SC QW Research Articles

OP33 Efficacy and safety of subcutaneous guselkumab induction therapy in patients with moderately to severely active Crohn’s disease: Results through Week 48 from the phase 3 GRAVITI study

Abstract Background Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that was efficacious in phase 3 trials (GALAXI 2/3) of pts with CD using IV induction and SC maintenance. We evaluated the efficacy and safety of GUS SC induction/maintenance in GRAVITI, a phase 3 treat-through trial in pts with moderately to severely active CD. Methods Eligible pts had a history of inadequate response or intolerance to oral corticosteroids, AZA, 6-MP, MTX, or biologics (BIO-IR). Randomization was stratified by baseline (BL) CDAI, SES-CD, and BIO-IR status, with 347 pts allocated 1:1:1 to GUS 400mg SC q4w (x3)→GUS 200mg SC q4w (N=115), GUS 400mg SC q4w (x3)→GUS 100mg SC q8w (N=115), or PBO (N=117). Pts were rescued at Wk16: PBO pts switched to GUS, and GUS pts stayed on GUS per treat-through design (sham rescue). The co-primary endpoints were clinical remission at Wk12 and endoscopic response at Wk12. Other multiplicity-controlled endpoints were clinical remission at Wk24, PRO-2 remission at Wk12, clinical response at Wk12, clinical remission at Wk48, and endoscopic response at Wk48. All endpoints assessed through Wk12 compared the combined GUS 400mg SC treatment arm to PBO; assessments after Wk12 compared each GUS SC maintenance regimen to PBO. All pts who met rescue criteria were considered not to have met efficacy endpoints after Wk16. Safety was assessed through Wk48. Results BL characteristics were similar across groups (overall mean age, 37.5yrs; mean CD disease duration, 8.0yrs; mean CDAI, 296.9; mean SES-CD, 12.0; BIO-IR, 46.4%). The co-primary and all multiplicity-controlled endpoints were met. GUS 400mg SC induction demonstrated superiority to PBO at Wk12. Both SC maintenance dose regimens were also superior to PBO at Wks 24 and 48 (Figure). In prespecified analyses of subpopulations defined by prior biologic history, greater proportions of GUS-treated pts achieved the endpoints than PBO. Key safety event rates per 100 pt years through Wk48 were similar among groups (Table). Proportions of GUS-treated pts experiencing ≥1 serious AE or AE leading to discontinuation of study agent were not greater than PBO. The numbers of GUS-treated pts with serious infections or AEs of special interest were low. Conclusion GRAVITI established the efficacy of GUS SC induction followed by SC maintenance in CD. These results build on the GALAXI 2/3 data and demonstrate that both IV and SC induction are efficacious. Safety findings were consistent with the known safety profile of GUS in approved indications.

OP35 Low remission recapture after ustekinumab dose optimization in Crohn’s disease: results of the randomized placebo-controlled double-blind REScUE study.

Abstract Background In Crohn’s disease (CD), an exposure-response relationship exists for ustekinumab, with higher serum levels associated with better outcomes. Although several retrospective and observational studies demonstrate dose-escalation of ustekinumab can be effective in case of secondary loss of response (LOR), prospective placebo-controlled data are lacking. The aim of the REScUE study (NCT04245215) was to investigate the effect of 2 different re-induction regimens with ustekinumab on clinical, endoscopic, biological and pharmacological outcomes in patients with CD. Methods This Belgian multicentre prospective double-blind randomized placebo-controlled trial included adult patients with CD treated with ustekinumab who presented with secondary LOR to ustekinumab after documented primary response. Secondary LOR was defined by PRO-2 (AP> 1 AND SF> 3) and confirmed by either an elevated biomarker (CRP >5 mg/L or faecal calprotectin >250 µg/mg) or endoscopic signs of inflammation. All patients received a single IV re-induction with ustekinumab (≈6mg/kg) and were then randomized 1:1 to blinded maintenance ustekinumab 90 mg SC Q4W (intervention) or 90 mg SC Q8W (control) for 48 weeks. Primary endpoint was proportion of patients with steroid-free clinical remission (definition in fig 1) at week 48, with missing data were handled using non-responder imputation. Results In total, 132 patients were screened, and 108 patients were included: 67% female, median [IQR] age 41 [32-54] year, median disease duration 14 [7-22] years. Prior anti-TNF exposure was reported in 92% of patients, while ustekinumab was the first-line advanced treatment in 7% of patients. The primary endpoint of steroid-free clinical remission at week 48 was achieved by 9/54 (17%) patients in the q4w regimen vs 8/54 (16%) in the q8w regimen (p=0.96) (fig 1). Endoscopic remission (SES-CD <3) was achieved in 5/54 (10%) vs 3/54 (6%) (p=0.52), endoscopic response (≥50% decrease in SES-CD from baseline) was achieved in 11/54 (22%) vs 6/54 (12%) (p=0.23) and 0.52biomarker remission was achieved in 20/54 (38%) vs 13/54 (26%) (p=0.19) in the q4w regimen vs the q8w regimen, respectively. Time to first clinical remission was similar between groups (fig 2). Association with ustekinumab serum levels will be reported. No new safety signals were observed. Conclusion In patients with CD experiencing secondary LOR to ustekinumab, dose optimization with a single IV re-induction followed by intensified maintenance dosing (90 mg SC q4W) was not superior to a single IV re-induction followed by conventional maintenance dosing (90 mg SC q8W) in achieving steroid-free clinical remission. The secondary endpoints were numerically higher but not significant in the intensified regimen.

P1030 Efficacy and safety of subcutaneous guselkumab in East Asian participants with moderately to severely active Crohn’s disease: Subgroup analysis of the Phase 3 GRAVITI study

Abstract Background Guselkumab (GUS) is a dual-acting interleukin-23 p19 subunit inhibitor that was efficacious in phase 3 trials of participants (pts) with Crohn’s disease (CD) using either intravenous (IV; GALAXI 2/3) or subcutaneous (SC; GRAVITI) induction and SC maintenance.1,2 We evaluated the efficacy and safety of GUS SC induction and SC maintenance in a post hoc subgroup analysis of East Asian (China, Japan, Korea, and Taiwan) pts from GRAVITI, a phase 3 treat-through trial in pts with moderately to severely active CD. Methods The GRAVITI study (NCT05197049) included pts with CD with a history of inadequate response or intolerance to oral corticosteroids, AZA, 6-MP, MTX, or biologics (BIO-IR). Randomization was stratified by baseline Crohn’s Disease Activity Index (CDAI), Simple Endoscopic Score for Crohn’s Disease (SES-CD), and BIO-IR status, and pts were allocated 1:1:1 in a treat-through design to GUS 400mg SC every 4 weeks (q4w) (x3)→GUS 200mg SC q4w, GUS 400mg SC q4w (x3)→GUS 100mg SC every 8 weeks (q8w), or placebo (PBO). Participants in the placebo group who met rescue criteria received GUS 400mg SC at Wk16, Wk20, and Wk24 followed by GUS 100mg SC q8w; GUS pts stayed on GUS per treat-through design (sham rescue). The co-primary endpoints were clinical remission at Wk12 and endoscopic response at Wk12. Additional endpoints were patient-reported outcome 2 (PRO-2) remission at Wk12, clinical response at Wk12, clinical remission at Wk24, clinical remission at Wk48, and endoscopic response at Wk48. All endpoints assessed through Wk12 compared the combined GUS 400mg SC treatment arm to PBO; assessments after Wk12 compared each GUS SC maintenance regimen to PBO. All pts who met rescue criteria were considered not to have met efficacy endpoints after Wk16. Safety was assessed through Wk48. Results This analysis included 71 East Asian pts. At Wk12, higher proportions of pts in the GUS 400mg SC cohort achieved clinical remission, clinical response, endoscopic response, and PRO-2 remission relative to PBO pts. At Wk24 and Wk48, higher proportions of pts achieved clinical remission in both GUS SC maintenance dose regimens compared with PBO. Endoscopic response at Wk48 was achieved in a higher proportion of pts in both GUS SC maintenance dose regimens compared with PBO (Figure 1). Key safety event rates through Wk48 were similar among treatment groups (Table 1). No deaths were reported in East Asian pts. Conclusion Efficacy of GUS as SC induction followed by SC maintenance therapy in the subgroup of East Asian pts from GRAVITI was consistent with that observed in the overall study population. The safety profile was consistent with the known safety profile of GUS in approved indications and with the overall study population.

