Monotherapy Trials Research Articles

Abstract 3641: Pharmacodynamic and predictive biomarker results from the phase I dose escalation study of NGM707, an ILT2/ILT4 dual antagonist antibody, in patients with advanced solid tumors

Abstract Background: NGM707 is a dual antagonist antibody that binds a shared epitope of the immune inhibitory receptors ILT2 (LILRB1) and ILT4 (LILRB2). In preclinical studies, NGM707 reprogrammed suppressive myeloid cells via blockade of ILT2/ILT4 and enhanced NK and CD8+ T cell activity via blockade of ILT2; furthermore, NGM707 and pembrolizumab acted additively in vitro to enhance CD4+ T cell activation in mixed lymphocyte reactions. NGM707-IO-101 (NCT04913337) is a first-in-human Phase 1/2 clinical trial of NGM707 monotherapy and combination with pembrolizumab. Here we report pharmacodynamic and predictive biomarker data from NGM707-IO-101 monotherapy and combination dose escalation cohorts. Methods: Eligible patients with advanced or metastatic solid tumors were enrolled into escalating dose cohorts from 6 to 1800 mg NGM707, alone or in combination with 200 mg pembrolizumab, administered Q3W iv. Biomarker assessments of tumors comprised RNA-sequencing and immunohistochemistry (including ILT2, ILT4, CD163) of archival/baseline (N= 41 IHC, 47 RNA) and paired on-treatment tumor biopsies (N=13 IHC, 21 RNA). Peripheral blood biomarker samples were collected on days 1, 4, 8, and 15 of cycle 1 and prior to dosing at each subsequent cycle. Blood biomarker assessments included circulating cytokines/chemokines, PBMC RNA-sequencing, and flow cytometry immunophenotyping. Baseline biomarkers were associated with anti-tumor activity per RECIST v1.1. Results: Pre-treatment biopsies from patients with disease control (DC) showed higher expression of genes in the 18-gene tumor inflammation signature (TIS) than patients with progressive disease (PD). A composite gene signature incorporating gene sets related to TIS, NK cell activity, and tumor cell proliferation had a statistically stronger association with DC than TIS genes alone. Baseline ILT2/ILT4 target expression (≥1% of tumor area) was observed in 31 (75.6%) patients, with similar levels observed in patients with DC and PD. Pharmacodynamic changes were observed in tumor samples following treatment, including increased expression of gene signatures that reflect myeloid cell activation and a proinflammatory tumor microenvironment. Decreased protein expression of the immunosuppressive myeloid marker CD163 was observed following treatment in both blood and tumor for a subset of patients. Proinflammatory chemokines including CXCL9 increased in serum following treatment. Conclusion: Baseline gene expression signatures have shown an encouraging association with clinical benefit from NGM707 and merit further investigation as promising predictive biomarkers. Protein and gene expression changes reflecting the expected modes of action of NGM707 and pembrolizumab were observed in both peripheral blood and tumor biopsies following treatment. Citation Format: Lisa K. Blum, Hung-I H. Chen, Anushka De Costa, Anjushree Iyer, Geoffrey W. Stone, Nicole D. Galicia, Jerry Chan, Brenda Dampier, Katherine Wu, Ursula Jeffry, Kefei Zhou, Joanne Sloan-Lancaster, Dhiraj Abhayankar, Vladimir Hanes, Hsiao D. Lieu, Daniel D. Kaplan, Julie M. Roda. Pharmacodynamic and predictive biomarker results from the phase I dose escalation study of NGM707, an ILT2/ILT4 dual antagonist antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3641.

Abstract 1177: The chronology of immune-related adverse events (irAEs)-mechanistic implications

Abstract Immune Oncology (IO) is a novel component of the oncology armamentarium given its distinct mechanism of action, and by extension, unique mechanisms of toxicity (Tx). To recognize these unusual Txs, the term irAEs was popularized in clinical trials. Most organs have been involved by irAEs and autoimmunity has been implicated commonly by practicing oncologists. The onset of irAEs has not been studied well, however. We reasoned that autoimmune phenomena would be expected early after IO, since this is the timeframe within which T-cells expand to exert their effects on tumor and other ‘self’ tissues. It follows that if autoimmunity is the sole mechanism of irAEs, such toxicities should be reported early. Mechanism(s) of irARs may prove important for IO duration discussions. In some cases, tumor antigenic epitopes may mimic self-tissues, and in such cases irAEs develop early after initiation of IO. We hypothesized that irAEs have distinct chronology: earlier events representing autoimmunity (unavoidable); later events reflecting an intercurrent exposure to an antigen (e.g., virus) and therefore are avoidable by limiting duration of IO. Methods: We reviewed published IO monotherapy trials if individual patient data (swimmers’ plot) were reported. We derived the timing and frequency of Tx. We used therapy discontinuation without progressive disease as a surrogate for Tx if reported before the planned 24 months IO therapy.Results: Table depicts the data on included clinical trialsConclusion: The emergence of irAEs after IO extends over a protracted periods with 86% of events occurring beyond 4 months of IO. Though responses occasionally develop late after IO, for Tx consideration, T-cell expansion starts within days of IO initiation, and if autoimmunity is the mediator of Tx, irAEs would emerge only early. Our results suggest dual mechanisms and provide one more impetus to consider shortening IO duration. Tumor Author Discontinued IO (n) Months of IO Discontinuation 0-2 3-4 5-6 7-8 9-10 11-12 13-14 15-16 17-18 19-20 21-22 NSCLC Topalian 12 1 1 4 1 1 3 1 Dart 11 3 4 3 1 Warburton 56 2 2 7 8 7 22 1 3 1 2 1 Melanoma Topalian 13 4 1 2 1 2 2 1 Weber 2 1 1 Demetriou 66 8 4 6 5 6 10 6 10 6 5 RCC Topalian 3 1 2 Total 163 14 10 15 25 14 38 9 15 10 11 2 8% 6% 9% 15% 8% 23% 5% 9% 6% 7% 1% Citation Format: Farah Mazahreh, Haya Safar, Liyan Mazahreh, A. Mazin Safar. The chronology of immune-related adverse events (irAEs)-mechanistic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1177.

