+R2 was tolerable vs R2: Grade (Gr) ≥3 treatment-emergent adverse events (TEAEs) were 88% vs 77%, serious TEAEs were 60% vs 50%, and Gr 5 TEAEs were 12% vs 8%, respectively. Most common TEAEs were neutropenia (46% vs 32%), anemia (29% vs 27%), and diarrhea (31% vs 23%). Rates of peripheral neuropathy for BV+R2 vs R2 were 31% vs 24% (all Gr) and 6% vs 2% (Gr 3). Median treatment duration was 3.6 mos with BV+R2 vs 2.0 mos with R2. Conclusions: Treatment with BV+R2 triplet, compared to R2, demonstrated statistically significant and clinically meaningful improvements in all key efficacy outcomes including OS in high-risk subgroups, with manageable safety. This triplet regimen represents a novel treatment option for pts with heavily pretreated R/R DLBCL. Clinical trial information: NCT04404283 .

Background: Menin, a protein involved in transcriptional regulation, plays a role in the genesis of multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, oral small-molecule inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 is the first and only covalent menin inhibitor in clinical development and is being evaluated in multiple hematologic malignancies, solid tumors, and diabetes mellitus. COVALENT-101 (NCT05153330) is a Phase I dose-escalation and -expansion study of BMF-219 in R/R AL (Cohort 1), DLBCL (Cohort 2), MM (Cohort 3), and CLL (Cohort 4). Here we report preliminary safety, PK and anticancer activity data from Cohort 1 (AL). Methods: Doses of BMF-219 are escalated independently for each indication, initially in single-subject cohorts followed by a “3 + 3” design. Eligible patients (pts) include adults with R/R AL ineligible for standard therapy. Initially pts were enrolled agnostic to molecular status. A subsequent amendment introduced quotas for KMT2Ar (MLL1r), NPM1 and other known menin-dependent mutations: CEBP/A, MLL1-PTD, MN1, NUP98, NUP214, PICALM-AF10, SETBP1. Prior exposure to reversible menin inhibitor therapy is permitted. Subjects receive BMF-219 daily for continuous 28-day cycles until progression/intolerability. There are 2 parallel dose-escalation arms: pts not taking (Arm A) or taking (Arm B) moderate or strong CYP3A4 inhibitors. The study is ongoing and accruing in the escalation. Expansion cohorts will enroll pts to obtain further safety and efficacy data at the OBD/RP2D. Results: As of data cutoff of 7/24/2023, 26 pts with R/R AL (24 AML; 2 ALL) are enrolled; 7 remain on study treatment. Baseline characteristics include 17(65%) males and 9(35%) females with a median age of 57.5 years (range 33-84). There is a median of 4 (range 1-8) prior lines of therapy and 11 (42%) with prior HSCT(s). Six pts (23%) had KMT2Ar, 3 (12%) KMT2A-PTD, 4 (15%) NPM1, and 13 (50%) WT for KMT2A and NPM1. Dosing began with single-patient cohorts at 100 mg QD (Arm A) and 25 mg QD (Arm B) and has been escalated through 4 dose levels. Thus far, pts have been dosed up to 500 mg QD (Arm A) and 125 mg QD (Arm B). BMF-219 exposures were comparable between arms, with ~2-4-fold higher exposures observed with co-administration of a moderate or strong CYP3A4 inhibitor. At the highest dose (DL4) in which PK was evaluated, Arm A (500 mg QD) and Arm B (125 mg QD), pts on average achieved ~50% of target exposure (2000 ng*hr/mL) with some pts surpassing it. Higher QD dosing or corresponding BID dosing is expected to achieve desired exposure. BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. No related QTc prolongation was observed. At the time of data cutoff, 23 of 26 pts were included in the safety population. Common TRAEs (≥10%) include vomiting 13% (3) and Differentiation Syndrome (DS) 13% (3). No Grade 5 TRAEs were reported. The only common Grade ≥3 TRAE (≥5%) was DS 13% (3). The efficacy evaluable population includes AML pts who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least one scheduled response assessment (or had a minimum of 7 doses if discontinued prematurely). Thus far, 2 of 5 efficacy evaluable patients achieved a complete remission (1 CR; 1 CRi) and both continue BMF-219 treatment. Patient A: 39/M, NUP98-NSD1, ECOG=0, 500 mg QD, Arm A, 4 prior lines of treatment including intensive chemotherapy and allo-HSCT. At C1D27, marrow blasts were reduced to 6% from 13% at study entry. The patient achieved CR at C2D28 with 0% blasts.Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. At C1D28, marrow blasts were reduced to 34% from 52% at study entry. The patient achieved CRi with 3% blasts at C2D28. Conclusion: BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups. The trial is ongoing and includes enrollment for pts diagnosed with AL, DLBCL, MM and CLL.

