Abstract: Ofatumumab is a human monoclonal antibody that binds to a unique CD20 epitope on the surface of B lymphocytes, resulting in efficient lysis of CD20‐expressing cells via complement‐dependent cytotoxicity and antibody‐dependent cell‐mediated cytotoxicity. The potential effect of ofatumumab on cardiac repolarization and the relationship between ofatumumab concentration and change in corrected QT interval (ΔQTcF) were evaluated in data from three clinical trials in 82 patients with chronic lymphocytic leukemia receiving ofatumumab alone (n = 14), ofatumumab with chemotherapy (n = 33), and chemotherapy alone (n = 35). Because of ofatumumab accumulation, baseline QTcF interval was recorded prior to the first infusion for each patient. No patient had a post‐baseline QTcF interval 〉 480 milliseconds or a ΔQTcF 〉 60 milliseconds; five patients (four on ofatumumab) had a ΔQTcF between 30 and 60 milliseconds. At cycle 6 (week 21; 308 μg/mL), there was an increase in QTcF in patients on ofatumumab treatment, with an estimated between‐treatment difference (90% CI) of 12.5 (4.5, 20.5) milliseconds. However, at the visit with the highest median concentration (week 8; 1386 μg/mL), median ΔQTcF was 4.8 milliseconds. There was no significant relationship between ofatumumab plasma concentration and ΔQTcF. Ofatumumab did not have a clinically significant effect on cardiac repolarization.

Abstract: 9020 Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third generation EGFR-TKI, showed superior efficacy to comparator EGFR-TKIs as first line treatment for EGFR mutation-positive (EGFRm) advanced NSCLC. In an exploratory analysis, we investigated clinical outcomes associated with detection of plasma EGFRm at 3 or 6 weeks (wks) after start of treatment. Methods: Treatment-naïve patients (pts) with EGFRm (ex19del or L858R) locally advanced or metastatic NSCLC were randomized 1:1 to receive osimertinib 80 mg once daily (QD) or comparator EGFR-TKIs (gefitinib 250 mg QD or erlotinib 150 mg QD). Plasma EGFR mutation analysis was conducted at baseline (BL), wks 3 and 6 by droplet digital PCR. Clearance was defined as undetectable levels of EGFRm in ctDNA at wks 3/6, where they were detectable at BL. Progression-free survival (PFS) was investigated based on early clearance of EGFRm. Results: In total 489/556 (88%) pts (osimertinib: 244/279; comparator: 245/277) had evaluable ctDNA at BL and wks 3/6. Of these, 342/489 (70%; osimertinib: 168/244; comparator: 174/245) had detectable BL EGFRm and were included in this analysis. See table. Conclusions: Clearance of plasma EGFRm after 3/6 wks of EGFR-TKI therapy was associated with a numerical improvement in PFS. The efficacy of osimertinib was superior to comparator EGFR-TKIs regardless of clearance status. Clinical trial information: NCT02296125. [Table: see text]

Abstract: We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non–small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions, including 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with ≥ one measurable CNS lesion. Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014 [nominally statistically significant] ). CNS objective response rates were 91% and 68% in patients with ≥ one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066) and 66% and 43% in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively. Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs. Conclusion Osimertinib has CNS efficacy in patients with untreated EGFR-mutated non–small-cell lung cancer. These results suggest a reduced risk of CNS progression with osimertinib versus standard EGFR-TKIs.