Abstract 937: Prioritizing treatment targets for an adolescent with metastatic processive malignancy using proteomics and personalized xenograft models within an actionable timeframe

Abstract Translation of precision oncology data into feasible precision therapies for hard-to-cure childhood, adolescent and young adult malignancies remains a significant challenge. Identifying therapeutic targets at the protein and pathway level and demonstrating treatment response in personalized models hold great promise, particularly for combination therapies, but may be considered complex and time consuming. Here, we present the case of an adolescent with metastatic, progressive spindle epithelial tumor with thymus-like differentiation (SETTLE) and evaluate how proteomics combined with rapid patient-derived models can identify treatment options not apparent at the genome or transcript level. Mass spectrometric proteome analysis of macro-dissected tumor and adjacent normal from formalin fixed paraffin embedded sections was completed within two weeks of biopsy and identified key proteins involved in one-carbon metabolism, including SHMT2 and DHFR as possible targets for single or combination therapy. Elevated SHMT2 levels were validated by immunohistochemistry and compared to levels across AYA tumors. Based on the suitability for an innovative therapy trial, we prioritized single-agent sertraline, a commercially available anti-depressant medication that inhibits SHMT2, and confirmed a positive drug response in both chicken chorioallantoic membrane (CAM) and larval zebrafish xenografts generated from the patient. Retrospective expansion in a murine xenograft enabled metabolic tracing on isolated SETTLE- patient-derived xenograft cells using 13C6-glucose confirming SHMT2 activity and response to in vitro treatment. Following failure of cytotoxic chemotherapy and second-line sorafenib treatment, a monotherapy trial of sertraline was initiated by the patient but stopped after 8 weeks after evidence of progressive disease. Possible combination therapies were evaluated further in the patient-derived models. Combining sertraline with the common antibiotic trimethoprim, resulted in enhanced growth inhibition of SETTLE cells in the larval zebrafish xenografts. Significance: Overall, we demonstrate that proteomics and personalized xenograft models may provide supportive pre-clinical data in a clinically meaningful timeframe to support medical decision-making and impact clinical practice. Citation Format: Georgina D. Barnabas, Tariq A. Bhat, Verena Goebeler, Pascal Leclair, Nadine Azzam, Nicole Melong, Jason N. Berman, Jennifer A. Chan, Donna L. Senger, Seth Parker, Christopher A. Maxwell, Gregor S. Reid, Jonathan Bush, Caron Strahlendorf, Rebecca Deyell, C James Lim, Philipp F. Lange. Prioritizing treatment targets for an adolescent with metastatic processive malignancy using proteomics and personalized xenograft models within an actionable timeframe [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 937.

Ticagrelor or Clopidogrel Monotherapy vs Dual Antiplatelet Therapy After Percutaneous Coronary Intervention

Among patients undergoing percutaneous coronary intervention (PCI), it remains unclear whether the treatment efficacy of P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) depends on the type of P2Y12 inhibitor. To assess the risks and benefits of ticagrelor monotherapy or clopidogrel monotherapy compared with standard DAPT after PCI. MEDLINE, Embase, TCTMD, and the European Society of Cardiology website were searched from inception to September 10, 2023, without language restriction. Included studies were randomized clinical trials comparing P2Y12 inhibitor monotherapy with DAPT on adjudicated end points in patients without indication to oral anticoagulation undergoing PCI. Patient-level data provided by each trial were synthesized into a pooled dataset and analyzed using a 1-step mixed-effects model. The study is reported following the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data. The primary objective was to determine noninferiority of ticagrelor or clopidogrel monotherapy vs DAPT on the composite of death, myocardial infarction (MI), or stroke in the per-protocol analysis with a 1.15 margin for the hazard ratio (HR). Key secondary end points were major bleeding and net adverse clinical events (NACE), including the primary end point and major bleeding. Analyses included 6 randomized trials including 25 960 patients undergoing PCI, of whom 24 394 patients (12 403 patients receiving DAPT; 8292 patients receiving ticagrelor monotherapy; 3654 patients receiving clopidogrel monotherapy; 45 patients receiving prasugrel monotherapy) were retained in the per-protocol analysis. Trials of ticagrelor monotherapy were conducted in Asia, Europe, and North America; trials of clopidogrel monotherapy were all conducted in Asia. Ticagrelor was noninferior to DAPT for the primary end point (HR, 0.89; 95% CI, 0.74-1.06; P for noninferiority = .004), but clopidogrel was not noninferior (HR, 1.37; 95% CI, 1.01-1.87; P for noninferiority > .99), with this finding driven by noncardiovascular death. The risk of major bleeding was lower with both ticagrelor (HR, 0.47; 95% CI, 0.36-0.62; P < .001) and clopidogrel monotherapy (HR, 0.49; 95% CI, 0.30-0.81; P = .006; P for interaction = 0.88). NACE were lower with ticagrelor (HR, 0.74; 95% CI, 0.64-0.86, P < .001) but not with clopidogrel monotherapy (HR, 1.00; 95% CI, 0.78-1.28; P = .99; P for interaction = .04). This systematic review and meta-analysis found that ticagrelor monotherapy was noninferior to DAPT for all-cause death, MI, or stroke and superior for major bleeding and NACE. Clopidogrel monotherapy was similarly associated with reduced bleeding but was not noninferior to DAPT for all-cause death, MI, or stroke, largely because of risk observed in 1 trial that exclusively included East Asian patients and a hazard that was driven by an excess of noncardiovascular death.