e19553 Background: The combination of tafa + LEN has accelerated approval in the United States (2020) and conditional approval in Canada and Europe (2021) for R/R DLBCL in ASCT-ineligible adult pts. A tolerable safety profile for R-CHOP + tafa ± LEN in pts with newly diagnosed DLBCL in the Phase Ib First-MIND study (NCT04134936) was previously reported, with numerically superior efficacy for R-CHOP + tafa + LEN (ASH 2021; #3556). We report PK, PD, and immunogenicity of R-CHOP + tafa ± LEN in this first line setting. Methods: Eligible pts ≥18 years with treatment-naïve DLBCL, IPI 2–5, and ECOG PS 0–2 were randomized 1:1 to either six 21-day (D) cycles (C) of R-CHOP (R-CHO, D1; P, D1–5) + tafa (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafa + LEN (25 mg orally, D1–10) (Arm B). Secondary endpoints included tafa serum conc and number and percentage of pts developing anti-tafa Abs. Exploratory endpoints included natural killer (NK) cell, T-cell, and B-cell count in peripheral blood. Results: Data cut-off: 13 March 2021 for safety analysis, incl. ≥1 month follow-up after EoT visit for all pts; 15 September 2021 for efficacy. Tafa serum conc reached steady state by C3 (geometric mean trough conc: Arm A, 186.40–216.55 µg/mL; Arm B, 171.77–201.54 µg/mL) and steadily declined after treatment completion. Anti-tafa Abs were detected in 1/65 (1.5%) pts. This pt showed pre-existing tafa Abs at baseline, which decreased during treatment. Median NK cell count decreased from baseline at C1D8 but was at baseline or higher levels by EoT visit (Arm A) and C1D15 (Arm B; Table). T-cell count decreased from baseline at C1D8 in both arms but was at baseline level or higher by C1D15 (Arm A) and EoT visit (Arm B). Median B-cell count decreased from baseline to 0 cells/μL (Arm A, C1D15; Arm B, C1D8); at 6-month follow-up after EoT visit, B-cell count had recovered to measurable levels in ̃50% of pts. Conclusions: Tafa serum conc reached and maintained a therapeutic dose level in this first-line regimen and declined in line with known tafa half-life (̃16 days) after treatment completion; tafa levels were comparable between the two treatment arms. No pt developed treatment-induced or treatment-boosted anti-tafa Abs. Median NK-cell, T-cell, and B-cell counts were comparable between treatment arms in all cycles. Clinical trial information: NCT04134936. [Table: see text]

Abstract Introduction Tafasitamab is a humanized, Fc-modified, anti-CD19 monoclonal antibody (mAb) shown to enhance antibody-dependent cellular cytotoxicity and phagocytosis. It is approved by the FDA under accelerated approval (July 2020) in combination with lenalidomide (LEN) for treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in adult patients ineligible for autologous stem cell transplantation. To evaluate if newly diagnosed DLBCL patients would also benefit from this regimen, this Phase Ib study (First-MIND; NCT04134936) was designed to first assess the safety and tolerability of tafasitamab ± LEN in addition to rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in newly diagnosed DLBCL patients. Methods Eligible patients were ≥18 years old, with treatment-naïve DLBCL, international prognostic index (IPI) 2-5 and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients with known double- or triple-hit and transformed lymphoma were excluded. Patients were randomized 1:1 to either six 21-day [D] cycles of R-CHOP (R-CHO, D1; P, D1-5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafasitamab + LEN (25 mg orally, D1-10) (Arm B). Granulocyte colony-stimulating factor and venous thromboembolism prophylaxis was mandatory. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs); secondary endpoints included overall response rate (ORR), positron emission tomography (PET)-complete response (CR) rate, and partial response (PR) rate at end of treatment (EOT). Tumor measurements by PET/CT or PET/MRI at EOT were performed according to Lugano 2014 criteria within 6±2 weeks after Day 21 of the last treatment cycle the patient started. Results From December 2019 to August 2020, 83 patients were screened in nine countries across 34 sites in Europe and the US; 66 were randomized (Arm A, n=33; Arm B, n=33). Data cut-off for this analysis: 13 March 2021. Median age was 64.5 years (range 