Abstract: Introduction: The randomized COMPLEMENT 2 study demonstrated a statistically significant improvement in independent reviewer committee-assessed median progression-free survival (PFS) in patients with relapsed chronic lymphocytic leukemia (CLL) who were treated with ofatumumab plus fludarabine and cyclophosphamide (OFC) compared with fludarabine and cyclophosphamide (FC) alone (28.9 vs. 18.8 months, p=0.0032) and that the addition of O was well tolerated (Robak T, et al. Haematologica 2015;100:abstract LB219). Moreover, the median overall survival was 56.4 months in the OFC arm and 45.8 months in the FC arm (p=0.1410) with a median follow-up of 34 months. In addition to the PFS benefit, it is important to consider the impact of adding O to FC on health-related quality of life (HRQoL) and patient-reported symptoms. Methods: In the COMPLEMENT 2 trial, patients with relapsed CLL (N=365) were randomized to either OFC or FC. F and C were administered as intravenous infusions (F: 25 mg/m2, Days 1-3 every 28 days for 6 cycles; C: 250 mg/m2, Days 1-3 every 28 days for 6 cycles). O was also administered intravenously (Cycle 1: 300 mg Day 1 and 1000 mg Day 8, subsequent cycles: 1000 mg Day 1). During the trial, the EORTC QLQ-C30 v3.0 and the QLQ-CLL16 questionnaires were administered at baseline, during Cycle 4 of 6 and throughout follow-up. Specified patient-reported endpoints were HRQoL as reported by the global health status/QoL domain of the QLQ-C30 questionnaire and a B symptom index including patient-reported symptoms of fatigue, night sweats, temperature changes, and weight loss as reported by certain items of the QLQ-C30 and QLQ-CLL16 questionnaires. Results: The least square mean change in HRQoL, measured on a scale scored from 0 (worse) to 100 (best), improved between baseline and Cycle 4 by 8.3 points in the OFC arm vs. 4.8 points in the FC arm. Although there was no significant difference between the least square mean changes in the two arms (p=0.09), the OFC arm surpassed the 5-point difference defined as being a clinically relevant change (Osoba D, et al. J Clin Oncol 1998;16;139-144). The least square mean change in B symptom index, measured on a scale of 0-100 with 0 meaning no symptoms, improved from baseline to Cycle 4 by 5.6 points and 4.5 points in the OFC and FC arms, respectively, with no significant difference between the arms (p=0.49). Patients who achieved a complete or partial response to therapy showed a larger mean improvement in B symptoms (OFC 6.5 improvement, FC 7.5 improvement) than those who did not respond (OFC 4.3 improvement, FC 3.5 worsening of symptoms) but these differences between the arms were not significant (p=0.51 and p=0.22, respectively). During follow-up, patients who did not progress maintained a consistent level of HRQoL in both arms (Figure). Conclusion: This study demonstrates durable improvements in both HRQoL and patient-reported B symptoms for patients being treated for relapsed CLL. Although there are no significant differences observed between the OFC and FC treatment arms in terms of the least square mean change in HRQoL or B symptom scores, the improvement in PFS in the OFC arm reported previously (Robak T, et al. Haematologica 2015;100:abstract LB219) suggests that these patients may enjoy HRQoL and symptom improvements for a longer duration. Figure 1. Least Squares Mean Change in HRQoL from Baseline Figure 1. Least Squares Mean Change in HRQoL from Baseline Disclosures Robak: GlaxoSmithKline: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Off Label Use: Ofatumumab (Arzerra) is approved in the frontline and refractory CLL setting but not in relapsed CLL. This Abstract presents the Health related quality of life and patient reported outcomes in patients receiving ofatumumab in combination with fludarabine and cyclophosphamide (FC) versus FC alone. Kryachok:GlaxoSmithKline: Honoraria, Other: Investigator for Study. Homenda:GlaxoSmithKline: Honoraria, Other: Intestigator in Clinical Trial - OMB110913 (COMPLEMENT 2). Blonski:GlaxoSmithKline: Research Funding. McKeown:GlaxoSmithKline: Equity Ownership; Novartis: Employment, Equity Ownership. Chang:GlaxoSmithKline: Equity Ownership; Novartis: Employment, Equity Ownership. Manson:GlaxoSmithKline: Employment, Equity Ownership; Novartis: Employment, Equity Ownership. Lisby:Genmab: Employment. Gupta:Novartis: Employment, Equity Ownership; GlaxoSmithKline: Equity Ownership.