P1149 Guselkumab improves health-related quality of life as measured by PROMIS-29 in participants with moderately to severely active Crohn’s disease: Phase 3 GRAVITI study

Abstract Background Patients (pts) with Crohn’s disease (CD) suffer from symptoms that impair health-related quality of life (HRQoL).1-3 The Phase 3 GRAVITI treat-through trial evaluated the efficacy and safety of SC induction and maintenance of guselkumab (GUS), an interleukin (IL)-23 p19 subunit antagonist, in pts with moderately to severely active CD who had demonstrated a history of inadequate response or intolerance to oral corticosteroids, AZA, 6-MP, MTX, or biologics. Here we report HRQoL as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS)-29 through Week (Wk) 48. PROMIS-29 consists of 7 domains (symptom domains: anxiety, depression, fatigue, pain interference, and sleep disturbance; functional domains: physical function and social participation) and a pain intensity item. Methods The GRAVITI programme for GUS in CD (NCT05197049) employs a treat-through design in which pts were allocated 1:1:1 to GUS 400mg SC every 4 weeks (q4w) (x3)→GUS 200mg SC q4w, GUS 400mg SC q4w (x3)→GUS 100mg SC every 8 weeks (q8w), or placebo (PBO). Pts in the placebo group who met the criteria for rescue therapy received guselkumab 400 mg SC at Wk16, Wk20, and Wk24 followed by guselkumab 100 mg SC q8w; GUS pts stayed on GUS per treat-through design (sham rescue). PROMIS-29 uses standardized T-scores, with a general population mean of 50 and standard deviation (SD) of 10. The physical component summary (PCS) and mental component summary (MCS) scores were calculated based on the domain T-scores. Clinically meaningful improvement (CMI) was according to previously defined thresholds for each domain, and the MCS and PCS.4 Higher scores indicate better health outcomes for the functional domains and two summary scores (PCS and MCS), and worse symptoms for the symptom domains, including the pain intensity item, which uses a numeric rating scale (NRS; 0 [no pain] to 10 [worst pain]). Results In the full analysis population, baseline mean PROMIS-29 domain scores were similar among all treatment groups in functional domain scores, symptom domain scores, and pain intensity scores. All baseline values were indicating impaired HRQoL (Table 1). GUS-treated pts achieved a greater improvement from baseline at Wk12 and Wk48 in each domain T-score, the pain intensity NRS score, and the PCS and MCS than PBO-treated pts. Additionally, the percentage of pts achieving CMI through Wk12 and Wk48 was greater for GUS vs PBO in each domain, the pain intensity NRS score, and the PCS and MCS scores (Figure 1). Conclusion Pts with moderately to severely active CD treated with GUS SC induction and maintenance experienced broad and clinically meaningful improvements in HRQoL compared with placebo pts as measured by PROMIS-29 through Wk12 and through Wk48.

P0891 Efficacy and safety of subcutaneous guselkumab rescue therapy in patients with moderately to severely active Crohn’s disease and inadequate response to ustekinumab: Phase 2 GALAXI 1 study long-term extension results

Abstract Background Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that is being evaluated in Crohn’s disease (CD). The GALAXI 1 study (NCT03466411) is a phase 2b study that evaluated GUS in participants (pts) with moderately to severely active CD. Pts treated with ustekinumab (UST) who met inadequate response criteria during long term extension (LTE) could cross over to GUS 200 mg q4w SC. Here, we present efficacy and safety results in pts who received GUS after experiencing an inadequate response to UST in the LTE. Methods Individuals with prior inadequate response or intolerance to UST were excluded from GALAXI 1; however, during the LTE, pts treated with UST ~6 mg/kg IV→UST 90 mg SC q8w who met inadequate treatment response criteria (not in clinical response [≥100-point reduction in CDAI score from baseline or CDAI<150] and CDAI ≥220) between Weeks 52-80 of the LTE were eligible for a treatment switch to GUS 200 mg q4w SC, without IV induction. Clinical response and clinical remission were both assessed 16 weeks after treatment switch. Endoscopic response and endoscopic remission were assessed at Weeks 96 and 144 (definitions in Figure). Safety was assessed through Week 144. Results In total, 17 pts treated with UST underwent treatment switch to continuing GUS 200 mg q4w SC therapy due to meeting inadequate treatment response criteria between Weeks 52-80 of the LTE. Pts who crossed over to GUS exhibited similar baseline demographics and disease characteristics to all GUS LTE pts (Table). The proportions of pts achieving clinical response and clinical remission 16 weeks after treatment switch from UST to GUS 200 mg SC q4w were 58.8% and 52.9%, respectively. The proportions of pts achieving endoscopic response and endoscopic remission were 52.9% and 35.3% at study Week 96, respectively, and were maintained through Week 144 (Figure). Key safety event rates through Week 144 were consistent with the known safety profile of GUS in approved indications. Conclusion Among pts who experienced inadequate response to UST in the LTE, more than half achieved clinical remission 16 weeks after treatment switch to GUS 200 mg SC q4w and >50% were in endoscopic response at Week 96. These data suggest pts with an inadequate treatment response to UST may benefit from GUS treatment. Results are limited by small sample size and direct treatment switch to GUS SC maintenance dosing without IV induction.

P0917 Corticosteroid sparing effects of treatment with guselkumab in patients with moderate to severely active Crohn’s disease: Phase 3 GALAXI 2/3 results through week 48

Abstract Background GALAXI 2 & GALAXI 3 (G2 & G3) are identical 48-week (Wk), randomized, double-blind, head-to-head, placebo- and active-comparator (ustekinumab; UST) treat-through trials assessing the efficacy and safety of guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, in participants (pts) with Crohn’s disease (CD). Here we report the corticosteroid (CS)-sparing effects of treatment with GUS vs UST from the pooled G2 & G3 studies through Wk48. Methods Pts with moderately to severely active CD (based on CDAI and SES-CD scoring) and inadequate response or intolerance to conventional or biologic (BIO-IR) therapy were eligible. Pts were randomized 2:2:2:1 to GUS 200mg IV q4w(x3)→200mg SC q4w, GUS 200mg IV q4w(x3)→100mg SC q8w, UST ~6mg/kg IV(x1)→90mg SC q8w, or placebo. Pts receiving oral CS upon entry (up to 40mg/day of prednisone-equivalent dose) were required to begin tapering their daily CS dose at Wk12, unless not medically feasible. CS use and 90-day CS-free clinical outcomes at Wk48 were assessed vs UST. Results The primary analysis (all pts) included 508 (G2) and 513 (G3) pts. Baseline (BL) characteristics were similar across trials: mean [SD] CDAI (G2: 295.0 [52.0], G3: 294.7 [53.8]), mean [SD] SES-CD (13.1 [7.3], 12.8 [7.3]), BIO-IR history (52.8%, 51.9%), BIO-naïve (41.9%, 41.5%), and oral CS use (37.4%, 36.1%). In analyses of pooled data (G2+G3), the proportion of pts receiving oral CS at BL was similar across treatment groups (GUS 100mg q8w: 38.1%; GUS 200mg q4w: 35.8%; UST: 37.5%). Greater proportions of pts receiving both GUS doses achieved 90-day CS-free Wk-48 outcomes of endoscopic response vs UST (100 mg q8w vs UST: ∆11.2%; 200 mg q4w vs UST: ∆14.5%), endoscopic remission (∆9.5%, ∆11.9%), the composite endpoint of clinical remission + endoscopic response (∆8.1%, ∆12.4%), the composite endpoint of clinical remission + endoscopic remission (∆8.0%, ∆10.9%), and clinical remission (∆4.1%, ∆5.3%) (Table 1). The 90-day CS-free outcomes vs UST in BIO-IR and BIO-naïve pts in the primary analysis were also assessed at Wk48 (Table 1). Among all pts receiving oral CS at BL, greater proportions of GUS-treated pts (100mg q8w: 71.6%; 200mg q4w: 75.5%) were not receiving CS at Wk 48 vs UST (67.0%). Also, among all pts receiving oral CS at BL, greater proportions of GUS-treated pts achieved 90-day CS-free outcomes at Wk48 vs UST, including endoscopic response (41.3%, 42.5% vs 31.2%) and endoscopic remission (30.3%, 28.3% vs 20.2%), and similar proportions for clinical remission (52.3%, 54.7% vs 53.2%). Conclusion In CD, greater proportions of GUS-treated pts achieved CS-free endoscopic-based efficacy outcomes through Wk48 vs UST, regardless of prior biologic exposure status.