Apremilast for the Treatment of Psoriasis in Special Areas in Pediatric Patients in the SPROUT Study

Introduction &amp; Objective: Psoriasis in special areas is difficult to treat and causes significant disease burden. Approved systemic therapies for moderate to severe plaque psoriasis in pediatric patients are limited and require subcutaneous injection. Apremilast, a unique oral immunomodulator that inhibits phosphodiesterase-4, is approved in multiple countries for use in adults with psoriasis, regardless of severity. In this study, the efficacy of apremilast for psoriasis in special areas in pediatric patients was assessed over 16 weeks. Materials &amp; Methods: SPROUT (NCT03701763) is a phase 3, randomized, double-blind, placebo-controlled study in patients 6-17 years with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index ≥12, body surface area ≥10%, and static Physician Global Assessment [sPGA] ≥3) inadequately controlled by/inappropriate for topical therapy. Patients were stratified by age and randomized 2:1 to receive apremilast (weight-based 20 mg or 30 mg twice-a-day) or placebo for 16 weeks, then apremilast through week 52. Scalp Physician Global Assessment (ScPGA) response, modified sPGA of genitalia (sPGA-G) response, Whole Body Itch-Numeric Rating Scale (WBI-NRS) response, and change from baseline in Children’s Dermatology Life Quality Index (CDLQI) were assessed through week 16. Results: Of 245 randomized patients (apremilast: 163; placebo: 82), 101 (41.2%) were 6-11 years and 144 (58.8%) were 12-17 years; 120 (49.0%) patients weighed ≥20 to &lt;50 kg and 125 (51.0%) weighed ≥50 kg. At baseline, 81.0% of the patients treated with apremilast and 84.1% of patients treated with placebo had moderate to severe scalp psoriasis (ScPGA ≥3). Significantly more patients achieved ScPGA response at week 16 with apremilast vs placebo (36.4% vs 18.8%; P=0.0091). At baseline, 110 patients (44.9%; 45.4% apremilast and 43.9% placebo) had moderate to severe genital psoriasis (sPGA-G ≥3). Achievement of sPGA-G response at week 16 was numerically greater with apremilast vs placebo (39.2% vs 25.0%), although not significant, possibly due to small sample size (apremilast: n=74; placebo: n=36). Significantly more patients achieved WBI-NRS response at week 16 with apremilast vs placebo (52.0% vs 32.1%; P=0.0110). Greater improvements in CDLQI were seen at week 16 with apremilast vs placebo (least-squares mean change from baseline −5.1 vs −3.2; P=0.0009). Adverse events were consistent with the known apremilast safety profile. In 21 patients vaccinated during the study (including for COVID-19, influenza, diphtheria, pertussis, tetanus, meningococcus, and hepatitis B), no new safety issues occurred. Conclusions: Apremilast significantly improved scalp psoriasis, itch, and quality of life in pediatric patients with moderate to severe psoriasis. At week 16, patients with moderate to severe genital psoriasis showed a trend toward improvement, although not significant due partially to the sample size.

Effect of statin add-on therapy on cardiovascular mortality.

Cardiovascular (CV) disease remains a leading cause of mortality despite statin therapy. Statin add-on lipid-lowering therapies have been investigated for CV risk reduction, but their effect on CV mortality has not been reviewed. This review describes CV outcomes trials of add-on therapies to statins, highlighting findings related to the primary composite CV endpoints and the more patient-centric endpoint of CV-related mortality. Add-on ezetimibe met its primary composite CV endpoint vs. statin alone (P = 0.016); however, the individual endpoint of death from CV causes did not differ between groups. Add-on therapy with proprotein convertase subtilisin/kexin type 9 inhibitors achieved the primary composite CV endpoints in the respective CV outcomes trials for alirocumab (P < 0.001) and evolocumab (P < 0.001); however, neither CV outcomes trial found a difference vs. placebo in CV-related mortality. In its CV outcomes trial, icosapent ethyl added to statin therapy significantly reduced the occurrence of the primary composite CV endpoint (P < 0.001) and the individual endpoint of risk of CV-related death (P = 0.03) vs. placebo. A CV outcomes trial of bempedoic acid monotherapy achieved its primary composite CV endpoint vs. placebo (P = 0.004) but not the endpoint of death from CV causes. Statin add-on therapies achieved their CV outcomes trial composite CV endpoints. Proprotein convertase subtilisin/kexin type 9 inhibitors and icosapent ethyl have approved indications for CV risk reduction. Only add-on therapy with icosapent ethyl demonstrated a significant reduction in CV mortality in the overall intent-to-treat population, possibly due to the unique pleiotropic mechanisms of eicosapentaenoic acid independent of lipid-lowering effects.

Superiority of Low-Dose Benzbromarone Add-On to Low-Dose Febuxostat Compared With Febuxostat Monotherapy in Gout With Combined-Type Hyperuricemia.

There is an unmet need for simpler urate-lowering therapy (ULT) regimens that achieve the serum urate target and improve the overall quality of gout care. We report a comparative effectiveness trial of febuxostat monotherapy versus benzbromarone add-on to low-dose febuxostat in gout specifically with combined renal urate underexcretion and overload. A prospective randomized trial was conducted on patients with combined-type hyperuricemia and estimated glomerular filtration rate >60 mL/min/1.73 m2 1:1 randomly assigned to febuxostat and benzbromarone combination therapy (initially febuxostat at 20 mg/day, with benzbromarone at 25 mg/day added onto 20 mg/day of febuxostat if not at target) or febuxostat monotherapy (initially 20 mg/day, escalating to 40 mg/day if not at target). The primary end point at 12 weeks was the proportion achieving a serum urate (SU) level <360 μmol/L. Other outcomes included altered liver and kidney function, new-onset urolithiasis, and gout flares. There were 250 participants randomized; 219 completed 12-week treatment. More patients in the febuxostat and benzbromarone combination group achieved the SU target compared to patients in the febuxostat monotherapy group (75.5% vs 47.7%; odds ratio 3.37 [95% confidence interval 1.90-5.98]). Safety profiles were comparable between the two groups. Simply adding on low-dose benzbromarone (25 mg/day) to low-dose (20 mg/day) febuxostat showed superior urate lowering compared to febuxostat monotherapy in gout with a combined-type hyperuricemia. For selected patients, expedited achievement of the SU target in more than 75% of patients using one titration step and low xanthine oxidase inhibitor and uricosuric doses is a potential alternative to standard ULT regimens.