Abstract: Introduction: Belantamab mafodotin is a first-in-class, monomethyl auristatin F (MMAF)-containing, B-cell maturation antigen (BCMA)-directed antibody-drug conjugate (ADC) that is approved in the United States and European Union for adult patients with relapsed/refractory multiple myeloma (RRMM). In the pivotal Phase II DREAMM-2 study, single-agent belantamab mafodotin (2.5 mg/kg administered intravenously every 3 weeks [Q3W]) demonstrated an objective response rate of 32% with a manageable safety profile in triple-class refractory adult patients with RRMM (Lonial et al. Lancet Oncol. 2020). At 13 months of follow-up, responses were durable, with a median duration of response of 11 months and an overall survival of 13.7 months (Lonial et al. ASH 2020, Poster 1417). Corneal events are common and expected with belantamab mafodotin and other MMAF-containing ADCs. In DREAMM-2, keratopathy (a pathological eye exam finding) presented as superficial punctate keratopathy and/or microcyst-like epithelial changes. Ocular symptoms, such as decline in best-corrected visual acuity or patient-reported adverse events (eg, blurred vision or dry eye), were also common during treatment. Corneal events with or without symptoms were managed with dose modifications (delays and reductions), and clinically meaningful responses were observed even with prolonged treatment-free intervals; this suggests that alternative dosing regimens of belantamab mafodotin may lower rates of corneal events without compromising efficacy. The goal of the DREAMM-14 study is to investigate whether an improved overall benefit/risk profile of single-agent belantamab mafodotin can be achieved by modifying the belantamab mafodotin dose, schedule, or both relative to the approved dosing regimen (2.5 mg/kg Q3W). Methods: This Phase II, 5-arm, randomized, parallel, open-label multicenter study will include patients with RRMM who have received at least 3 prior lines of therapy including an anti-CD38 monoclonal antibody (mAb), an immunomodulatory agent, and a proteasome inhibitor. Patients aged ≥18 years with Eastern Cooperative Oncology Group Performance Status ≤2 and who provide informed consent will be eligible. Patients with corneal epithelial disease (except mild punctate keratopathy) or prior exposure to BCMA-targeted therapies or ADCs will be excluded. Patients will be randomized into Arms A to D (n=40 each) and arm E (n=20) in parallel and stratified by the International Staging System (ISS) for MM (I vs II vs III) and prior lines of therapy (3 vs ≥4). Single-agent belantamab mafodotin will be administered at doses and schedules as follows-Arm A: 2.5 mg/kg Q3W (control); Arm B: 1.9 mg/kg Q3W; Arm C: 2.5 mg/kg Q6W; Arm D: 1.9 mg/kg Q6W; Arm E: 1.9 mg/kg Q6W with dose modifications based on oncology staff assessment of ocular symptoms (patient-reported symptoms using the Ocular Surface Disease Index) and visual acuity. Participants in all arms will have Q3W response assessments and Q3W ophthalmic examinations and monitoring by qualified eye care specialists. Ocular event-related dose modifications for all arms except Arm E will be guided by the Keratopathy and Visual Acuity (KVA) scale. Participants in all arms will be treated until progressive disease, unacceptable toxicity, or death. The primary endpoint will be incidence of Grade ≥2 ocular adverse events according to the KVA scale. Key secondary endpoints include ocular safety and tolerability, pharmacokinetics, and efficacy outcomes of belantamab mafodotin in all arms. Follow-up for progression-free survival will be Q3W until progressive disease, start of new anticancer therapy, withdrawal of consent, end of study, or death. Follow-up for overall survival will be Q12W from treatment discontinuation. The duration of this study will be approximately 22 months. The study is planned to start in the first quarter of 2022. Funding: GSK (Study 209628); drug linker technology licensed from Seagen; mAb produced using POTELLIGENT Technology licensed from BioWa. Disclosures Hultcrantz: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding. Kleinman: Calm Water Therapeutics LLC: Current Employment; GlaxoSmithKline: Consultancy; Eyeon Therapeutics Inc.: Current holder of individual stocks in a privately-held company; ONL Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company; Triphase Accelerator: Consultancy; Helixmith Co., Ltd: Consultancy; Aprea Therapeutics: Consultancy; Editas Medicine, Inc.: Consultancy; Olema Pharmaceuticals, Inc.: Consultancy. Ghataorhe: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. McKeown: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. He: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ling: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Jewell: Alcon: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Brunner: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Byrne: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; Adaptimmune: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Eliason: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Scott: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Opalinska: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company.