DOP060 Early disease efficacy of guselkumab therapy in biologic-naïve patients with moderately to severely active Crohn’s disease: Post-hoc analysis from the phase 3 GALAXI 2 & 3 studies

Abstract Background Early biologic treatment is associated with better outcomes in pts with CD. GALAXI 2 & 3 are identically designed trials assessing the efficacy and safety of guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, in pts with moderately to severely active CD, and the efficacy in BIO-naïve pts was previously reported.1,2,3 Here, we present results of a post-hoc analysis of GUS efficacy in BIO-naïve pts with disease duration ≤2yrs using data from the pooled GALAXI trials. Methods Pts had moderately to severely active CD (based on CDAI and SES-CD) and a history of inadequate response/intolerance to oral corticosteroids (CS), AZA, 6-MP, MTX, or biologics. Pts were randomized 2:2:2:1 to GUS 200mg IV q4w (x3)→200mg SC q4w, GUS 200mg IV q4w (x3)→100mg SC q8w, ustekinumab (UST) ~6mg/kg IV (x1)→90mg SC q8w (active comparator), or placebo (PBO). PBO pts not in clinical response at W12 switched to UST. GUS vs PBO was evaluated for clinical response, clinical remission, and endoscopic response at W12 and patient-level composite endpoints of clinical response at W12 + clinical remission at W48 and clinical response at W12 + endoscopic response at W48. GUS vs UST was evaluated at W48 for endoscopic response and endoscopic remission, patient-level composite endpoints of clinical remission + endoscopic response and deep remission, and clinical remission (definitions in Table). All p-values were nominal. Results Of the 426 BIO-naïve pts in the pooled analysis, 180 had disease duration ≤2yrs. Greater proportions of pts treated with GUS 200mg IV than PBO achieved clinical response at W12 (67.3% vs 25.0%; Δ=42.3%; p<0.001), clinical remission at W12 (51.0% vs 16.7%; Δ=30.8%; p=0.002), and endoscopic response at W12 (49.0% vs 29.2%; Δ=19.9%; p=0.058). Greater proportions of pts treated with either GUS 100mg SC or 200mg SC achieved clinical response at W12 + clinical remission at W48 and clinical response at W12 + endoscopic response at W48 vs PBO (Figure 1A). Compared to UST at W48 (Figure 1B), greater proportions of pts treated with either GUS 100mg SC or 200mg SC achieved endoscopic response, endoscopic remission, clinical remission + endoscopic response, and deep remission. High levels of clinical remission were achieved by GUS-treated pts at W48. Conclusion In GALAXI, GUS-treated BIO-naïve pts with disease duration ≤2yrs achieved clinical and endoscopic endpoints in greater proportions compared with PBO and endoscopic endpoints in greater proportions compared with UST. Overall, these robust results highlight the benefit of early biologic treatment and supports the use of GUS as an early therapeutic choice in CD.

A first-in-human, single and multiple dose study of lunsekimig, a novel anti-TSLP/anti-IL-13 NANOBODY® compound, in healthy volunteers.

Lunsekimig is a novel, bispecific NANOBODY® molecule that inhibits both thymic stromal lymphopoietin (TSLP) and interleukin (IL)-13, two key mediators of asthma pathophysiology. In this first-in-human study, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of lunsekimig in healthy adult participants. Participants received single ascending doses (SAD) of lunsekimig (10-400 mg intravenous [IV] or 400 mg subcutaneous [SC]) (SAD part) or multiple ascending doses (MAD part) of lunsekimig (100 or 200 mg, every 2 weeks [Q2W] for three SC doses), or placebo. Overall, 48 participants were randomized 3:1 in the SAD part and 4:1 in the MAD part for lunsekimig or placebo. The primary endpoint was safety and tolerability. The secondary endpoints included PK, antidrug antibodies (ADAs) and total target measurement. Lunsekimig was well tolerated and common treatment-emergent adverse events were COVID-19, nasopharyngitis, injection site reactions, and headache. Lunsekimig showed dose-proportional increases in exposure and linear elimination. Mean t1/2z of lunsekimig was around 10 days across all IV and SC doses of the SAD and MAD parts of the study. Increases in the serum concentration of total TSLP and IL-13 for lunsekimig versus placebo indicated target engagement. ADA of low titers were detected in four (11.1%) participants who received lunsekimig in the SAD, and seven (43.8%) in the MAD. In conclusion, lunsekimig was well tolerated in healthy participants with a linear PK profile up to single 400 mg IV and SC dose and multiple doses of 100 and 200 mg SC Q2W, with low immunogenicity.

Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): Analysis of minimal residual disease (MRD) in the PERSEUS trial.

7502 Background: In the primary analysis of the phase 3 PERSEUS study, subcutaneous DARA (DARA SC) + VRd (D-VRd) induction/consolidation (ind/consol) and D-R maintenance improved progression-free survival (PFS) and increased depth of response (complete response or better [≥CR] and MRD negativity [neg]) compared to VRd ind/consol and R maintenance for TE NDMM. Here, we report further results on deepening of response and MRD neg during maintenance. Methods: TE pts with NDMM were randomized 1:1 to D-VRd or VRd. Pts in both arms received up to six 28-day cycles (4 pre-ASCT ind, 2 post-ASCT consol) of VRd (V 1.3 mg/m2 SC on Days [D] 1, 4, 8, 11; R 25 mg PO on D 1-21; d 40 mg PO/IV on D 1-4, 9-12) followed by R maintenance (10 mg PO on D 1-28 until progressive disease [PD]). Pts in the D-VRd arm also received DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W during maintenance until PD. MRD-neg rate (clonoSEQ) was defined as the proportion of ITT pts who achieved both ≥CR and MRD neg. Results: In the 709 pts randomized (D-VRd, n=355; VRd, n=354), responses deepened over time with D-VRd vs VRd, including rates of ≥CR (end of consol: 44.5% vs 34.7%; P= 0.0078 and overall: 87.9% vs 70.1%; P<0.0001). MRD-neg rates increased over time and were higher with D-VRd vs VRd at 12, 24, and 36 mo after Cycle 1 Day 1 (all P<0.0001; Table). Rates of sustained MRD neg for ≥12 mo were higher for D-VRd vs VRd (10–5: 64.8% vs 29.7%; P<0.0001; 10–6: 47.3% vs 18.6%; P<0.0001); results were consistent across prespecified clinically relevant subgroups. Among pts who were MRD positive (pos) at end of consol, significantly higher proportions of pts in the D-VRd group vs the VRd group achieved MRDneg during maintenance at 10−5 (60.2% vs 40.5%; P= 0.0049) and 10−6 (56.7% vs 25.2%; P<0.0001) and sustained MRD neg for ≥12 mo at 10−5 (38.6% vs 17.4%; P= 0.0006) and 10−6 (31.3% vs 10.3%; P<0.0001). End of consol and overall MRD neg at both 10–5 and 10–6 were associated with improved PFS. Additional data on response rates in different study phases and sustained MRD neg will be presented. Conclusions: During maintenance, a greater proportion of pts with MRD-pos status achieved MRD neg with D-R vs R. The higher rates of deep (10–6) and sustained MRD neg achieved with D-VRd ind/consol and D-R maintenance vs VRd ind/consol and R maintenance translated to a clinically meaningful benefit of improved PFS. These data further support D-VRd and D-R maintenance as a new standard of care for TE pts with NDMM and highlight the benefit of DARA SC in maintenance. Clinical trial information: NCT03710603 . [Table: see text]

A phase 2, open-label, 2-cohort study to evaluate patient preference for nivolumab (NIVO) + relatlimab (RELA) fixed-dose combination (FDC) subcutaneous (SC) vs NIVO + RELA FDC intravenous (IV) and NIVO SC vs NIVO IV in participants with melanoma.