20-86). Many patients had high-risk disease: IPI 2: 24/66 (36.4%), IPI 3: 29/66 (43.9%), IPI 4: 11/66 (16.7%), IPI 5: 2/66 (3.0%); ECOG PS ≥2: 6/66 (9.1%). Most patients had Stage III/IV disease 62/66 (93.9%); 29/66 (43.9%) had bulky disease. All patients experienced at least one TEAE. The most frequent Grade ≥3 TEAEs by system organ class were blood and lymphatic disorders (81.8% patients overall), experienced by 24 patients (72.7%) in Arm A and 30 patients (90.9%) in Arm B. Grade ≥3 neutropenia and thrombocytopenia occurred in 19/33 (57.6%) and 4/33 (12.1%) (Arm A), and 28/33 (84.8%) and 12/33 (36.4%) (Arm B) patients, respectively; Grade ≥3 febrile neutropenia was experienced by 6/33 (18.2%) patients in each arm. Grade ≥3 infusion-related reactions to both rituximab and tafasitamab occurred in no patients in Arm A and one patient (3.0%) in Arm B, and 7/33 (21.2%) (Arm A) and 9/33 (27.3%) (Arm B) patients had a Grade ≥3 infection and/or infestation (Figure 1). Serious TEAEs occurred in 14/33 (42.4%) patients in Arm A and 17/33 (51.5%) patients in Arm B. Two out of 33 (6.1%) and one out of 33 (3.0%) patients discontinued study treatment due to TEAEs in Arms A and B, respectively. There were four deaths unrelated to tafasitamab and/or LEN (COVID-19 pneumonia, sepsis, and urosepsis). The average relative dose intensity of R-CHOP in each cycle was maintained in both arms. ORR at EOT was observed in 25/33 patients (75.8%; 95% confidence interval [CI]: 57.7-88.9) in Arm A and 27/33 patients (81.8%; 95% CI: 64.5-93.0) in Arm B. Conclusion These data suggest that both regimens are tolerable and do not impair dosing and scheduling of R-CHOP. Toxicities were similar to those expected with R-CHOP with or without LEN. With tumor follow-up still ongoing, the ORR at EOT suggests that patients with treatment-naïve DLBCL may achieve clinically meaningful efficacy tafasitamab and LEN in addition to standard treatment. A Phase III, multicenter, randomized, double-blind, placebo-controlled trial will assess efficacy and safety of R-CHOP + tafasitamab + LEN vs R-CHOP in newly diagnosed patients with high intermediate and high risk DLBCL, and is currently recruiting (frontMIND study; NCT04824092). Funding: MorphoSys AG. Figure 1 Figure 1. Disclosures Belada: Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Gilead Sciences: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen-Cilag: Consultancy, Research Funding; Takeda: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; MorphoSys AG: Consultancy, Research Funding; Debiopharm Group: Consultancy; Pharmacyclics: Research Funding; Archigen Biotech: Research Funding; Reddys: Research Funding. André: Johnson & Johnson: Research Funding; Roche: Other: Travel/accomodation/expenses, Research Funding; Incyte: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Research Funding; Celgene: Other: Travel/accomodation/expenses; AbbVie: Other: Travel/accomodation/expenses. Pérez Persona: Amgen: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; BMS/Celgene: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; AbbVie: Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; GSK: Consultancy; Incyte: Consultancy. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Trneny: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria. Brackertz: MorphoSys AG: Current Employment. Shah: MorphoSys AG: Current Employment. Sporchia: MorphoSys AG: Current Employment. Burke: MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; Bristol Myers Squibb: Consultancy; Kymera: Consultancy; X4 Pharmaceuticals: Consultancy; AbbVie: Consultancy; SeaGen: Consultancy, Speakers Bureau; Kura: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Beigene: Consultancy, Speakers Bureau. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Tafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. In combination with lenalidomide (LEN), it received accelerated approval in July 2020 for adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), including arising from lowâ€'grade lymphoma, who are ineligible for autologous stem cell transplant (ASCT). Following FDA approval, we are now evaluating the safety and efficacy of tafasitamab in combination with LEN as an add-on to first-line therapy with R-CHOP in newly diagnosed patients with DLBCL.

Introduction Approximately 15-20% of treatment-naïve patients with diffuse large B-cell lymphoma (DLBCL) have CD20-low tumors, while CD19 is homogeneously expressed in &gt;90% of cases of DLBCL. CD20-low DLBCL is associated with poor response to rituximab-based regimens (Johnson NA, et al. 2009). CD19 functions as a positive regulator of B-cell receptor signaling and is important for B-cell activation and proliferation and is therefore an attractive therapeutic target in addition to CD20. Tafasitamab (MOR208) is a humanized, Fc-enhanced, anti-CD19 monoclonal antibody with improved antibody-dependent cellular cytotoxicity and phagocytosis. Monotherapy with tafasitamab has shown clinical activity in relapsed/refractory (R/R) non-Hodgkin's lymphoma (Jurczak W, et al. 2018). In the Phase II, single-arm L-MIND study (NCT02399085) in patients with R/R DLBCL, combined treatment of tafasitamab with lenalidomide resulted in a high proportion of patients having a complete response (Salles GA, et al. 2020). First-MIND (NCT04134936) is a Phase Ib, randomized study of tafasitamab + R-CHOP (Arm A) or tafasitamab + lenalidomide + R-CHOP (Arm B) in patients with newly diagnosed DLBCL. Here, we report data from the safety run-in phase. Study design and methods Patients must be aged ≥18 years, treatment naïve, with histologically confirmed DLBCL not otherwise specified and have intermediate- to high-risk disease (International Prognostic Index [IPI] 2-5) and an ECOG performance status of 0-2. Known double- or triple-hit lymphoma and transformed lymphoma are excluded. Treatment consists of six 21-day cycles of tafasitamab (12 mg/kg intravenously [IV], on Day [D] 1, 8 and 15) in addition to R-CHOP (Arm A) or tafasitamab (12 mg/kg IV, on D1, 8 and 15) + lenalidomide (25 mg orally, on D1-10) in addition to R-CHOP (Arm B). Granulocyte-colony stimulating factor prophylaxis was mandatory in all patients. The study includes a safety run-in phase and a main phase. In the safety run-in phase, 24 patients were enrolled. The primary objective is to assess safety; secondary objectives include ORR, PET-CR rate at end of treatment, PFS, event-free survival, long-term safety, pharmacokinetics and immunogenicity of tafasitamab. Exploratory objectives include the assessment of circulating cell-free tumor DNA. Approximately 60 patients will be recruited in 9 countries across Europe and the US. Results Recruitment is ongoing. Thirty-six patients were randomized; 18 in each arm. The data presented for the safety run-in phase consist of 24 patients: 13 patients in Arm A and 11 patients in Arm B. All completed the first treatment cycle; 88% of patients entered into Cycle 2 and 50% of patients entered into Cycle 3 of treatment. At baseline, their median age was 67 years (range: 47-76; Arm A) and 65 years (range: 40-74; Arm B). Overall, 33% of patients were male and 67% female; IPI scores were: IPI 2, 33%; IPI 3, 42%; IPI 4, 25%. Most patients had advanced stages III/IV (92%) and approximately 50% had bulky disease. Cell of origin was determined to be germinal center B-cell (GCB) DLBCL in 13%, non-GCB DLBCL in 42% and not yet classified in 46% of cases. A total of 248 treatment-emergent adverse events (AEs) by system organ class were documented: 111 in Arm A and 137 in Arm B. Grade ≥3 neutropenia was observed in 54% (Arm A) and 46% (Arm B) of patients. Thrombocytopenia Grade ≥3 was observed in 8% (Arm A) and 18% (Arm B) of patients. Diarrhea, fatigue and vomiting were comparable between the two arms. Febrile neutropenia was uncommon in both arms, with one event each (Figure 1). To date, 23 serious AEs were observed: 11 in Arm A (Grade 2, 1; Grade 3, 6; Grade 4, 4) and 12 in Arm B (Grade 2, 3; Grade 3, 7; Grade 4, 2). One suspected unexpected serious adverse reaction was reported in Arm B - pneumocystis jirovecii pneumonia. No treatment-associated deaths occurred. Conclusions R-CHOP can be safely combined with tafasitamab or tafasitamab + lenalidomide in patients with treatment-naïve DLBCL. Toxicities appear to be similar to what is expected with R-CHOP alone or in combination with lenalidomide. Enrollment is ongoing and updated safety and early efficacy data will be presented at the meeting. Disclosures Belada: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nowakowski:NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. André:Takeda: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Johnson & Johnson: Research Funding; Celgene: Other, Research Funding; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Stevens:Amgen, MorphoSys: Consultancy. Trněný:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel Expenses; Gilead: Consultancy, Honoraria, Other: Travel Expenses. Pérez Persona:Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Jannsen: Consultancy, Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy. Klöpfer:MorphoSys AG: Current Employment. Brackertz:MorphoSys AG: Current Employment. Lohrmann:MorphoSys AG: Current Employment. Lahiry:MorphoSys AG: Current Employment. Shah:MorphoSys AG: Current Employment. Fingerle-Rowson:MorphoSys AG: Current Employment. Brugger:MorphoSys AG: Current Employment. Burke:Epizyme: Consultancy; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Kura: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; AbbVie: Consultancy; Verastem: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Adaptive: Consultancy; Morphosys: Consultancy.

Introduction: The phase 3 international, randomized, double-blind ROBUST clinical trial (NCT02285062) compared progression-free survival between patients with previously untreated ABC-type DLBCL treated with placebo plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (placebo-R-CHOP) versus lenalidomide + R-CHOP (R2-CHOP) for 6 21-day cycles. HRQoL, as measured by the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EuroQoL 5-dimension 3-level (EQ-5D-3L) patient-reported questionnaires, was evaluated as a secondary endpoint for the 2 treatment arms. Methods: For each treatment group, FACT-Lym and EQ-5D-3L scores were measured at baseline (BL), mid-, end-of-treatment (EOT), and post-treatment, in 12-week intervals from Week 34 onward. Patients were evaluated if they had completed BL and ≥ 1 post-BL calculable FACT-Lym subscale measurements. Non-inferiority (NI) of R2-CHOP versus placebo-R-CHOP was measured for 4 key FACT-Lym subscales: Physical Well-Being (PWB), Additional Concerns (AC), Functional Well-Being (FWB), and Trial Outcome Index (TOI). NI was assessed at EOT (typically 3-4 weeks after completing Cycle 6) and at post-treatment follow-up at Week 34 by analysis of covariance (ANCOVA). The NI margins were prespecified as 1 less than the higher published minimal important difference (MID) for each subscale. Since a range of MIDs have been published, a more conservative value was also used as a sensitivity analysis. Time to improvement (TTI), using published responder definitions, was also assessed for the FACT-Lym subscales. EQ-5D-3L scores were summarized descriptively. Results: Demographic and baseline disease characteristics were balanced across the 2 treatment arms (N = 285 per arm). The percentage of patients who completed the FACT-Lym out of the expected population remained &gt; 85% at all time points with &gt; 50 patients still on the study in each treatment arm up to Week 142. Completion rates and reasons for missing assessments were balanced across the 2 treatment arms. FACT-Lym subscale scores were generally higher after EOT, similar for both treatment groups, and mean changes from BL were close to or above MID (where defined), except for the Social/Family Well-Being subscale. Mean differences in FACT-Lym TOI between treatment arms are shown in Table 1. As positive treatment differences favor R2-CHOP and -10 was the predefined NI margin, NI was demonstrated for the FACT-Lym TOI subscale at both EOT and Week 34 assessments. Superiority of R2-CHOP was demonstrated at EOT as the confidence interval (CI) lies completely above 0 (P &lt; 0.04); however, this difference was not clinically meaningful. Furthermore, NI was also demonstrated when using the sensitivity analysis margin of -4.5. ANCOVA models were also fitted for the other key subscales of PWB, AC and FWB (Table 2). NI was demonstrated for all NI margins at both time points for the PWB and AC subscales. The FACT-Lym FWB subscale demonstrated NI for both margins at EOT and Week 34 for the primary NI margin of -2 based on the MID minus 1, but did not demonstrate NI when an NI margin of -1, based on an alternative published MID, was used. The TTI curves and associated summary statistics were similar for the 2 treatment arms, with a median TTI for the FACT-Lym TOI of 21 weeks (95% CI 15-22) for patients treated with R2-CHOP and 18 weeks (95% CI 15-22) for patients treated with placebo-R-CHOP. Mean EQ-5D-3L visual analogue scale (VAS) and Utility Index (UK weights) change from baseline scores were higher in both treatment arms and the mean changes were above, or close to, the published MID (7 for VAS, 0.1 for Utility Index) at EOT assessments. Prespecified sensitivity and subgroup analyses supported the conclusions from the primary HRQoL analyses. Conclusions: The predefined NI levels were met for the 4 key FACT-Lym subscales. Similar results were observed across the other HRQoL assessments, sensitivity, and subgroup analyses. Adding lenalidomide to the R-CHOP regimen did not adversely affect the HRQoL of patients with DLBCL as measured by FACT-Lym and EQ-5D-3L. These data serve as a benchmark for future clinical trials combining next-generation immunomodulatory drugs with standard R-CHOP to improve clinical efficacy while maintaining HRQoL in patients with DLBCL. HRQoL analyses should become an integral part of future clinical trials of novel combination regimens in DLBCL. Disclosures Chiappella: Roche: Speakers Bureau; Teva: Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau. Cocks:Adelphi Values: Employment; Amgen: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy; Endomag Ltd.: Consultancy. Greenwood:Adelphi Values: Employment. Williams:Adelphi Values: Employment. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Janssen: Consultancy, Research Funding. Yamamoto:SymBio: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria; Sanofi: Honoraria; Astra-Zeneca: Consultancy, Research Funding; Sumitomo Dainippon: Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Gilead Sciences: Research Funding; Solasia Pharma: Research Funding; Bayer: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; ARIAD: Research Funding; Pfizer: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Kyowa Kirin: Honoraria; MSD: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; Incyte: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Jurczak:Bayer: Research Funding; Takeda: Research Funding; Gilead: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Incyte: Research Funding; Celgene Corporation: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding. Özcan:Sanofi: Other: Travel support; Abdi Ibrahim: Other: Travel support; BMS: Other: Travel support; Takeda: Honoraria, Other: Travel support, Research Funding; Archigen: Research Funding; Roche: Other: Travel support, Research Funding; Bayer: Research Funding; Janssen: Other: Travel support, Research Funding; Celgene Corporation: Research Funding, Travel support; AbbVie: Other: Travel support, Research Funding; MSD: Research Funding; Novartis: Research Funding; Jazz: Other: Travel support; Amgen: Honoraria, Other: Travel support. Belada:Roche: Consultancy; Gilead Sciences: Consultancy; Takeda: Consultancy. Margunato-Debay:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Zhai:Celgene Corporation: Employment, Equity Ownership. Braverman:Celgene Corporation: Employment. Vitolo:Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.