Abstract: Mutations in NOTCH1 (NOTCH1mut ) have been found in CLL with an incidence of about 10% and have been associated with unmutated IGHV, +12q, and poor outcome in previous studies. In the CLL8 trial (1st line FCR vs. FC), NOTCH1mut was identified as an independent unfavorable prognostic factor for progression free survival (PFS) and a predictive factor for reduced benefit from the addition of Rituximab to FC. Methods We assessed the incidence and impact of NOTCH1mut in the OMB110911 trial (1st line Chl vs. O-Chl) in patients considered inappropriate for fludarabine-based therapy. Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative for the full trial population. The mutation hotspot fragment (chr9:139,390,619-139,390,840) of exon 34 of NOTCH1 was analyzed by Sanger sequencing and by NGS using Illumina MiSeq. NGS was used to evaluate the sensitivity of Sanger sequencing to detect c.7541_7542delCT mutation and to determine the exact variant frequency of the mutant allele. Results The c.7541_7542delCT mutation was found by Sanger sequencing and by NGS in 45 (12.0%) of 376 patients (24 in O-Chl and 21 in Chl). When comparing baseline characteristics, there were significant associations of NOTCH1mut with +12q (p=0.01), absence of 13q- (p=0.006) and unmutated IGHV (p=0.009), but not with gender, age , Binet stage, ECOG, CIRS, B symptoms, WBC, ß2-MG, 6q-, 11q-, and 17p-. Regarding response to treatment, there was no association between NOTCH1mut and ORR or CR, neither in the whole group nor when analyzing the treatment arms separately. At a median follow-up of 29.0 months for PFS there were 249 events, at the medium follow-up of 31.7 months for OS 63 events in the 376 patient cohort. Similar to the full trial cohort, also in our cohort, O-Chl as compared to Chl resulted into significant improved PFS (median 22.4 vs. 13.1 months, HR=0.54, p 〈 0.001). Of note, NOTCH1mut was associated with shorter PFS in the O-Chl arm (17.7 vs. 23.3, HR 1.86 p=0.01) but did not affect PFS in the Chl arm (10.3 vs. 13.3 months, HR 1.20 p=0.49). Correspondingly, in cases without NOTCH1mut a benefit from the addition of Ofatumumab was evident (HR 0.501 p 〈 0.001) while for NOTCH1mut patients a reduced benefit which did not meet statistical significance was observed (HR 0.734 p=0.35). To identify factors of independent clinical impact, we performed multivariable Cox regressions for PFS and OS including the following variables: treatment, gender, age, Binet stage, ECOG status, CIRS, B symptoms, WBC, ß2-MG, 11q, 17p, IGHV and NOTCH1. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.39, p 〈 0.001), WBC 〉 50Gl/l (HR 2.66, p 〈 0.001), CIRS Score 〉 8 (HR 1.70 p 〈 0.001), male gender (HR 1.39 p=0.04), unmutated IGHV (HR 1.38 p=0.04), 17p- (HR 3.19 p 〈 0.001) and NOTCH1mut (HR 1.47 p=0.05). Regarding OS, WBC 〉 50Gl/l (HR 2.58 p=0.01), ß2-MG 〉 5mg/l (HR 2.55 p=0.004), Binet Stage C (HR 2.13 p=0.01), 17p- (HR 4.97 p=0.001) and unmutated IGHV (HR 1.91 p=0.04) were identified as independent prognostic factors. Most likely due to the low frequency of NOTCH1mut of 12%, an interaction term in the multivariable model failed to achieve significance (HR 1.49, p=0.27). When comparing NGS and Sanger sequencing, all cases with a mutant allele burden of 〉 5% were detected by Sanger sequencing and in 34 of 45 NOTCH1mut patients, the hotspot mutation could be identified in a fraction 〉 20%. For this subgroup, the effect of NOTCH1mut on PFS in the O-Chl treatment arm was even more pronounced (O-Chl: HR 2.459, p 〈 0.01). Conclusion In the OMB110911 trial evaluating 1st line O-Chl against Chl, NOTCH1mut was associated with absence of 13q-, +12q, unmutated IGHV and a shorter PFS in multivariable analysis. Comparison of