TPS9619 Background: The oncology burden on healthcare resources and patients increases as the number of individuals with cancer grows, necessitating treatment options offering improved convenience to patients. SC delivery of monoclonal antibodies in various cancer indications has previously been shown to be effective, well tolerated, and preferred by patients over IV infusion. In CheckMate 67T (NCT04810078), noninferiority of exposure (time-averaged serum concentration at Day 28 and trough serum concentration at steady state) and efficacy (objective response rate by BICR) were previously reported for NIVO SC 1200 mg + recombinant human hyaluronidase PH20 (rHuPH20) vs IV in patients with locally advanced/metastatic clear cell renal cell carcinoma. RELATIVITY-127 (NCT05625399) is ongoing to establish exposure noninferiority of NIVO + RELA + rHuPH20 FDC SC to IV in patients with previously untreated metastatic/unresectable melanoma. This phase 2, open-label study CA224-1044 (NCT06101134) assesses patient preference for NIVO SC or NIVO + RELA FDC SC vs IV formulations after transitioning from IV to SC in patients with melanoma and aims to further characterize the safety profile of immuno-oncology therapy during IV-to-SC switch. Methods: Cohort 1 includes adult patients with previously untreated stage III (unresectable) or stage IV (metastatic) melanoma who will receive NIVO + RELA FDC IV every 4 weeks (Q4W) for 2 cycles (28-day cycle) followed by NIVO + RELA + rHuPH20 FDC SC Q4W until disease progression, unacceptable toxicity, or a maximum total treatment duration of 2 years, whichever comes first. Cohort 2 includes adult patients with completely resected stage IIB/C, stage III or stage IV melanoma who will receive NIVO IV Q4W for 2 cycles (28-day cycle) followed by NIVO SC + rHuPH20 Q4W until disease recurrence, unacceptable toxicity, or a maximum total treatment duration of 1 year, whichever comes first. The primary endpoint is the proportion of participants preferring the SC route of administration based on question 7 of the Patient Experience and Preference Questionnaire after the Cycle 4 Day 1 dose. This question evaluates patient preference for IV or SC or no preference in treatment administration and was previously used in CheckMate 8KX. Secondary endpoints include safety outcomes such as adverse events (AEs), serious AEs, treatment-related AEs, AEs leading to discontinuation, immune-mediated AEs, other events of special interest, injection/infusion-related AEs, deaths, and laboratory abnormalities. Safety is assessed for IV period, SC period (8 weeks each) and overall study period. Exploratory endpoints include additional measures of patient experience and preference for IV vs SC. The study is recruiting to enroll 50 patients per cohort. Clinical trial information: NCT06101134 .

Joint Exposure‐Response Analysis of PET Amyloid Plaque Data from the BACE1 Inhibitor Verubecestat and Amyloid mAbs Trials in Prodromal to Moderate Alzheimer’s Disease

AbstractBackgroundPositron‐emission tomography (PET) with amyloid radiotracers allows the quantification of pathological amyloid deposition in brain tissues. An exposure‐response (E‐R) analysis of individual study data of the β‐secretase‐1 inhibitor verubecestat and summary level data of four amyloid mAbs in patients with Alzheimer’s disease (AD) was conducted, to quantify the drug effects and plaque turnover rates and facilitate prediction of unstudied regimens.MethodIndividual (n = 188) verubecestat amyloid‐PET plaque data and exposures from APECS [Egan et.al, 2019] were pooled with summary. amyloid‐PET data and serum exposures from literature for aducanumab [Sevigny J, et al. 2016], donanemab [Lowe SL, et al. 2021, Lily ADPD, 2021], gantenerumab [Klein G, et al. 2019, Portron A, et al. 2020] and lecanemab [Swanson CJ, et al. 2021]. Amyloid plaque levels in SUVR units were converted to Centiloid [Klunk WE, et al. 2015]. All data were fit simultaneously in a joint model by nonlinear mixed‐effects modelingResultAn indirect response (turnover) model with verubecestat inhibiting plaque formation, and amyloid mAbs stimulating plaque removal well represented the available data (Figure 1). All plaque time course data from natural progression (control arms), β‐secretase‐1 inhibition and amyloid mAb treatment arms were well described by a joint model. The plaque turnover was estimated to be 0.00028 per day, corresponding to a half‐life of plaque of ∼ 6.8 years. Verubecestat AUC50 was estimated as 0.313 uM*h, commensurate to a 93.5% reduction in plaque formation at the typical 40 mg exposure and consistent with the >60% reductions in CSF Aβ40 and 42 observed in APECS. Aducanumab 10 mpk Q4W, donanemab 1400 mg Q4W, lencanemab 10 mpk Q2W, and gantenerumab 1200 mg SC Q4W were estimated to results in 13.5‐, 16.4‐, 16.6‐, and 12.6‐fold increases in plaque removal rate, respectively.ConclusionThe joint turnover model, linking drug exposure with amyloid plaque load, was adequate to describe natural progression and treatment response, and allows for estimation of the underlying turnover rate. This approach improves cross‐study comparisons and prediction of alternative regimens and therapeutic approaches by accounting for differences in baseline plaque load, dosing and titration regimens, and mechanism of action.

KP104, a Bifunctional C5 Antibody/Factor H Fusion Protein, Effectively Controls Both Intravascular and Extravascular Hemolysis: Interim Results from a Phase 2 Study in Complement Inhibitor-Naïve PNH Patients