523 - Efficacy and safety of amlitelimab (an anti-OX40 ligand antibody) in patients with moderate-to-severe atopic dermatitis: 24-week results from a phase 2b trial (STREAM-AD)

Abstract Introduction/Background Targeting and binding OX40 ligand (OX40L) expressed on antigen-presenting cells may inhibit the persistent immune response that drives atopic dermatitis (AD) pathophysiology. Amlitelimab (SAR445229; KY1005) is a potential first-in-class, fully human, non-depleting anti-OX40L monoclonal antibody that blocks OX40L-OX40 interactions and has shown efficacy and an acceptable safety profile in a Phase 2a trial in adults with moderate-to-severe AD. Here, we present 24-week efficacy and safety results (Part 1) from an ongoing dose-ranging Phase 2b trial. The study remains blinded to individual patient data (Part 2 ongoing). Objectives To evaluate the efficacy and safety of amlitelimab in adults with moderate-to-severe AD. Methods STREAM-AD (NCT05131477) is a 52-week, randomised, double-blinded, placebo-controlled Phase 2b monotherapy trial. This study is designed with 2 parts (double-blind throughout): a 24-week treatment period (Part 1, completed and presented here) and a 36-week maintenance/withdrawal period (Part 2, ongoing). Adults (18 to &amp;lt;75 years; n=390) with moderate-to-severe AD were randomised 1:1:1:1:1 to receive subcutaneous amlitelimab Q4W (250 mg with 500 mg loading dose [LD], n=77; 250 mg without LD, n=78; 125 mg without LD, n=77; or 62.5 mg without LD, n=79) or placebo Q4W (n=79). The primary endpoint was percentage change in Eczema Area and Severity Index (EASI) from baseline at Week 16. Key secondary endpoints included percentage change in EASI at Week 24 and percentage of patients with at least 75% reduction from baseline in EASI (EASI-75), percentage of patients with Investigator Global Assessment response of 0 (clear) or 1 (almost clear) and a reduction from baseline of ≥2 points (IGA 0/1), and proportion of patients with a weekly average reduction of Peak Pruritus Numerical Rating Scale (PP-NRS) ≥4 points from baseline. The primary efficacy analysis included all randomised patients who completed Week 24 or discontinued treatment or study prior to Week 24 visit (n=390), whereas the safety analysis included all treated patients (n=388). Results Treatment with amlitelimab resulted in statistically significant improvements in percentage change in EASI from baseline to Week 16 compared to placebo for all four doses studied. The 250 mg with LD group had the numerically highest response versus placebo at Week 16, with a least-squares mean change from baseline of –32.1% (95% CI: –43.9, –20.3; P&amp;lt;0.0001); the remaining groups without LD had the following responses versus placebo: 250 mg, –27.3 (95% CI: –39.1, –15.6; P&amp;lt;0.0001); 125 mg, –22.2 (95% CI: –34.0, –10.4; P=0.0002); and 62.5 mg, –30.2 (95% CI: –41.9, –18.5; P&amp;lt;0.0001). There were also clinically meaningful improvements in all key secondary efficacy outcome measures, with all amlitelimab dose groups demonstrating nominally significant (P&amp;lt;0.05) efficacy versus placebo for EASI-75, IGA 0/1, and PP-NRS ≥4, except 250 mg (no LD) in IGA 0/1 at Week 16 (P=0.0562). Continued improvements were generally observed through Week 24 in primary and key secondary efficacy outcomes. Amlitelimab was well tolerated across all dose groups, with no safety concerns identified. Conclusions In this dose-ranging Phase 2b trial of amlitelimab in adults with moderate-to-severe AD, amlitelimab demonstrated clinically meaningful efficacy over 24 weeks with an acceptable safety profile across all four dose groups.

Efficacy and safety of brigimadlin (BI 907828), an MDM2–p53 antagonist, in patients (pts) with advanced biliary tract cancer: Data from two phase Ia/Ib dose-escalation/expansion trials.

487 Background: Outcomes remain poor for pts treated with standard-of-care chemotherapy for advanced biliary tract cancer (BTC). Hence, there is a clinical need for novel therapeutic strategies. One such emerging strategy is antagonism of mouse double minute 2 (MDM2), which is amplified in 5–8% of cases of BTC. Brigimadlin (BI 907828) is a MDM2–p53 antagonist that blocks the MDM2–p53 interaction, thereby restoring p53 activity and leading to cell-cycle arrest and apoptosis in TP53 wild-type tumors. Brigimadlin is currently being assessed in two Phase Ia/Ib dose-escalation/expansion trials in pts with advanced/metastatic solid tumors as monotherapy (NCT03449381) and in combination with an anti-PD-1 antibody, ezabenlimab (NCT03964233). Here, we present data in pts with advanced BTCs treated in these trials. Methods: Pts in the monotherapy trial received escalating doses of brigimadlin on day 1 of 21-day cycles (Q3W). Pts in the combination trial received escalating doses of brigimadlin and 240 mg ezabenlimab on day 1 Q3W (doublet); one pt also received the anti-LAG-3 antibody BI 754111 (which has since been discontinued; triplet). Results: At data cut-off (June 2023), a total of 16 pts with BTC have been enrolled (10 in the monotherapy and 6 in the combination trial). In the monotherapy trial, 9 pts received brigimadlin 45 mg Q3W and 1 received 80 mg Q3W. In the combination trial, 5 pts received 30 mg/45 mg brigimadlin doublet and 1 received 45 mg triplet. Across both trials, 7 pts with MDM2 -amplified tumors achieved partial response (PR), 3 in the monotherapy trial and 4 in the combination trial. In the monotherapy trial, the responding pts had intrahepatic cholangiocarcinoma (iCC; 80 mg, 73% tumor shrinkage, progression-free survival [PFS] 13.3 months), ampullary adenocarcinoma (45 mg, 72% tumor shrinkage, PFS censored at 666 days), and extrahepatic cholangiocarcinoma (45 mg, 68% tumor shrinkage, PFS censored at 164 days). In the combination trial, 3 responding pts had iCC (pt 1, 30 mg doublet, 54% tumor shrinkage, PFS 9.6 months; pt 2, 45 mg doublet, 49% tumor shrinkage, PFS 7.5 months; pt 3, 45 mg doublet, 39% tumor shrinkage, PFS censored at 5.5 months) and 1 had gallbladder cancer (45 mg doublet, 50% tumor shrinkage, PFS 7.9 months). A further 7 pts (5 in the monotherapy trial and 2 in the combination trial) achieved stable disease (SD). In both trials, the most common any-grade treatment-related AE (TRAE) was nausea; the most common grade ≥3 TRAEs were thrombocytopenia and neutropenia. Conclusions: Brigimadlin showed a manageable safety profile and encouraging preliminary efficacy in pts with BTC, with 7 PRs and 7 SDs in 16 pts. A Phase IIa/IIb trial of brigimadlin in patients with MDM2 -amplified, TP53 wild-type BTC and other solid tumors is ongoing (Brightline-2). Clinical trial information: NCT03449381 and NCT03964233 .