the impact of NOTCH1mut in both treatment arms suggests NOTCH1mut is a predictive marker for reduced benefit from the addition of Ofatumumab in the O-Chl treatment arm. Disclosures: Tausch: GSK: Research Funding, Travel support Other. Off Label Use: First line Ofatumumab in combination with CBL in a clinical trial. Hillmen:GlaxoSmithKline: Honoraria, Research Funding. Offner:GlaxoSmithKline: Membership on an entity’s Board of Directors or advisory committees. Janssens:Mundipharma: Speakers Bureau; Roche: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau. Mayer:Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Panagiotidis:Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Danhauser-Riedl:GlaxoSmithKline GmbH & Co KG: Employment. McKeown:GSK: Employment. Winter:GlaxoSmithKline: Employment, Equity Ownership. Gupta:GSK: Employment. Stilgenbauer:GSK: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel support Other.

Abstract: TPS8073 Background: Belantamab mafodotin (belamaf: BLENREP) is a first-in-class, monomethyl auristatin F (MMAF)-containing, B-cell maturation antigen (BCMA)-directed antibody–drug conjugate (ADC). In the DREAMM-2 study, belamaf showed deep responses with a manageable safety profile in patients with relapsed/refractory multiple myeloma (RRMM). At 13 months of follow-up, the median duration of response was 11 months and overall survival was 13.7 months at the 2.5 mg/kg Q3W dose. Corneal events are common and expected with belamaf and other MMAF-containing ADCs. In DREAMM-2, corneal events were managed with dose modifications. Clinical responses were observed even with prolonged dose holds, suggesting alternative dosing regimens may lower corneal event rates without compromising efficacy. The DREAMM-14 study (NCT05064358) will investigate if an improved benefit/risk profile of single-agent belamaf can be achieved by modifying the dose, schedule, or both, relative to the approved dosing regimen (2.5 mg/kg Q3W). Methods: This Phase II, randomized, open-label study will include adults with RRMM who had ≥3 prior lines of therapy (LOT), including an anti-CD38 monoclonal antibody, an immunomodulatory agent, and a proteasome inhibitor. Patients with corneal epithelial disease (except nonconfluent superficial punctate keratitis) or with prior exposure to BCMA-targeted therapies, or ADCs will be excluded. Patients will be randomized into Arms A–D (n=40 each) and Arm E (n=20) in parallel and stratified by the International Staging System (I vs II vs III) and prior LOT (3 vs ≥4). Belamaf will be administered as follows—Arm A: 2.5 mg/kg Q3W; Arm B: 1.9 mg/kg Q3W; Arm C: 2.5 mg/kg Q6W; Arm D: 1.9 mg/kg Q6W; Arm E: 1.9 mg/kg Q6W with ocular event-related dose modifications based on oncology staff assessment of ocular symptoms (patient-reported symptoms using the Ocular Surface Disease Index), and visual acuity (Snellen chart or equivalent) in addition to corneal findings assessed by an eye care specialist. Patients in all Arms will have response assessments, safety assessments, and ophthalmic exams performed by an eye care specialist Q3W regardless of dosing schedule. Ocular event-related dose modifications (except in Arm E) will be guided by a modified Keratopathy and Visual Acuity scale. The primary endpoint will be incidence of ocular events. Key secondary endpoints include ocular safety and tolerability, overall safety and tolerability, pharmacokinetics, and efficacy outcomes. Follow-up for progression-free survival will be Q3W until progressive disease, start of new anticancer therapy, withdrawal of consent, end of study, or death. Status: Recruitment is ongoing. Funding: GSK (Study 209628); drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT05064358.