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disease characterized by intravascular and extravascular hemolysis (IVH and EVH) mediated by complement activation through both the terminal and alternative pathways (TP and AP). The current treatment options for PNH are limited to addressing only a single complement pathway, resulting in either unresolved EVH with TP inhibitors or potentially exposing patients to the risk of life-threatening breakthrough hemolysis with AP inhibitors (Notaro et al. N Engl J Med 2022;387:160-6). KP104 is an innovative fusion protein comprised of a humanized anti-C5 mAb and the functional domain of complement regulator factor H to inhibit both TP and AP activation. We report here the interim results from a phase 2 study of KP104 in complement inhibitor-naïve PNH patients. Methods This open-label Phase 2 clinical trial (NCT05476887) aims to assess the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KP104 in patients diagnosed with PNH who have not received prior complement inhibitors. The primary objectives of the study are to evaluate key clinical markers including lactate dehydrogenase (LDH) and hemoglobin (Hgb) levels, transfusion requirements, and FACIT-fatigue scores. The first part of the study consists of three cohorts, with an enrollment of 6 patients per cohort. The study includes an initial treatment period of 12 or 13 weeks of KP104 dosing regimen, followed by a 9-month extension treatment period. The specific dosing regimens for each cohort are as follows: Cohort 1: 1,200 mg IV (Day 1) + 720 mg SC QW (starting Day 8) Cohort 2: 2,400 mg IV (Day 1) + 1,920 mg SC Q2W (starting Day 8) Cohort 3: 3,600 mg IV (Day 1) + 2,880 mg SC Q2W (starting Day 8) Results Interim results include data from 15 patients who completed 16/17 weeks of treatment (6 patients each from Cohort 1 and 2, and 3 from Cohort 3), as of the data cutoff on July 12 th, 2023. Among these patients (4 males and 11 females, mean (±SD) age 33(±12) years, a median of 3 transfusions were required 12 months prior to the study and 9 patients were previously diagnosed with aplastic anemia. Baseline mean (SD) Hgb and LDH levels were 7.0 (±1.5) g/dL and 1,824 (±512) U/L, respectively. By week 16/17, all 15 patients demonstrated positive clinical improvements. Mean (SD) Hgb levels increased by 4.9 (±1.7) g/dL, 5.8 (±1.6) g/dL, and 5.8 (±2.8) g/dL over baseline, and mean (SD) LDH levels reduced by 88.0 (±3.67) %, 83.5 (±7.45) %, and 89.5 (±4.05) % over baseline for Cohort 1, 2 and 3, respectively. Additionally, 9/15 (60%) patients achieved hemoglobin levels ≥12 g/dL (3/6, 5/6 and 1/3 for Cohort 1, 2 and 3, respectively), and all 15 patients had LDH levels below 1.5xULN. None of the 15 patients required transfusions or encountered any thromboembolic events after receiving KP104 treatment. Positive changes were observed in absolute reticulocyte count and bilirubin levels, along with significant enhancements in FACIT-fatigue scores seen in all 3 cohorts, with mean (SD) increases of 13.8 (±7.91), 12.8 (±9.15), and 9.3 (±10.69) for Cohorts 1, 2, and 3, respectively. Dose-dependent reductions in two PD biomarkers, C3b deposition and free C5 levels, further confirmed KP104's dual mechanism of AP and TP inhibition. KP104 was well tolerated, with no serious adverse events or treatment-emergent adverse events (TEAEs) that led to drug discontinuation or study withdrawal. 10/15 (67%) patients reported at least one mild or moderate TEAE, with no observed dose dependency. The most frequently reported TEAEs included transient injection site induration, headache, and COVID-19 infection, all of which were promptly or duly resolved. A single occurrence of clinical breakthrough hemolysis, observed in the lowest dose cohort and concurrent with an episode of gastroenteritis, was quickly resolved after an extra dose. Conclusion The interim results of this phase 2 study demonstrate the safety and efficacy of KP104 in effectively controlling IVH and EVH in complement inhibitor-naïve PNH patients. The findings provide compelling clinical evidence that a bifunctional inhibitor targeting the AP and TP can properly address the current treatment gaps associated with single complement pathway inhibitors, potentially eliminating the need for cumbersome and costly combination therapies (Notaro et al. N Engl J Med 2022;387:160-6).

Final results from TACTI-002 Part C: A phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with metastatic 2nd line head and neck squamous cell carcinoma unselected for PD-L1.

6029 Background: Eftilagimod alpha (E), a soluble LAG-3 protein, acts as an MHC class II agonist triggering activation of antigen-presenting cells (APC) and CD8 T-cells. Using efti to enhance patients’ immunity may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We report final results from Part C of the TACTI-002 trial (NCT03625323) where 2nd line metastatic head and neck squamous cell carcinoma (HNSCC) patients (pts) unselected for PD-L1 were treated with E + P. Methods: Pts with metastatic HNSCC, unselected for PD-L1 expression with disease progression on or after 1st line platinum-based therapy (± cetuximab) were enrolled. Primary endpoint (EP) was objective response rate (ORR) by iRECIST. Other EPs included tolerability, progression free survival (PFS), duration of response (DoR), and overall survival (OS). Pts received E (30 mg SC Q2W for eight 3-week cycles and then Q3W up to 1 yr) with P (200 mg IV Q3W up to 2 yrs). Imaging was performed Q9W. PD-L1 was retrospectively assessed using the IHC 22C3 kit. The study was approved by ethic committees and institutional review boards. Results: 39 pts were enrolled between Mar 2019-Jan 2021 (cut-off Jul 2022) with HNSCC of oropharynx (38%), oral cavity (32%), hypopharynx (19%) and larynx (16%). Median age was 63 yrs (48-84 yrs) and 90% were male. ECOG PS was 0 and 1 in 35% and 65% of pts. Two pts were excluded from efficacy results due to fatal COVID-19 prior to their first post-baseline scan. The primary EP, ORR by iRECIST, was 30% with 14% complete responders (see table). ORR by RECIST 1.1 was comparable (24%). Median PFS by iRECIST was 2.1 mo with 32% of pts progression-free at 6 mo. Median OS was 8.7 mo with 46% alive at 12 mo. Median DoR by iRECIST was not reached with 17 mo min FU. Responses were seen in all PD-L1 subgroups (see table). ORR, 6-mo PFS, 12-mo OS rates for PD-L1 CPS ≥20 were 60%, 53%, 73% with a median OS of 15.5 months. Two pts (5%) discontinued due to adverse events (AE) (fatigue and arthralgia [each grade 2]; pneumonitis [grade 3]) that were related to study treatment (efti and/or pembro). The most common (≥15%) AEs were hypothyroidism (21%), asthenia (21%), cough (18%), anemia (18%), weight decrease (18%), and fatigue (15%). Conclusions: Efti + pembrolizumab is safe, showing encouraging antitumor activity in platinum and partially cetuximab pre-treated, 2nd line HNSCC patients. TACTI-003 (NCT04811027) a randomized study in 1st line HNSCC is currently recruiting. Response by iRECIST: Clinical trial information: NCT03625323 . [Table: see text]

Phase I evaluation of PRGN-2009 alone and in combination with bintrafusp alfa in patients (pts) with recurrent/metastatic (R/M) HPV-associated cancers (HPV-C).

2628 Background: Combinatorial treatments may improve efficacy in checkpoint blockade resistant (CBR) R/M HPV-C. PRGN-2009 is a gorilla adenovirus immunotherapy vaccine containing 35 non-HLA-restricted epitopes of HPV-16 and 18. We conducted a first-in-human Phase I study of PRGN-2009 alone and combined with bintrafusp alfa (BA), a bifunctional TGF-β “trap”/anti-PD-L1 fusion protein in adult pts with pretreated R/M HPV-C. We report safety and efficacy results. Methods: Pts received PRGN-2009 1x1011 or 5x1011 particle units (PU) SC Q2W for 3 times, then Q4W (dose escalation part, DEP) or the recommended phase 2 dose (RP2D) of PRGN-2009 plus BA 1200 mg IV Q2W (combination part, CP) until progressive disease, unacceptable toxicity or patient withdrawal. Primary endpoints were safety and RP2D; secondary endpoints included overall response rate (RECIST 1.1). Exploratory endpoints included the induction of HPV-16/18 specific T-cell responses in peripheral blood mononuclear cells collected pre- and post-PRGN-2009 treatment. Results: Between August 11, 2020, and May 5, 2022, 17 pts were enrolled. Median follow-up at data cutoff was 7.4 months and 18.6 months for the DEP and CP, respectively. In the DEP, 6 pts received PRGN-2009, for a median duration of 3.0 months (range 1.8-17.9). Five pts had ≥2 prior lines of anticancer therapy. There were no dose limiting toxicities. Adverse events (AE) related to treatment (TRAE) were Grade 1-2 flu-like syndrome, injection site reactions, fatigue, rash. 5x1011 PU was selected as RP2D. Stable disease was noted in 4 pts, longest duration being 14.9 months. In the CP, 11 high-risk HPV positive pts received PRGN-2009 with BA for a median duration of 10.0 months (range 0.5-23.0). Four pts (36.3%) had received ≥3 prior treatment lines; 10 pts (90.9%) were CBR. Grade 3 TRAEs occurred in 1 pt (9.1%; duodenal hemorrhage [DH] attributable to BA); 2 pts (18.1%) had grade 4 TRAEs (DH, pharyngeal mucositis [n=1 each], attributable to BA). Both pts with DH were concurrently receiving NSAIDs. No treatment-related deaths occurred; one pt with DH died after refusing core standard medical management. Of 10 pts evaluable for response one CBR pt had a complete response (duration 15.3 months); partial responses were seen in two pts (one CBR). Overall response rate was 30.0% (95% CI 6.7-65.3%). Two pts were treated beyond progression without delayed response. Median overall survival was 7.4 months (95% CI, 2.9-26.8 months) for DEP and 12.5 months (95% CI, 9.6-inestimable) for CP. Post vaccination 14/16 (88%) pts developed T-cell responses to HPV-16 and/or HPV-18, with 6/6 in DEP and 8/10 in CP. Conclusions: PRGN-2009 is safe, well-tolerated, and induces HPV-specific T-cell immune responses. Further, PRGN-2009 combined with BA demonstrated clinical activity in pts with pretreated HPV-associated cancers, naïve or resistant to checkpoint blockade. Clinical trial information: NCT04432597 .