Topical Clindamycin For Acne Vulgaris: Pharmacovigilance Safety Review and Retrospective Analysis of Gastrointestinal Events

Background: Clindamycin, a lincosamide antibiotic, was the 125th most prescribed medicine in the US in 2020. Topical formulations that combine clindamycin with benzoyl peroxide or a retinoid are commonly used for acne vulgaris (AV) treatment. While oral and topical clindamycin carry warnings/contraindications regarding the development of gastrointestinal (GI) adverse events (AEs), the real-world incidence of these AEs with topical clindamycin is unknown. The objective is to provide an overview of safety data for topical clindamycin when used for AV treatment.&#x0D; Methods: Safety data from published literature on PubMed® (case reports, clinical trials data, retrospective data), previously unpublished worldwide pharmacovigilance data (from January 1, 1900-December 31, 2022), and two unpublished retrospective cohort studies of US electronic medical records (EMR; January 1, 2011 to January 31, 2019) were reviewed, with a focus on inflammatory bowel disease (IBD) and GI AEs following topical clindamycin monotherapy or combination treatment&#x0D; Results: There have been only 4 published case reports of topical clindamycin-associated GI AEs, which were all published between the years 1981-1997. In 8 published pivotal phase 3 clinical trials of topical clindamycin monotherapy or combination treatment for AV, GI-related AEs were reported in 1.4% of clindamycin-treated participants (38/2,672; safety populations). According to the pharmacovigilance data, the rate of GI-related adverse drug reactions with topical clindamycin-containing products was 0.000045% (64/141,084,533). In 1 published retrospective report, there were 0 reports of colitis from the 1,124 patients estimated to have received topical clindamycin prescriptions in the years 1977-1980. In the first retrospective EMR study, results indicate that physicians prescribe topical clindamycin for AV treatment equally to patients with a history of IBD (19.0%; 98/515) or without (20.7%; 14,495/70,151). The second retrospective EMR study showed that among patients with AV and an initial prescription for topical clindamycin (monotherapy or combination; n=18,012), there were 3 (0.02%) incident cases of pseudomembranous colitis within 30 days; none of these cases had a history of IBD.&#x0D; Conclusions: A review of published case reports, clinical trials safety data, worldwide pharmacovigilance data, and retrospective US prescription data demonstrate that GI events—including colitis or pseudomembranous colitis—in patients exposed to topical clindamycin is extremely low, regardless of IBD history.&#x0D; Support: Ortho Dermatologics

Reactive cutaneous capillary endothelial proliferation following camrelizumab monotherapy or combination therapy for multi-cancers: a large-scale pooled analysis of 10 studies in China.

Skin toxicities are the most common adverse events related to immunotherapy, such as reactive cutaneous capillary endothelial proliferation (RCCEP) following treatment with the anti-programmed cell death-1 antibody camrelizumab. This study aimed to comprehensively analyze the clinical features and prognostic value of RCCEP in patients with malignancies who received camrelizumab alone (Camre) or in combination with the angiogenesis-targeted agent apatinib (Camre-Apa) or chemotherapy (Camre-Chemo). A large-scale pooled analysis. Individual patient-level data were derived from 10 clinical trials of camrelizumab monotherapy, camrelizumab plus apatinib, or camrelizumab plus chemotherapy (n = 1305). RCCEP occurred in 77.0% (516/670) of patients with Camre, 23.6% (70/296) with Camre-Apa, and 67.8% (230/339) with Camre-Chemo. Most RCCEP lesions were grade 1 or 2 in severity. The median time to onset was 0.8 months [interquartile range (IQR), 0.6-1.2] with Camre, 5.0 months (IQR, 2.7-8.0) with Camre-Apa, and 1.6 months (IQR, 1.0-4.2) with Camre-Chemo; and the median duration was 4.8 months (IQR, 2.6-8.8), 4.4 months (IQR, 1.7-8.9), and 7.2 months (IQR, 4.1-14.3), respectively. In all the three groups, patients with RCCEP showed significantly better clinical outcomes compared with those without [objective response rate: 23.8% versus 1.9% with Camre, 48.6% versus 21.2% with Camre-Apa, and 78.7% versus 54.1% with Camre-Chemo; median progression-free survival: 3.2 versus 1.7 months (hazard ratio (HR) = 0.36), 10.2 versus 4.5 months (HR = 0.39), and 12.7 versus 7.3 months (HR = 0.38); median overall survival: 13.3 versus 3.8 months (HR = 0.34), 29.2 versus 13.5 months (HR = 0.46), and not reached versus 12.8 months (HR = 0.19); all p < 0.0001]. Although RCCEP occurred frequently with camrelizumab, most lesions were mild and self-limiting. The occurrence of RCCEP was strongly associated with the antitumor activity and survival of camrelizumab, both as monotherapy and in combination therapy.

Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial

Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins. WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing. Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%]). In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988). Dizal Pharmaceutical.

Antiviral Effect of Triple Combination of VP1 Ligands against Coxsackievirus B3 Infection in Newborn Mice

The Coxsackie B viruses (CVB), are distributed worldwide and cause a broad spectrum of diseases. Currently, clinically effective antivirals for the treatment of these infections do not exist. It was found that the unsatisfactory effectiveness of enteroviral inhibitors in vivo has been associated with the rapid development of drug resistance and that explains why effective antivirals have failed in monotherapy trials. Combination therapy with two or more drugs has the potential to successfully inhibit viral infection more effectively than either drug alone. It could achieve greater effects and avoid side effects using lower drug concentrations, and thus, they could prevent the rapid development of drug resistance. In this work, we examine the combined treatment effect of three enterovirus replication inhibitors – pleconaril, pocapavir, and vapendavir, which are VP1 hydrophobic pocket ligands. All of them have passed clinical double-blind trials as monotherapy courses, but none of them have been approved for clinical application, because of slide effects. We evaluate the effectiveness of the combination pleconaril/pocapavir/vapendavir (PPV) applied via CAA treatment scheme on Coxsackievirus B3 (CVB3) infection in newborn mice.

Valemetostat for Relapsed or Refractory B-Cell Lymphomas: Primary Results from a Phase 1 Trial

Introduction: B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), are among the most common NHLs. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze the trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional mark is broadly associated with gene silencing. EZH2 is involved in mediating B-cell development. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1. The clinical activity of valemetostat in patients (pts) with relapsed or refractory (R/R) NHL was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary clinical outcomes for the subgroup of pts in J101 with R/R B-NHLs, including DLBCL and FL. Methods: This phase 1, open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were aged ≥ 18 years (y; US) or ≥ 20 y (Japan), had confirmed B-NHL or T-cell NHL (T-NHL), and were relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation portion (Japan only) followed by a dose-expansion phase (Japan &amp; US). Pts with a histological diagnosis of B-NHL were enrolled in the dose-escalation phase and received valemetostat once daily at doses of 150-300 mg/day (d) in continuous 28-d treatment (Tx) cycles. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, and duration of response (DOR). DOR was estimated for responding pts using Kaplan-Meier methods. Due to the small number of pts with B-NHL, safety was assessed among all enrolled pts, including those with T-NHL in the dose-escalation and dose-expansion cohorts. Results: At the primary trial cutoff (Dec 31, 2022), 19 pts with R/R B-NHLs were registered and had received ≥ 1 dose of study drug, including 7 with DLBCL, 7 with FL, 3 with indolent B-NHL, and 2 with other B-NHLs. Median age was 66 (range 44-88) y. Most (79%) pts had an Eastern Cooperative Oncology Group performance status score of 0. Median number of prior therapies was 2.0 (range 0-6); no pt in this cohort had received prior hematopoietic cell transplantation. Overall, 90 pts with R/R NHLs were enrolled. All pts experienced at least 1 treatment-emergent adverse event (TEAE), including 78 (87%) who had treatment-related TEAEs. The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%). The most common grade ≥ 3 TEAEs were cytopenias, including decreased neutrophil count (24%), platelet count (24%), and lymphocyte count (19%). TEAEs required Tx interruption for 42 (47%) pts, dose reduction for 9 (10%) pts, and Tx discontinuation for 7 (8%) pts. The overall response rate in pts with R/R B-NHL was 47% (9/19; 95% confidence interval [CI], 24.4-71.1). Clinical responses were seen in 3/7 pts with DLBCL and 4/7 pts with FL; 1 pt in each of these groups achieved CR ( Table). Of 19 pts, 9 (47%) achieved reductions of ≥ 50% from baseline in the sum of target lesion areas during valemetostat Tx ( Figure). A gain-of-function EZH2 mutation was identified in 1 pt with FL, and this pt achieved a partial response. Median time to response overall was 3.7 (range 1.9-10.1) months (mo) and estimated median DOR for the 9 responding pts was 18.4 mo (95% CI, 5.3 mo to not reached). Among all pts who received valemetostat 200 mg/d with pharmacokinetic (PK) data available (n = 74), mean [standard deviation; SD] maximum plasma concentration (C max) on cycle 1 day 1 was 2140 [1620] ng/mL, with a median time to C max (T max) of 3.9 (range 0.2-27.8) h and a mean [SD] AUC tau of 17,500 [21,400] ng × h/mL. Conclusions: Valemetostat demonstrated encouraging clinical activity in pts with R/R B-NHLs. The safety profile of valemetostat was acceptable; cytopenias were common but manageable and did not require Tx discontinuation between 150-300 mg/d. Clinical responses were durable, with a median DOR of &amp;gt; 1.5 y. Results for pts in this trial with R/R T-NHLs are presented in another abstract (Jacobsen et al.) at this congress. Ongoing trials of valemetostat in pts with R/R B-NHLs include a phase 2 monotherapy trial in France and Belgium (NCT04842877) and a phase 1/2 trial of valemetostat plus rituximab and lenalidomide (R 2) in the US (NCT05683171).

Outcomes of Patients with Relapsed/Refractory Lymphoplasmacytic Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis

Outcomes of Patients with Relapsed/Refractory Lymphoplasmacytic Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis

Baseline CD4 T Cells Are Associated with Improved Response to CD20-CD3 Bispecifics in Lymphoma

Background: Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. Mosun is approved for the treatment of patients (pts) with relapsed/refractory follicular lymphoma (FL) after two or more systemic therapies and has shown activity in both aggressive non-Hodgkin lymphoma (aNHL) and indolent (iNHL). Previous reports have shown that CD20 loss is a common mechanism of resistance to Mosun (Schuster SJ, ASCO 2022). However, as the mechanism of action of Mosun is T cell mediated killing of tumor cells, we sought to characterize the immune microenvironment of tumor samples from patients with NHL treated with Mosun. Here we report integrated biomarker analysis of pt samples from the phase I/II Mosun monotherapy trial (NCT02500407). Methods: Baseline and at-progression biopsies were collected from 240 relapsed/refractory NHL pts from the fixed dosing (arm A) and Cycle 1 step-up dosing (arm B) cohorts, including 78 DLBCL, 89 FL, 37 transformed FL (trFL), and 36 other aNHL and iNHL histologies (including MCL, MZL, SLL, &amp; RS). A total of 265 biopsies were profiled via RNASeq, including 58 paired baseline and at-progression samples. As a proxy for immune subset prevalence, immune gene signatures were calculated using principal component analysis. Association with best overall response was calculated using limma with histology and archival status included as covariates for the pooled cross-histology analysis, or with archival status for within-histology comparisons. Significance for exploratory analysis was defined as false-discovery rate (FDR)&amp;lt;0.05. Results: Pooled analysis of all baseline biopsies identified expression of 76 genes as significantly associated with response (Figure 1A). A number of immune-related genes, such as ITGAL, IL6R, and TOX2 were expressed at higher levels in responders. Gene signature analysis revealed that most of the top hits were T cell related, with T follicular helper (Tfh) signatures most strongly associated with response. Analysis of individual histologies revealed that the majority of genes identified had indication-specific associations, with significant hits in DLBCL (n=472) or trFL (n=4). No hits were found in FL after FDR correction. DLBCL hits appeared mostly tumor-specific (HLA-E, DOK1, and ITGA2), while trFL hits were more associated with CD4 T cell biology (TIGIT and FOXN3). The Tfh signature was the most strongly associated with response in trFL, and was also nominally significant in FL (Figure 1B). The signature displayed a histology-specific expression profile, with lower expression in aNHL and higher expression in iNHL. A split was observed in trFL, with responders showing signature scores similar to iNHL and non-responders like aNHL. Other CD4-but not CD8-signatures showed a similar profile. At progression, a small number of genes showed sustained changes, with reductions in XCR1 &amp; CLEC9A, and induction of ALOX15B seen in patients up to 2 years after the last Mosun administration, suggesting long-term changes in the immune microenvironment during the development of resistance. Conclusions: Baseline biomarker data reveal an important role for CD4 T cells in Mosun response and suggest that higher prevalence of CD4s may be a factor in the improved response to Mosun in indolent NHL. Our data specifically point to Tfh cells as potential drivers of response, although the mechanisms by which Tfh contributes to response, as well as the implications for other bispecifics, requires more exploration.

Novel CD20 Mutations As a Mechanism of Resistance to CD20-CD3 Targeted Therapies in Non-Hodgkin's Lymphoma

Non-Hodgkin's Lymphoma (NHL) is one of the most common blood cancer types in the world. CD20 is a B cell restricted lineage marker that is a well-established target for the treatment of NHL and anti-CD20 agents are included as in standard of care regimens. Given the success of these targeted therapies, strategies to further enhance therapeutic activity are being explored, including the CD20-CD3 bispecific molecule, mosunetuzumab, which is approved for treatment of relapsed and refractory Follicular Lymphoma in adults who have received &amp;gt;2 lines of treatment. Mosunetuzumab acts by redirecting CD3+ T cells to engage and eliminate CD20-expressing B cells. As with other targeted therapies, mutations and loss of target expression have been described following mosunetuzumab therapy [1]. Here we describe the impact of novel mutations identified in patient biopsy samples from the mosunetuzumab monotherapy trial, GO29781 that were located within the extracellular and transmembrane domains of CD20 on protein expression, localization and T-cell mediated killing. NHL cell lines, SU-DHL-16 and MAVER-1, were engineered using CRISPR-Cas9 system to create CD20 knock out (KO) cell lines. Wild-type (WT) or mutant CD20 were exogenously re-expressed in the CD20 KO cell lines and in the CD20 negative acute lymphoblastic leukemia cell line, REH, to create isogenic cell lines for further analysis. Complete CD20 loss was observed in cells expressing CD20 P160fs (frameshift) and Q187* (truncating) mutations. CD20 missense mutations located in the extracellular domain (C167G, K175E) expressed CD20 protein levels comparable to CD20 WT cells and membrane localization was confirmed by flow cytometry and immunofluorescence microscopy. To test the functional effect of CD20 mutations, in vitro co-culture cell killing assays were carried out using healthy donor CD8+ T cells, isogenic cell lines (3:1 effector to tumor cell ratio) and a proof-of-concept CD20-CD3 bispecific antibody. Differences in T-cell mediated killing were observed across mutation types. CD20 WT cell lines demonstrated 95-99% cell killing following 48 hour treatment while the CD20 KO, frameshift and truncating mutations all showed negligible T-cell mediated killing (~10-17% cell death). Cells expressing the missense mutations in the extracellular domain showed resistance to T-cell mediated killing (~30-45% cell death) compared to CD20 WT cells. T-cell activation was assessed by CD69 (early) and CD25 (late) surface markers. In all co-cultures, the level of CD69+ T cells was equivalent, while the CD69+CD25+ CD8 T cells were only significantly increased in the CD20 WT co-cultures, consistent with the high level of T-cell mediating killing. We have confirmed that these mutations can play a role in the development of resistance through both loss of target protein expression and interference within the anti-CD20 binding site. These studies help to characterize mechanisms of resistance to mosunetuzumab that could be extended to other anti-CD20 targeted agents. [1] Schuster et al. Journal of Clinical Oncology 2022, 40 (16), 7526.

Abrocitinib efficacy and safety in moderate-to-severe atopic dermatitis by race, ethnicity, and Fitzpatrick skin type

BackgroundResponse to abrocitinib treatment for moderate-to-severe atopic dermatitis (AD) has not been evaluated across racial and ethnic subpopulations. ObjectiveTo assess the efficacy and safety of abrocitinib on the basis of patient race, ethnicity, and Fitzpatrick skin type (FST). MethodsData were pooled post hoc from patients treated with abrocitinib 200 mg, 100 mg, or placebo in 3 monotherapy trials (NCT02780167, NCT03349060, and NCT03575871). Race and ethnicity were self-reported; FST was determined by study investigators. Evaluations through Week 12 include the following: (1) Investigator's Global Assessment of clear or almost-clear skin; (2) greater than or equal to 75% improvement in Eczema Area and Severity Index or SCORing AD; (3) a greater-than-or-equal-to 4-point improvement in Peak Pruritus Numerical Rating Scale score; (4) least squares mean changes in Dermatology Life Quality Index and Patient-Oriented Eczema Measure scores; and (5) treatment-emergent adverse events. ResultsThe sample comprised 628 White, 204 Asian, and 83 Black patients; 37 were Hispanic or Latino; 624 had FST I to III and 320 had FST IV to VI. Treatment with either abrocitinib dose was associated with greater proportions of patients achieving Investigator's Global Assessment of clear or almost-clear skin, ≥ 75% improvement in Eczema Area and Severity Index, ≥ 75% improvement in SCORing AD, and a ≥ 4-point improvement in Peak Pruritus Numerical Rating Scale, or greater score changes from baseline in Dermatology Life Quality Index and Patient-Oriented Eczema Measure vs placebo regardless of race, ethnicity, or FST. Dose-response was most prominent in White patients. In Black patients, the effects of the 2 doses were similar. Treatment-emergent adverse events were more common in White and Black than in Asian patients. ConclusionAbrocitinib was more efficacious than placebo across the racial and ethnic groups and ranges of phototypes analyzed. Studies with increased representation of populations of color are warranted to elucidate potential variations in response across diverse populations. Trial RegistrationClinicaltrials.gov Identifier: NCT02780167 (phase 2b), NCT03349060 (phase 3 MONO-1), and NCT03575871 (phase 3 MONO-2).

A Mini Review of the Impact of Baseline Disease Severity on Clinical Outcomes: Should We Compare Atopic Dermatitis Clinical Trials?

Based on clinical trials of systemic treatments in adults with moderate-to-severe atopic dermatitis (AD) reported between 2014 and 2023, we used linear regression to investigate relationships between baseline Eczema Area and Severity Index (EASI) scores and (1) study start date, (2) EASI response, and (3) rescue medication rates. Analysis 1 was conducted with all patients from monotherapy and combination therapy trials; analyses 2 and 3 used monotherapy trial placebo arms. Across 32 trials with a baseline inclusion criterion of EASI ≥ 16, baseline mean EASI scores decreased with study start date. The lowest and highest baseline mean EASI scores were 25.1 and 33.6 (median 21.1 and 30.5), reported for the WW001 Phase 2 trial of rademikibart (formerly CBP-201; start date, July 2020) and the SOLO1 Phase 3 trial of dupilumab (start date, December 2014), respectively. In placebo arms, lower baseline EASI scores tended to be associated with greater percent reductions in EASI scores at Week 16 and less rescue medication usage. The WW001 trial placebo arm had the lowest baseline EASI score (mean 25.2; median 22.1), lowest rescue medication rate (14.3%), and a large reduction in least squares mean EASI scores (- 39.7%) at Week 16. In summary, baseline mean EASI scores have decreased across clinical trials conducted during the last decade. Less severe AD at baseline tended to be associated with greater placebo response and less use of rescue medications in placebo arms. Intertrial differences in variables, such as baseline AD severity, limit the validity of indirectly comparing clinical trials.

GLOBRYTE: A Phase III, Open-Label, Multicenter, Randomized Trial Evaluating Glofitamab Monotherapy in Patients with Relapsed or Refractory Mantle Cell Lymphoma

Background and Significance: There is currently no standard of care for patients (pts) with relapsed or refractory (R/R) mantle cell lymphoma (MCL). Although Bruton tyrosine kinase inhibitors (BTKi) have improved clinical outcomes in R/R MCL, there is a high unmet need for new treatment options for pts who do not respond to, or progress through, BTKi therapy. Chimeric antigen receptor (CAR) T-cell therapies, such as brexucabtagene autoleucel, have shown promising outcomes, but alternative systemic therapies are still needed in this pt population. Glofitamab is a CD20xCD3 T-cell-engaging bispecific antibody that redirects T cells to eliminate B cells. A Phase I/II trial of glofitamab monotherapy with step-up dosing (SUD) and obinutuzumab pretreatment (Gpt; 1000 or 2000mg) to mitigate the risk of cytokine release syndrome (CRS) showed high and durable complete response (CR) rates (73.0%) and manageable, mostly low-grade CRS in heavily pretreated pts with R/R MCL (n=37), most of whom had failed prior BTKi therapy (Phillips et al. ASH 2021, Phillips et al. ASH 2022). Study Design and Methods : The GLOBRYTE study (GO43878; EU CT: 2023-503206-37-00) is a Phase III, open-label, multicenter, randomized, controlled trial that will evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (biomarkers) of glofitamab monotherapy in pts with R/R MCL, in comparison with an investigator's choice of rituximab + bendamustine (BR) or rituximab + lenalidomide (R-Len). Pts with histologically confirmed R/R MCL who have received ≥1 prior line of systemic therapy (including a BTKi) and have an Eastern Cooperative Oncology Group performance status of 0-2 are eligible for enrollment. Exclusion criteria include leukemic, non-nodal MCL; prior CAR T-cell therapy or CD20xCD3 bispecific antibodies; primary or secondary central nervous system (CNS) lymphoma or history of CNS lymphoma; and current or prior CNS disease (including stroke or transient ischemic attack in the past 2 years and residual neurologic deficits, epilepsy, or CNS vasculitis). Eligible pts will be randomly assigned (1:1) to receive glofitamab or investigator's choice of BR or R-Len stratified by line of therapy (1 vs ≥2) and response to last therapy (relapsed vs refractory). Pts will receive intravenous (IV) Gpt (2000mg) on Day (D) 1 of Cycle (C) 1, 7 days prior to the first glofitamab dose (Gpt may be split over 2 days as 1000mg doses if needed: the second 1000mg dose must be administered ≥1 day before initial glofitamab treatment). Pts will receive glofitamab for a fixed duration of 12 cycles, unless progressive disease (PD) or unacceptable toxicity occurs earlier. Glofitamab IV SUD will be given on C1D8 (2.5mg), C1D15 (10mg), and then the target dose (30mg) on D1 of C2-12 (21-day cycles). Pts randomized to the investigator's choice will receive 375mg/m 2 IV rituximab on D1 in combination with either 90mg/m 2 IV bendamustine on D1-2 of each cycle (BR for six cycles) or 20mg/day oral lenalidomide on D1-21 of each cycle (R-Len until PD); the cycle length for BR or R-Len is 28 days. Crossover to glofitamab from the investigator's choice is permitted in pts with radiologic confirmation of PD ( Figure). The primary endpoint is progression-free survival (PFS) determined by independent review committee (IRC). Treatment comparisons will be made with a 2-sided, level 0.05 stratified log-rank test. Secondary endpoints include overall survival (OS); IRC- and investigator-assessed CR rate, objective response rate, duration of response, and duration of CR; PFS (investigator-assessed); safety; health-related quality of life including time to deterioration in physical functioning or fatigue evaluated by the EORTC QLQ-C30; glofitamab PK; and immune response to glofitamab (including presence of anti-drug antibodies). Response will be determined according to Lugano criteria (Cheson et al. J Clin Oncol 2014). Stratified hazard ratios with 95% confidence intervals (95% CI) will be calculated for PFS and OS, and odds ratios (95% CI) will be calculated for the difference in CR rate and overall response rate between treatment arms. Predictive and prognostic biomarkers (to characterize high-risk subgroups and minimal residual disease kinetics) will also be explored. An estimated 80 sites globally will enroll approximately 182 pts with R/R MCL (glofitamab n=91; BR or R-Len n=91 total) starting in Oct-Nov 2023 (APAC, US, and EU regions).