MorphoSys

3102 Background: EZH2 inhibition antitumor activity occurs through various mechanistic pathways in multiple tumor types, including via synthetic lethality in advanced ARID1A -mutated ovarian clear cell carcinoma (OCCC) and endometrial carcinoma (EC). Oral, next-generation, dual EZH2/EZH1 inhibitor tulmimetostat is in Phase II evaluation in multiple disease cohorts (NCT04104776; Oaknin et al. ASCO 2024, ESMO 2024). We report updated efficacy and safety data from the ARID1A -mutated OCCC/EC cohorts, including dose optimization and expansion arms. Methods: Phase II Stage 1 evaluated tulmimetostat 350 mg once daily (QD). Stage 2 dose-optimization design randomizes further patients with OCCC (M2) or EC (M3) to 200 mg or 300 mg tulmimetostat QD in Stage 2a, with an efficacy gateway for each arm to open Stage 2b. Primary endpoint is objective response rate (complete response [CR] + partial response [PR]), and secondary objectives include safety. Results: As of October 15, 2024, enrollment into the M2/M3 200 mg, 300 mg, and 350 mg arms included 20/10, 21/21 and 14/11 patients, respectively. A total of 56.4% M2 and 61.9% M3 patients received ≥3 prior lines of therapy. Most responses were seen in the M2 200 mg arm and in the M3 350 mg arm (n=4 each; Table). The safety profile across arms was consistent with the EZH1/2 drug class. In M2/M3 cohorts, treatment-emergent adverse events (TEAEs) leading to dose modifications were reported in 55.0%/60.0%, 71.4%/85.7%, and 92.9%/90.9% of patients at 200 mg, 300 mg, and 350 mg, respectively. TEAEs leading to treatment discontinuation were reported in 5.0%/20.0%, 4.8%/4.8%, and 14.3%/9.1%, respectively. Serious TEAEs considered at least possibly related (TRAEs) to tulmimetostat treatment were reported in 5.0%/0%, 9.5%/14.3%, and 21.4%/27.3%, respectively. Grade ≥3 TRAEs were mainly hematologic (Table); no TRAEs leading to death were reported. Conclusions: Tulmimetostat showed an improved and acceptable safety profile in OCCC and EC at 200 mg and 300 mg doses (versus 350 mg) with promising antitumor activity, supporting further clinical investigation. Clinical trial information: NCT04104776 . Best confirmed responses and most common grade ≥3 related TEAEs. Cohort M2: OCCC M3: EC Dose, mg 200 300 350 200 300 350 Efficacy evaluable*, N 20 20 14 10 15 11 Best confirmed response † , n CRPRStable disease 0410 0210 0 17 008 115 042 Progressive diseaseNo post-baseline response assessment 51 71 60 11 71 41 Safety evaluable, N 20 21 14 10 21 11 Grade ≥3 related TEAEs ‡ , n (%) Thrombocytopenia 1 (5) 3 (14) 4 (29) 0 4 (19) 2 (18) Anemia 3 (15) 0 7 (50) 0 5 (24) 1 (9) Neutropenia 0 0 2 (14) 0 0 4 (36) Diarrhea 0 4 (19) 0 0 0 2 (18) Data cut off: October 15, 2024. *Patients who received ≥1 dose, had ≥1 post-baseline response assessment, or discontinued treatment prior to first post-baseline assessment for any reason. † RECIST 1.1. ‡ >10% in any M2/M3 arm.

Aim: Patient reporting of adverse events (AE) is still rare in oncological drug development. It should however be a crucial part of clinical studies and medical decision making. The PRO-CTCAE instrument has been generated from observer based AE assessment to represent the patients’ view in 124 items. This review examines the psychometric quality of the PRO CTCAE as tested in selected cancer patient groups and published in core papers. Method: A literature review identified 3 league papers describing the original development of the PRO-CTCAE. Using the COSMIN quality criteria for patient-reported outcome measures, the psychometric performance of the PRO-CTCAE was systematically examined. Results: Sufficient information on COSMIN quality standards were only present in 2 of the 10 criteria with EORTC QLQ-C30 used as a validation anchor, providing only limited evidence for reliability or validity. For 5 out of the 10 criteria no information at all is available. Conclusion: PRO-CTCAE is a useful list of items which has been psychometrically tested on individual item level, but not on a scale level. The development of a measurement model and consecutive psychometric testing is recommended to provide information on test-theoretical performance on the aggregate level including scoring and comparison to reference populations. This would transform the PRO-CTCAE items from a list to a tool which can be used in patient-reported AE assessments within and across oncological trials. Future research should focus on explaining potential differences between physicians and patient ratings, on cross-cultural comparability of the tool, and on the impact of PRO-CTCAE as a unique instrument for patient reported outcomes in clinical research and medical decision making.

BACKGROUND:Antibody-mediated rejection is a leading cause of kidney-transplant failure. The targeting of CD38 to inhibit graft injury caused by alloantibodies and natural killer (NK) cells may be a therapeutic option. METHODS:In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with antibody-mediated rejection that had occurred at least 180 days after transplantation to receive nine infusions of the CD38 monoclonal antibody felzartamab (at a dose of 16 mg per kilogram of body weight) or placebo for 6 months, followed by a 6-month observation period. The primary outcome was the safety and side-effect profile of felzartamab. Key secondary outcomes were renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels. RESULTS:A total of 22 patients underwent randomization (11 to receive felzartamab and 11 to receive placebo). The median time from transplantation until trial inclusion was 9 years. Mild or moderate infusion reactions occurred in 8 patients in the felzartamab group. Serious adverse events occurred in 1 patient in the felzartamab group and in 4 patients in the placebo group; graft loss occurred in 1 patient in the placebo group. At week 24, resolution of morphologic antibody-mediated rejection was more frequent with felzartamab (in 9 of 11 patients [82%]) than with placebo (in 2 of 10 patients [20%]), for a difference of 62 percentage points (95% confidence interval [CI], 19 to 100) and a risk ratio of 0.23 (95% confidence interval [CI], 0.06 to 0.83). The median microvascular inflammation score was lower in the felzartamab group than in the placebo group (0 vs. 2.5), for a mean difference of -1.95 (95% CI, -2.97 to -0.92). Also lower was a molecular score reflecting the probability of antibody-mediated rejection (0.17 vs. 0.77) and the level of donor-derived cell-free DNA (0.31% vs. 0.82%). At week 52, the recurrence of antibody-mediated rejection was reported in 3 of 9 patients who had a response to felzartamab, with an increase in molecular activity and biomarker levels toward baseline levels. CONCLUSIONS:Felzartamab had acceptable safety and side-effect profiles in patients with antibody-mediated rejection. (Funded by MorphoSys and Human Immunology Biosciences; ClinicalTrials.gov number, NCT05021484; and EUDRACT number, 2021-000545-40.).

In the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19+ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior antitumor effects and overall survival compared with CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in the inhibition of CART19 overactivation, leading to diminished CAR T apoptosis and pyroptosis of tumor cells.