P29 PHASE 1/2 RESULTS OF TALQUETAMAB, A G PROTEIN-COUPLED RECEPTOR FAMILY C GROUP 5 MEMBER D X CD3 BISPECIFIC ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM) (MONUMENTAL-1)

Introduction: G protein-coupled receptor family C group 5 member D (GPRC5D) is a promising immunotherapy target for patients (pts) with multiple myeloma (MM). Talquetamab (Tal), a first-in-class, off-the-shelf, T-cell redirecting bispecific antibody, targets both GPRC5D and CD3. In phase (ph) 1 of MonumenTAL-1, two recommended ph 2 doses (RP2Ds) for Tal were identified. We report ph 1/2 results pts with RRMM treated at the RP2Ds. Methods: Ph 1 enrolled pts with measurable MM that progressed or were intolerant to standard therapies. Pts enrolled in ph 2 received ≥3 prior lines of therapy (LOT, including ≥1 proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody [triple-class exposed]). Ph 1 putative RP2D 0.405mg/kg SC once weekly (QW) was modified to 0.4mg/kg SC QW in ph 2, with step-up dosing used to mitigate risk of severe cytokine release syndrome (CRS). Ph 1/2 data were combined for analysis. Ph2 primary endpoint was overall response rate (ORR). Secondary endpoints were duration of response (DOR), rate of very good partial response or better (≥VGPR), rate of complete response or better (≥CR), time to response (TOR), progression-free survival (PFS), and adverse events (AEs). Pharmacodynamics (PD) parameters were measured at baseline (BL) and through Cycle 2 Day 1. Results: As of May 16, 2022, 288 pts with no prior exposure to T-cell redirecting therapies received Tal RP2Ds in ph 1 or 2. In 143 pts (median age, 67 years [y]) treated at 0.4mg/kg QW (median time since diagnosis: 6.7 y), pts received a median of 5 prior LOT, 100%/74% were triple-class exposed/refractory, and 73%/29% were penta-drug exposed/refractory. Median follow-up was 11.0 months (mo) (range 0.5±26.1). BL characteristics were similar in 145 pts treated at 0.8 mg/kg every two weeks (Q2W) (median follow-up 5.1 mo). In 143 pts treated at 0.4 mg/kg QW, ORR was 73% (≥VGPR: 58%; ≥CR: 29%), and responses were durable and deepened over time (Figure). Median TOR was 1.2 mo (range 0.2–5.0), median time to CR was 2.1 mo (range 1.1–12.4), median DOR was 9.3 mo (95% CI, 6.6–20.2; range 1–23+), and median PFS was 7.5 mo (95% CI, 5.7–9.2 [38% censored]). ORRs in triple-class refractory (72% [76/106]) and penta-drug refractory (71% [30/42]) pts were comparable to overall population. Efficacy at 0.8 mg/kg Q2W will be presented at meeting. Most common AEs (0.4 mg/kg QW/0.8 mg/kg Q2W) were CRS (79%/72%; grade 3 [gr]: 2%/1%; gr 4: 0%/0%), dysgeusia (48%/46%; gr 3/4: not applicable [NA]), anemia (45%/39%; gr 3: 31%/25%; gr 4: 0%/0%]), skin-related AEs (56%/68%; gr 3: 0%/1%; gr 4: NA), and nail disorders (52%/43%; gr 3: 0%/0%; gr 4: NA). Neutropenia 34%/28% (gr 3: 20%/17%; gr 4: 10%/6%) and thrombocytopenia 27%/27% (gr 3: 10%/8%; gr 4: 10%/8%) were limited to few cycles. Infections occurred in 57%/50% pts (gr ≥3: 19%/13%), 4.9%/6.2% discontinued, 8.4%/13.8% had dose delays, and 14.7%/6.2% had dose reductions due to AEs. Two deaths reported due to COVID-19 (1 pt at each RP2D). Tal exposure was comparable at the 2 RP2Ds. No clinically significant effect of anti-Tal antibodies on pharmacokinetics, efficacy, or AEs were observed. PD changes were comparable at both RP2Ds and consistent with Tal activity, including T-cell activation, redistribution, and induction of cytokines. Conclusion: Tal demonstrated robust efficacy and manageable safety in heavily pretreated pts with RRMM. Tal in combination with other agents is being evaluated in additional ph 1 studies (NCT04586426; NCT04108195; NCT05050097) in pts with RRMM.

Trials in progress: TAM kinase inhibitor PF-07265807 and sasanlimab plus axitinib in patients with advanced or metastatic renal cell carcinoma—A phase 1, open-label, pharmacokinetic, safety and tolerability study.

TPS743 Background: Tumor-associated macrophage kinases (TAMK) are expressed on tumor cells during malignant transformation. Inhibition of AXL and MERTK, members of the TAMK family, may lower the immune activation threshold and promote antitumor immunity. PF-07265807 (ARRY-067) is a small-molecule inhibitor of MERTK and AXL showing antitumor activity in preclinical models as monotherapy or combined with anti-programmed cell death protein 1 (anti-PD-1) antibodies (ab). Sasanlimab is an anti-PD-1 ab with acceptable safety profile being tested (300 mg SC Q4W, Phase 3) in non-muscle invasive bladder cancer. Axitinib is a VEGF inhibitor approved (single agent and combined with anti-PD-1 inhibitors) for advanced renal cell carcinoma (RCC). This first-in-human Phase 1, open-label, multi-center study (NCT04458259) will evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PF-07265807 in patients (pts) with advanced or metastatic solid tumors as a single agent and in combination with sasanlimab with or without axitinib. We describe here the dose escalation (Part 3) and dose expansion (Part 4) for the triplet combination of PF-07265807 + sasanlimab + axitinib. Methods: Eligible participants for the triplet cohorts are adult pts with confirmed unresectable advanced or metastatic clear cell RCC, with estimated creatinine clearance ≥30 mL/min and urinary protein <2+ or ≥2+ but 24-h urine protein:creatinine ratio <2 g/24 h. Pts for Part 4 need to have intermediate and poor risk RCC and no prior systemic therapy for metastatic disease. Other key eligibility criteria: measurable disease by RECIST 1.1 or non-measurable disease, ECOG PS 0–2, adequate bone marrow and liver function, and resolved acute effects of prior therapy. Each cycle is 21 days. Part 3 will determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of PF-07265807 in triplet therapy using a Bayesian logistic regression model and the escalation with overdose control principle. After the MTD/RP2D is identified, Part 4 will further evaluate the safety and preliminary efficacy of PF-07265807 combined with sasanlimab and axitinib. Treatment with study drug will continue until disease progression, consent withdrawal, or unacceptable toxicity, whichever occurs first. Primary endpoints of Part 3 are incidence of dose-limiting toxicities, adverse events (AE), and laboratory (lab) abnormalities. For Part 4, the primary endpoints are objective response rate and complete response rate; secondary endpoints include disease control rate; time-to-event endpoints; AEs; lab abnormalities; concentrations of PF-07265807 and its metabolite, sasanlimab, and axitinib; and incidence and titer of anti-sasanlimab anti-drug antibodies response. The study started in late 2020 and is recruiting. Clinical trial information: NCT04458259 .

P578 Exploring duration of corticosteroid withdrawal in definitions of corticosteroid-free remission endpoints in ustekinumab clinical trials: results from the IM-UNITI, UNIFI, and SEAVUE trials

Abstract Background Remission off steroids is a major treatment goal in inflammatory bowel disease. In the recent CORE-IBD consensus,1 the preferred definition of “corticosteroid-free” remission in clinical trials was withdrawal ≥12 weeks before the assessment timepoint. We evaluated the rates of corticosteroid-free remission according to three different definitions (ie, cross-sectional, ≥30, and ≥90 days) in the analysis of the corticosteroid-free remission endpoint using data from the IM-UNITI and SEAVUE trials of patients with Crohn’s disease (CD) and the UNIFI trial of patients with ulcerative colitis (UC). Methods In IM-UNITI and UNIFI, patients with moderate-to-severe CD and UC, respectively, who had previously responded to ustekinumab (UST) induction were randomized to placebo (PBO), UST 90mg SC q12w, or UST 90mg SC q8w. In SEAVUE, biologic naïve patients with moderate-to-severe CD were randomized to adalimumab 160mg SC at week 0, 80mg SC at week 2, and 40mg SC q2w or UST ~6mg/kg IV at week 0 and 90mg SC q8w. Each trial included protocols for mandatory corticosteroid tapering after the induction phase unless medically inappropriate (required in IM-UNITI and UNIFI starting at week 8 and recommended in SEAVUE starting at week 8 but required starting at week 16). Corticosteroid-free remission was defined as clinical remission (CDAI<150 in IM-UNITI and SEAVUE and a Mayo score ≤2 with no individual subscore >1 in UNIFI) and not receiving steroids at the assessment timepoint or ≥30 or ≥90 days before the assessment timepoint. Corticosteroid-free remission at week 44 was a major secondary endpoint in IM-UNITI and UNIFI (both cross-sectional). Corticosteroid-free remission (≥30 days before week 52) was a major secondary endpoint in SEAVUE. Results The proportions of patients who achieved corticosteroid-free remission were consistent, regardless of the corticosteroid-free duration used in the assessment (Tables 1 and 2). The results were consistent for both ustekinumab treatment groups (q12w and q8w) and placebo in the pivotal IM-UNITI and UNIFI studies (Table 1) and for both ustekinumab and adalimumab groups in the SEAVUE study (Table 2). Conclusion In CD and UC clinical trials of ustekinumab maintenance, which included protocol-mandated corticosteroid tapering regimens, corticosteroid-free remission results at 1 year were similar regardless of the corticosteroid-free duration used in the outcome definition.

P519 Mirikizumab pharmacokinetics and exposure-response relationships in patients with moderately to severely active ulcerative colitis: results from randomised phase 2 and phase 3 induction and maintenance trials

Abstract Background Mirikizumab (MIRI) is a p19-targeted anti–interleukin-23 developed for ulcerative colitis (UC), and has demonstrated efficacy in Phase 2 (AMAC, NCT02589665) and Phase 3 (LUCENT-1, NCT03518086; LUCENT-2, NCT03524092) trials in patients with moderately to severely active UC. We characterised MIRI pharmacokinetics (PK) and the exposure-response (E-R) relationship between MIRI exposure and clinical outcomes in these 3 trials. Methods Patients received 12-week MIRI induction (50, 200 or 600 mg [AMAC] or 300 mg [LUCENT-1] intravenous [IV] every 4 weeks [Q4W]), and induction responders then received MIRI maintenance (200 mg subcutaneous [SC] Q4W or every 12 weeks for 92 weeks in AMAC; 200 mg SC Q4W for 40 weeks in LUCENT-2). Serum PK parameters were analysed by non-linear mixed-effects modelling, and covariate effects on MIRI exposure were evaluated using simulation-based estimations. Relationships between MIRI exposure and clinical remission, clinical response, endoscopic remission and symptomatic remission, based on the Mayo scoring system, were assessed using logistic regression models. Results MIRI PK (clearance, 0.022 L/hr (95% CI 0.02,0.03); volume of distribution for central and peripheral compartments, 3.11 L (95% CI 3.07, 3.15) and 1.69 L (95% CI 1.03, 2.57); half-life, 9.5 days) were best described by a 2-compartment model with first-order absorption. Clearance increased with body weight and decreased with albumin concentration, and bioavailability decreased with body mass index, but impacts of covariates were small relative to random variability. MIRI SC bioavailability was 48%. Modelling of E-R relationships during MIRI induction in AMAC revealed statistically significant positive associations of MIRI exposure with clinical response and with change in Modified Mayo Score. Maximum effect was predicted at 300 mg, with no significant improvement at higher doses. Steep positive relationships between exposure and efficacy in LUCENT-1 were not explained by patient covariates, and analyses suggest confounding by unknown variables. MIRI exposure during maintenance was not a significant predictor of efficacy in AMAC and LUCENT-2. Conclusion MIRI PK characteristics were typical of an immunoglobulin G monoclonal antibody. The MIRI E-R relationship revealed an apparent lack of sensitivity of efficacy to individual patient exposures at the dose levels studied in Phase 3. Overall, the PK and E-R data suggest that dose adjustments due to patient factors are not justified.

Analysis of Transplant-Eligible Patients (Pts) Who Received Frontline Daratumumab (DARA)-Based Quadruplet Therapy for the Treatment of Newly Diagnosed Multiple Myeloma (NDMM) with High-Risk Cytogenetic Abnormalities (HRCA) in the Griffin and Master Studies

Introduction: DARA as monotherapy and combination therapy is approved across lines of treatment for multiple myeloma. The single-arm phase 2 MASTER study (NCT03224507) evaluated DARA + carfilzomib/lenalidomide/dexamethasone (D-KRd), which demonstrated promising clinical efficacy in transplant-eligible NDMM. The primary endpoint analysis (median follow-up, 25.1 mo) showed that minimal residual disease (MRD) negativity at the 10-5 threshold was achieved by 80% of D-KRd pts(Costa, et al. JCO. 2021). The randomized phase 2 GRIFFIN study (NCT02874742) evaluated DARA + lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible NDMM; the primary endpoint analysis (median follow-up, 13.5 mo) showed that the rate of stringent complete response by the end of consolidation was significantly higher for D-RVd versus RVd (42.4% vs 32.0%; 1-sided P = 0.068, meeting the prespecified 1-sided α of 0.1) (Voorhees, et al. Blood. 2020). Here, we present an analysis of pts with HRCA, defined as having ≥1 genetic abnormality: del17p, t(4;14), t(14;16), t(14;20), and/or gain/amp1q (≥3 copies of chromosome 1q21) from MASTER (median follow-up, 31.1 mo) and GRIFFIN (median follow-up, 49.6 mo). Methods: In MASTER, enrolled pts (no age limit with enrichment for high-risk disease) received 4 D-KRd induction cycles, autologous stem cell transplant (ASCT), and 0, 4 or 8 D-KRd consolidation cycles with treatment cessation upon achievement of 2 consecutive MRD-negative assessments, or lenalidomide (R) maintenance therapy if 2 consecutive MRD-negative assessments were not achieved. Pts received 28-day cycles of K (20/56 mg/m2 IV Days [D] 1, 8, 15), R (25 mg PO D1-21), d (40 mg PO or IV D1, 8, 15, and 22), and DARA (16 mg/kg IV: D1, 8, 15, and 22 for Cycles 1-2; D1 and 15 for Cycles 3-6; and D1 for Cycles 7+). In GRIFFIN, enrolled pts (age ≤70 years) were randomized 1:1 to receive 4 D-RVd/RVd induction cycles, ASCT, 2 D-RVd/RVd consolidation cycles, and up to 2 years of maintenance with R ± DARA. For induction/consolidation (21-day cycles), pts received R (25 mg PO on Days 1-14), V (1.3 mg/m2 SC on Days 1, 4, 8, and 11), and d (40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4 and D1 of Cycles 5-6). During maintenance (28-day cycles), pts received R (10 mg PO D1-21; if tolerated, 15 mg Cycles 10+) ± DARA (16 mg/kg IV Q8W or Q4W, or 1800 mg SC Q4W per protocol amendments). Following completion of study therapy, pts could continue R maintenance per local standard of care. Before the randomized phase, a safety run-in was conducted to assess D-RVd dose-limiting toxicities. Results: Among pts in MASTER (D-KRd, n = 123), 43% (n = 53) had standard risk (0 HRCA), 37% (n = 46) had high risk (1 HRCA), and 20% (n = 24) had ultra-high risk (≥2 HRCA) NDMM. Among 120 pts in GRIFFIN who received D-RVd (n = 104 randomized phase pts and n = 16 safety run-in pts), 56% (n = 67) had NDMM with 0 HRCA, 28% (n = 34) had 1 HRCA, 11% (n = 13) had ≥2 HRCA, and 5% (n = 6) were not evaluable. In an analysis of best response on study, rates of complete response or better (≥CR) for pts with 0, 1, and ≥2 HRCA were 91%, 89%, and 71% for D-KRd pts in MASTER, respectively, and 91%, 79%, and 62% for D-RVd pts in GRIFFIN. MRD-negativity rates at the 10-5 threshold were 80%, 86%, and 83% for D-KRd for pts with 0, 1, and ≥2 HRCA, respectively, and MRD-negativity rates at the 10-6 threshold were 68%, 80%, and 67%. For D-RVd pts, MRD-negativity rates at the 10-5 threshold were 76%, 56%, and 62% for pts with 0, 1, and ≥2 HRCA, respectively, and MRD-negativity rates at 10-6 were 45%, 26%, and 15%. MRD negativity (10‒5) with ≥CR occurred in 76%, 79%, and 67% of D-KRd pts with 0, 1, and ≥2 HRCA, respectively, and 75%, 53%, and 54% of D-RVd pts. In MASTER, 24-month progression-free survival (PFS) rates were 92%, 96%, and 66% for D-KRd pts with 0, 1, and ≥2 HRCA, respectively (Figure A). In GRIFFIN, 24-month PFS rates were 97%, 94%, and 64% for D-RVd pts with 0, 1, ≥2 HRCA, respectively, and 48-month PFS rates were 94%, 91%, and 54% (Figure B). Conclusions: In MASTER and GRIFFIN, pts with NDMM and 0 HRCA or 1 HRCA who received DARA-based quadruplet therapy achieved high rates of ≥CR, MRD negativity, and 2-year PFS rates. These data support use of DARA-based quadruplet therapy as frontline treatment among pts with high cytogenetic risk. However, among pts with NDMM and ≥2 HRCA, results were not similar, and the subgroup was small suggesting that more research is needed for pts with the poor prognosis of ultra-high-risk disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Daratumumab Plus Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) in Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): Final Analysis of Griffin Among Clinically Relevant Subgroups

Introduction: Daratumumab (DARA) is approved across lines of therapy for multiple myeloma. In the primary analysis of the randomized phase 2 GRIFFIN trial (NCT02874742) (median follow-up, 13.5 mo), addition of DARA to RVd improved the stringent complete response (sCR) rate by end of post-autologous stem cell transplant (ASCT) consolidation (D-RVd, 42.4% vs RVd, 32.0%; odds ratio [OR], 1.57; 95% CI, 0.87-2.82; 1-sided P = 0.068, which met the pre-specified 1-sided α of 0.1) (Voorhees PM, et al. Blood. 2020). Here, we present an end-of-study post hoc analysis of clinically relevant subgroups in GRIFFIN (≥65 years; International Staging System [ISS] stage III disease; high cytogenetic risk [defined as ≥1 of the following: del17p, t(4;14), or t(14;16)]; revised high cytogenetic risk [defined as ≥1 of the following high-risk chromosomal abnormalities (HRCA): del17p, t(4;14), t(14;16), t(14;20) or gain/amp1q (≥3 copies of chromosome 1q21)]; gain/amp1q; 1 HRCA (per the revised definition); gain/amp1q plus 1 HRCA; and ≥2 HRCA). The final analysis of GRIFFIN (median follow-up, 49.6 mo) occurred after all pts completed ≥1 year of long-term follow-up after completion of study treatment, discontinued, or withdrew. Methods: In GRIFFIN, pts with transplant-eligible NDMM were randomized 1:1 to D-RVd or RVd. All pts received 4 D-RVd/RVd induction cycles, ASCT, 2 D-RVd/RVd consolidation cycles, and maintenance with lenalidomide (R) ± DARA for 24 months. All pts received 21-day cycles of R (25 mg PO on Days [D] 1-14), bortezomib (1.3 mg/m2 SC on D1, 4, 8, 11), and dexamethasone (40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4 and D1 in Cycles 5-6). During maintenance (Cycles 7-32; 28-day cycles), pts received R (10 mg PO on Days 1-21; if tolerated, 15 mg in Cycles 10+) ± DARA (16 mg/kg IV Q8W/Q4W or 1800 mg SC Q4W per protocol amendments). The primary endpoint was the sCR rate by end of consolidation. Results: 207 pts were randomized (D-RVd, n = 104; RVd, n = 103); each subgroup had a similar number of pts per arm: ≥65 years (n = 28; n = 28), ISS stage III disease (n = 14; n = 14), high cytogenetic risk (n = 16; n = 14), revised high cytogenetic risk (n = 42; n = 37), gain/amp1q (n = 34; n = 28), 1 HRCA (n = 32; n = 29), gain/amp1q plus 1 HRCA (n = 9; n = 6), and ≥2 HRCA (n = 10; n = 8). Outcomes for pts with baseline extramedullary plasmacytomas (D-RVd, n = 1; RVd, n = 2) were explored but not included due to small pt numbers. Among response-evaluable pts, the rate of sCR at the end of maintenance therapy was numerically higher for D-RVd versus RVd among pts with age ≥65 years (63.0% vs 40.7%; OR, 2.47; 95% CI, 0.83-7.39), high cytogenetic risk (50.0% vs 38.5%; OR, 1.60; 95% CI, 0.36-7.07), gain/amp1q plus 1 HRCA (55.6% vs 33.3%; OR, 2.50; 95% CI; 0.29-21.40), and ≥2 HRCA (50.0% vs 37.5%; OR, 1.67; 95% CI, 0.25-11.07), but similar for D-RVd and RVd pts with ISS stage III disease (64.3% vs 61.5%; OR, 1.13; 95% CI, 0.24-5.37), revised high cytogenetic risk (56.1% vs 55.6%; OR, 1.02; 95% CI, 0.42-2.52), gain/amp1q (57.6% vs 57.1%; OR, 1.02; 95% CI, 0.37-2.82), and 1 HRCA (58.1% vs 60.7%; OR, 0.90; 95% CI, 0.32-2.54). MRD-negativity (10-5) rates at the end of maintenance favored D-RVd over RVd across all subgroups (Figure A). At 49.6 months of median follow-up, PFS rates among subgroups favored D-RVd over RVd except for pts with ≥2 HRCA (Figure B). In pts ≥65 years, grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 88.9% of D-RVd and 77.8% of RVd pts; the most common grade 3/4 TEAEs (≥20%) were neutropenia (D-RVd, 37.0%; RVd, 29.6%) and lymphopenia (25.9%; 11.1%). TEAEs led to study treatment discontinuation in 37.0% of D-RVd and 25.9% of RVd pts. In pts ≥65 years, death as outcome of a TEAE occurred in 1 D-RVd pt (pneumonia; unrelated to study treatment). Conclusions: In this final analysis of GRIFFIN by clinically relevant subgroups, addition of DARA to RVd induction/consolidation and R maintenance, with ASCT, was associated with higher MRD-negativity (10-5) rates for all subgroups and PFS estimates favored all high-risk groups except pts with ≥2 HRCA. Among pts ≥65 years, the rates of grade 3/4 TEAEs and TEAEs leading to study treatment discontinuation were slightly higher for the D-RVd group, although only 1 pt died due to a TEAE unrelated to study treatment. Results of this subgroup analysis support the use of DARA in transplant-eligible pts with NDMM among both clinically and cytogenetic high-risk subgroups, although larger studies are needed, especially in pts with ≥2 HRCA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal