Frequent Treatment-emergent Adverse Events Research Articles

Pirtobrutinib in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) Patients with Prior cBTKi: Safety and Efficacy Including High-Risk Subgroup Analyses from the Phase 1/2 BRUIN Study

Background: Despite the efficacy of covalent (c) Bruton tyrosine kinase inhibitors (BTKi) in R/R MCL, disease relapse arises through evolution of resistance mechanisms or development of cBTKi intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of the intrinsic rate of BTK turnover. Pirtobrutinib is the first BTKi to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated R/R MCL and was well-tolerated with a low frequency of treatment discontinuation due to toxicity (Wang et al., JCO, 2023). Pirtobrutinib is approved in the USA to treat relapsed or refractory MCL after at least two lines of systemic therapy including a prior cBTKi. Here, we report updated results of pirtobrutinib therapy in all patients (pts), including those with biologically high-risk R/R MCL with a median survival follow-up of 24.2 months (range, 18.2-29.8). Methods: Pts with R/R MCL received pirtobrutinib monotherapy in the multicenter Phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in all cBTKi pre-treated pts, as well as in cBTKi treatment-naïve pts. Key endpoints included overall response rate (ORR) as assessed by independent review committee per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Pts were included across the dose escalation range and expansion (25-300 mg/day) with 93% (n=141) receiving at least one dose of 200 mg/day, the FDA-approved dose. A data cut of 05 May 2023 was utilized. Results: Among all 152 pts with R/R MCL who received a prior cBTKi, the median age was 70 years (range, 46-88), and 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. Median prior lines of therapy were 3 (range, 1-9), including an anti-CD20 antibody (96.7%), chemotherapy (90.1%), immunomodulator (17.1%), stem cell transplant (21.7%), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%), and PI3K inhibitor (3.9%). Among pts with high-risk biomarker data available, 30/60 (50%) had TP53 mutations and 45/63 (71%) had a Ki-67 index of ≥30%. The ORR for cBTKi pre-treated pts was 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51), whilst cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2). The ORR among 128 pts who had discontinued a prior cBTKi due to PD and 21 pts who had discontinued for toxicity/other reasons was 43.0% and 90.5%, respectively. Among the 75 responding cBTKi pre-treated pts, the median DOR was 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The 18- and 24-month DOR rates were 51.9% (95% CI, 37-64.8) and 38.9% (95% CI, 22.7-54.8), respectively. ORR and DOR by high-risk subgroups (including blastoid/pleomorphic variants, Ki-67 index ≥30%, and TP53 mutations) are shown in Table 1. The 18- and 24-month DOR rates among 12 responding cBTKi naïve pts were both 90.0% (95% CI, 47.3-98.5). The median PFS and OS for cBTKi pre-treated pts was 5.6 months (95% CI, 5.3-9.2), and 23.5 months (95% CI, 17.1-NE), respectively. In the MCL cohort (n=166), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%) and the rate of Grade ≥3 infections was (19.9%). Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. Overall, 8 pts (5%) had treatment-related AEs leading to dose reductions and 5 (3%) had treatment-related AEs leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. High ORRs were observed in pts who had PD on a prior cBTKi, and in pts with high-risk disease features including blastoid/pleomorphic variants, elevated Ki-67 index, and TP53 mutations.

A Phase II Study of Chidamide Plus R-GDP Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Transplantation: Efficacy and Safety Analysis

Background: A significant subset of Diffuse large B-cell lymphoma (DLBCL) patients (30%-40%) face treatment failure, necessitating effective salvage chemotherapy. We conducted a phase II study evaluating the efficacy and safety of chidamide plus R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin) in relapsed/refractory (r/r) DLBCL patients. Methods: This open-label, single-arm study included 27 patients with r/r DLBCL who were ineligible for autologous stem cell transplantation. Prior to the induction monotherapy phase, chidamide was administered orally at a dose of 30 mg twice a week for one week. The combination therapy phase consisted of oral chidamide at a dose of 20 mg twice a week for two weeks, with a one-week discontinuation period, along with intravenous administration of rituximab, gemcitabine, dexamethasone, and cisplatin on a 21-day cycle. Results: A total of 27 patients received at least one dose of Chidamide plus R-GDP and were evaluated for safety. The median follow-up period was 17.0 months (range: 3.5 to 55 months). Radiological response assessment was available for 24 patients, who constituted the efficacy population. Fourteen patients completed six cycles of chidamide plus R-GDP (per-protocol population), while 10 patients discontinued treatment at the data cutoff. The baseline characteristics of enrolled patients included a median age of 67 years, predominantly older than 65 years. Approximately half of the patients exhibited elevated lactate dehydrogenase levels. All patients had received prior therapy with R-CHOP or equivalent chemoimmunotherapy. The majority of cases were classified as stage III/IV and non-germinal center B-cell-like (non-GCB) type by immunohistochemistry. Refractory or relapsed DLBCL within 1 year since the last treatment was observed in 74.0% of patients. Efficacy Outcomes: The investigator-assessed best objective response rate (ORR) was 79.2% (95% CI: 75.1% to 83.3%), with a complete response (CR) rate of 45.8% (95% CI: 41.6% to 49.9%) and a partial response (PR) rate of 33.3% (95% CI: 29.3% to 37.4%). The median time to response was 1.2 months, and the median time to CR or CRu (unconfirmed complete response) was 3.9 months. The best disease control rate was 87.5%. Among the patients who completed six cycles of chidamide plus R-GDP, the best ORR was 100%, with 71.4% achieving CR and 28.6% PR. Kaplan-Meier plots reveal that the median investigator-assessed progression-free survival (PFS) for the efficacy population was 5.9 (95% CI, 3.1 to 12.4) months. The median overall survival was 48.3 (95% CI, 13.1 to not reach (NR)) months. Safety Outcomes: A total of 13 patients (48.1%) required treatment interruption, primarily due to adverse events (22.2%) and disease progression (18.5%). Among patients who completed six cycles of chidamide plus R-GDP, 57.1% required a chidamide dose reduction. The most frequent treatment-emergent adverse event was anemia, occurring in all patients. Thrombocytopenia was the most common grade ≥3 adverse event leading to treatment interruption or dose reduction, affecting 48.1% of patients. Non-hematologic events included hypocalcemia (59.3%), hyponatremia (55.6%), and hypokalemia (44.4%). Three patients experienced grade 3 pneumonitis, and one patient had grade 3 skin rash. Conclusion: Chidamide plus R-GDP salvage chemotherapy demonstrated promising efficacy (ORR: 79.2%; CR rate: 45.8%) in r/r DLBCL patients. Adverse events were manageable but necessitated monitoring. Larger trials are needed to validate these findings and establish chidamide plus R-GDP as a potential treatment option for this challenging population. Keywords: relapsed/refractory DLBCL, salvage chemotherapy, chidamide, R-GDP, efficacy, safety

Pirtobrutinib in Post-cBTKi CLL/SLL: ~30 Months Follow-up and Subgroup Analysis With/Without Prior BCL2i from the Phase 1/2 BRUIN Study

Background: The treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has benefited from covalent (c) Bruton tyrosine kinase inhibitors (BTKi), however, therapy can fail due to progression or intolerance. Sequential treatment with B-cell lymphoma 2 protein inhibitor (BCL2i) venetoclax, either as monotherapy or combined with an anti-CD20 monoclonal antibody, has been the primary treatment option for CLL/SLL patients (pts) whose disease has progressed on cBTKi. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that demonstrated promising efficacy in patients with relapsed or refractory CLL/SLL (Mato et al, NEJM, 2023). Here, we report on the efficacy of pirtobrutinib treatment in CLL/SLL in the post-cBTKi setting, including subgroups with or without prior BCL2i, using data from the BRUIN study (NCT03740529) with more than 2 years follow-up. Methods: Pts with previously treated CLL/SLL were eligible for treatment with pirtobrutinib in the multicenter Phase 1/2 BRUIN study. Key endpoints included ORR (including partial response with lymphocytosis; PR-L) as assessed by an independent review committee per 2018 iwCLL response criteria, DoR, PFS, OS, and safety. A data cut of 05MAY2023 was utilized. Results: In total, 282 pts with CLL/SLL who received prior cBTKi were included in this analysis. Median age was 69 years (range, 36-88), 68% were male, and median number of prior therapies was 4 (range, 1-11). Of 282 pts, 154 (55%) had not received prior-BCL2i therapy (Naïve; BCL2i-N) and 128 (45%) had (Exposed; BCL2i-E). BCL2i-N pts were exposed to fewer prior therapies than BCL2i-E pts (median prior therapies 3 and 5, respectively), including anti-CD20 antibody (83% and 97%), chemotherapy (74% and 89%), PI3K inhibitor (11% and 42%), CAR-T cell therapy (1% and 12%), and hematopoietic cell transplantation (1% and 6%). The ORR for all post-cBTKi pts was 72% (95% CI, 66.4-77.1), and ORR including PR-L was 82% (95% CI, 76.5-85.9). Post-cBTKi pts included a subgroup of 19 pts with one prior line of cBTKi-containing therapy and second line therapy of pirtobrutinib, who had ORR including PR-L of 89.5% (CI 95%, 66.9-98.7). The ORR including PR-L was 83.1% (95% CI, 76.2-88.7) for BCL2i-N pts, and 79.7% (95% CI, 71.7-86.3) for BCL2i-E pts. Median DoR was 18.4 months (95% CI, 15.3-20.4) for all cBTKi pre-treated pts, 24.9 months (95% CI, 18.4-32.0) for BCL2i-N, and 14.8 months (95% CI, 12.0-17.4) for BCL2i-E. With a median follow up of 27.5 months, the median PFS was 19.4 months (95% CI, 16.6-22.1) among all cBTKi pre-treated pts, 23.0 months (95% CI, 19.6-28.4) for BCL2i-N, and 15.9 months (95% CI, 13.6-17.5) for BCL2i-E (Figure). With a median follow up of 29.3 months, the median OS was not estimable for all cBTKi pre-treated pts, BCL2i-N, and BCL2i-E; the 24-month OS rates were 73.2% (95% CI, 67.4-78.2), 83.1% (95% CI,75.9-88.2), 60.6% (50.9-68.9), respectively. In the CLL/SLL cohort (N=282), the most frequent treatment-emergent adverse events (TEAE), regardless of attribution, were fatigue (36.9%), diarrhea (28.4%), cough (27.3%) and contusion (26.2%). The most frequent Grade ≥3 TEAE was neutropenia/neutrophil count decreased (28.4%). Grade ≥3 TEAEs of hypertension (4.3%) and atrial fibrillation/flutter (1.8%) were infrequent. The AE profile of BCL2i-N and BCL2i-E pts was overall similar. Though Grade ≥3 neutropenia/neutrophil count decreased was higher in BCL2i-E pts (36.7% and 21.4%), this may have been attributed to the higher frequency of baseline neutropenia in BCL2i-E pts (27.3% and 11.0%). In total, 7 (2.5%; 4 BCL2i-N, 3 BCL2i-E) pts had treatment-related AE leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate promising and durable efficacy in pts with post-cBTKi heavily pretreated CLL/SLL. ORR was high regardless of prior BCL2i status. Longer PFS was observed in BCL2i-N pts than BCL2i-E pts, likely due to the more heavily pretreated status of the BCL2i-E population which can be associated with poorer prognosis. Pirtobrutinib was well-tolerated with low-rates of discontinuation due to drug-related toxicity among both BTKi-N and BTKi-E pts. These results suggest that continuation of BTK pathway inhibition following a cBTKi may be an important sequencing approach to consider in the treatment of CLL/SLL.

Infectious adverse events in patients with atopic dermatitis treated with baricitinib.

Baricitinib is a JAK1-2 inhibitorrecently approved in Europe and Japan for the treatment of moderate-to-severe atopic dermatitis in adult patients at doses of 2and 4mg daily. The aim of this article is to discuss the safety profile of baricitinib in atopic dermatitis using data from clinical trials and the supporting literature, with a focus on infectious adverse events. An integrated analysis of safety data from eightclinical trials described infections as the most frequent treatment-emergent adverse events, mainly of mild-to-moderate severity, notably upper respiratory tract infections and herpes simplex exacerbations. Real-world data are still limited and will contribute to precisely profile the patients that might benefit from this treatment.

A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer

BackgroundWe assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC).MethodsThis phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1–21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D.ResultsIn phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses.ConclusionsNofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC.Clinical trial registr ationClinicaltrials.gov (NCT03475251).

RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts

Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean Tmax of 6.0–10.5 h and clearance from plasma within 24–48 h after dosing with a mean t½ of 3.9–6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean −45% to −78%) 85 days after dose. Reductions in triglyceride (median −34% to −54%) and non-HDL-C (mean −18% to −29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224

AFM24 in combination with autologous NK cells (SNK01) in patients with advanced/metastatic epidermal growth factor receptor (EGFR) expressing solid tumors: Initial results from the phase 1 dose-escalation study.

26 Background: AFM24 is a novel tetravalent bispecific IgG1-scFv fusion antibody (scFv-IgAb) binding specifically to EGFR on target cells and CD16A on NK cells, mediating specific lysis of EGFR+ tumor cells via NK cell-mediated antibody-dependent cellular cytotoxicity. SNK01 cell therapy is an NK cell-derived adoptive cellular immunotherapy technology that can produce large scale ex vivo expanded and activated autologous NK cells (1,000–10,000-fold expansion of NK cells with >95% cell purity), even in patients with low primary NK cell counts. The antitumor activity of SNK01 may be enhanced when combined with AFM24. Methods: This is a proof-of-concept phase 1, 3+3 dose escalation study to determine the maximum tolerated dose and/or recommended phase 2 dose of AFM24 in combination with SNK01 (NCT05099549). Secondary endpoints are safety/tolerability, preliminary efficacy and pharmacokinetics (PK). Patients with advanced or metastatic, histologically or cytologically confirmed EGFR+ solid tumors (≥1% of positive tumor cells) refractory to standard-of-care therapies were enrolled. AFM24 starting dose was 160 mg followed by 480 mg. AFM24 is administered once weekly, concomitantly with 4.0 x109 SNK01 cells once weekly until disease progression, intolerable toxicity, patient withdrawal. Cycles are 28 days and CTs are at screening, cycle 2, 4, 6, 8, and every 3 cycles thereafter. Results: As of January 27, 2023, 6 patients (5 microsatellite stable colorectal and 1 head and neck cancer) received combination therapy, 3 in each cohort. Median (range) age was 59 (41–64), mean number (range) of prior therapies was 5 (3–7). ECOG performance status was 0 for 3 patients and 1 for the other 3. No dose limiting toxicities or unexpected toxicities were observed. Preliminary results suggest consistent safety events with both drugs in monotherapy. The most frequent treatment-emergent adverse events related to AFM24 was Grade 1/2 infusion related reactions occurring in 5/6 patients. There were no Grade ≥3 events related to AFM24 or SNK01. In the low dose cohort (160 mg), 2 patients had stable disease for 106 days (15 weeks) and 100 days (14 weeks), respectively. At 480 mg, 1 patient with SD had 2% tumor burden reduction and 2 subsequent carcinoembryonic antigen reductions. The patient proceeded to Cycle 3. No difference in PK data was observed in comparison to AFM24 alone. Enrollment continues at 480 mg. Conclusions: In this first study combining a bispecific NK cell engager with autologous NK cell infusions; two dose cohorts have completed, and escalation has proceeded. Early PK data are consistent with AFM24 monotherapy with no new safety signals, suggesting that the combination of AFM24 and SNK01 cells is tolerated and warrants further investigation. Clinical trial information: NCT05099549 .

Cariprazine in Pediatric Patients with Autism Spectrum Disorder: Results of a Pharmacokinetic, Safety and Tolerability Study.

Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This study, which is the first to evaluate cariprazine in pediatric patients with autism spectrum disorder (ASD) (including children 5-9 years of age) using an oral solution formulation, evaluated the safety, tolerability, pharmacokinetics (PK), and exploratory efficacy of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Methods: This clinical pharmacology, open-label, multiple-dose study enrolled 25 pediatric patients from 5 to 17 years of age, who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for ASD. All patients began treatment with cariprazine 0.5 mg once daily (QD) and underwent a titration over 7 days to maintenance doses of 1.5 or 3 mg QD for patients 13-17 years of age at Screening, 0.75 or 1.5 mg QD for patients 10-12 years of age at Screening, and 0.5 or 1.5 mg QD for patients 5-9 years of age at Screening. After 6 weeks total of dosing, there was a 6-week follow-up period. Study assessments included adverse events (AEs), safety parameters, noncompartmental PK parameters, and exploratory efficacy assessments, including the Aberrant Behavior Checklist-Irritability Subscale (ABC-I), Clinical Global Impressions (CGI-S), Caregiver Global Impressions (CgGI-S), Children's Yale-Brown Obsessive Compulsiveness Scale Modified for ASD (CYBOCS-ASD), Social Responsiveness Scale (SRS), and Vineland Adaptive Behavior Scale (VABS-III). Results: All AEs were mild or moderate in severity. Most frequent treatment-emergent adverse events (TEAEs) were increased weight, increased alanine aminotransferase, increased appetite, dizziness, agitation, and nasal congestion. Increases in weight were not considered clinically meaningful. Two subjects reported extrapyramidal symptom-related TEAEs that resolved without leading to discontinuation. Dose-normalized exposures of all analytes were modestly higher in pediatric patients from 5 to 9 years of age when compared to older patients. Consistent with previous studies, at steady state, the rank of exposure in plasma was DDCAR > cariprazine > DCAR. There was numerical improvement on all exploratory endpoints (ABC-I, CGI-S, CgGI-S, CYBOCS-ASD, SRS, and VABS-III). Conclusions: PK of cariprazine and its metabolites were characterized in pediatric patients with ASD at doses up to 3 mg QD (13-17 years) and 1.5 mg QD (5-12 years). Caripazine treatment was generally well tolerated and results from this study will inform the selection of appropriate pediatric doses for subsequent studies.

Attrition of methylnaltrexone treatment-emergent adverse events in patients with chronic noncancer pain and opioid-induced constipation: a post hoc pooled analysis of two clinical trials.

Background: Opioids prescribed for the management of chronic noncancer pain are associated with nausea, vomiting, and constipation. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, has demonstrated robust efficacy and was well-tolerated in treating opioid-induced constipation without affecting central analgesia. Our objective was to assess changes in the frequency of treatment-emergent adverse events (TEAEs) after the first or second dose of methylnaltrexone or placebo. Methods: This post hoc analysis pooled data from two randomized, placebo-controlled clinical trials assessing methylnaltrexone for opioid-induced constipation in the outpatient setting. Patients received subcutaneous methylnaltrexone (12 mg once daily or 12 mg once every other day), oral methylnaltrexone (150, 300, or 450 mg daily), or placebo. TEAEs, opioid withdrawal symptoms, pain intensity, and rescue-free bowel movements (RFBMs) within 4 hours of the first dose (i.e., RFBM responders) were assessed. Associations between TEAE frequencies and RFBM response were also evaluated. Results: The analysis included 1263 adult patients with chronic noncancer pain. TEAE rates declined from treatment day 1 to 2 (methylnaltrexone: 16.2%-5.3%; placebo: 6.6%-5.4%). Among methylnaltrexone-treated patients, significantly greater proportions of RFBM responders versus nonresponders reported gastrointestinal TEAEs on day 1. No associations between RFBM response and the frequency of TEAEs were observed in the placebo group. No meaningful changes in opioid withdrawal symptoms or pain intensity were observed. Conclusions: Early-onset TEAEs following methylnaltrexone treatment, particularly gastrointestinal TEAEs, are at least partially due to laxation. Methylnaltrexone treatment effectively relieves opioid-induced constipation without affecting the central analgesic effects of opioids.

Abrocitinib efficacy and safety in patients with moderate-to-severe atopic dermatitis: Results from phase 3 studies, including the long-term extension JADE EXTEND study.

Abrocitinib improved signs and symptoms of moderate-to-severe atopic dermatitis (AD) at 12 or 16 weeks in phase 3 studies with a manageable safety profile. Further understanding of the abrocitinib long-term efficacy and safety profile is important for its appropriate use in treating chronic AD. To evaluate the abrocitinib efficacy up to 48 weeks and long-term safety in patients with moderate-to-severe AD. JADE EXTEND (NCT03422822) is an ongoing, phase 3, long-term extension study that enrolled patients from previous abrocitinib AD trials. This analysis focusses on patients from the phase 3 JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871) and JADE COMPARE (NCT03720470) studies who completed the full treatment period of placebo or abrocitinib (200 mg or 100 mg once daily) and subsequently entered JADE EXTEND. Efficacy endpoints included the proportion of patients achieving skin clearance (Investigator's Global Assessment [IGA] 0/1 [clear/almost clear]; ≥75% improvement in Eczema Area and Severity Index [EASI-75]) and itch response (Peak Pruritus Numerical Rating Scale [PP-NRS] severity ≥4-point improvement). Safety endpoints included treatment-emergent adverse events (TEAEs), serious TEAEs and TEAEs leading to discontinuation. Data cut-off: April 22, 2020. As of the data cut-off, ~70% and ~45% of patients received abrocitinib for ≥36 and ≥48 weeks, respectively. Nasopharyngitis, atopic dermatitis, nausea and upper respiratory tract infections were the most frequent TEAEs. Serious TEAEs occurred in 7% and 5% and TEAEs leading to study discontinuation occurred in 9% and 7% of patients receiving abrocitinib 200 mg and 100 mg, respectively. Week 48 efficacy responses with abrocitinib 200 mg and 100 mg were as follows: IGA 0/1 52% and 39%; EASI-75 82% and 67%, and PP-NRS severity ≥4-point improvement 68% and 51%. In patients with moderate-to-severe AD, long-term abrocitinib treatment resulted in clinically meaningful skin and pruritus improvement. The long-term safety profile was manageable and consistent with previous reports.

373 Safety of lebrikizumab in adults and adolescents with moderate-to-severe atopic dermatitis: data from eight trials

Abstract Lebrikizumab (LEB) is a monoclonal antibody that binds with high affinity to interleukin (IL)-13, thereby blocking the downstream effects of IL-13 with high potency. To report integrated safety information in adult and adolescent patients with moderate-to-severe atopic dermatitis treated with LEB, from an integrated safety analysis of eight clinical Phase 2 and 3 trials. These data include adult and adolescent patients who received at least one dose of study drug from a total of eight atopic dermatitis clinical trials: ADvocate1, ADvocate2, ADhere, ADore, ADjoin (ongoing), ARBAN, TREBLE and a Phase 2b study. Treatment duration ranged from a single dose to 100 weeks. This analysis includes all placebo-controlled Week 0- to 16-safety data in patients treated with LEB 250 mg every 2 weeks (LEBQ2W, n = 783) compared with placebo (n = 404) known as ALL PC Weeks 0–16, and all patients who received at least one dose of LEB (n = 1720) known as ALL LEB. Conjunctivitis cluster is defined by MedDRA-preferred terms of conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis and giant papillary conjunctivitis. Exposure adjusted incidence rates (IR) are provided as per 100 patient-years. In ALL PC Weeks 0–16 analysis, the frequency of treatment-emergent adverse events (TEAE) was 49.2% in LEBQ2W (n = 384) compared with 53.1% in placebo (n = 215). The majority of TEAEs reported were mild or moderate in severity with 2.3% (n = 18) reported as severe in LEBQ2W and 4.4% (n = 18) in placebo. Serious adverse events (SAEs) were reported by 1.3% (n = 10) in LEBQ2W and 1.9% (n = 8) in placebo. No deaths reported in LEBQ2W and one death in placebo. The most frequently reported TEAE in LEBQ2W was conjunctivitis and in placebo was atopic dermatitis. Conjunctivitis cluster was reported by 8.5% (n = 67) in LEBQ2W and 2.5% (n = 10) in placebo. All conjunctivitis cluster events were mild or moderate. Injection site reactions (ISRs) were reported by 2.6% (n = 20) in LEBQ2W and 1.5% (n = 6) in placebo. Adverse events leading to discontinuation were reported by 2.3% (n = 18) in LEBQ2W and 1.4% (n = 6) in placebo. In ALL LEB, the frequency of TEAEs was 64.3% (n = 1106, IR: 137.9), with the majority being mild or moderate in severity. Severe TEAEs were reported by 5.3% (n = 91). The incidence rates of TEAE did not increase with duration of treatment exposure. The SAEs were reported by 3.3% (n = 56, IR: 3.5). Three (0.2%) deaths occurred in ALL LEB. Conjunctivitis cluster was reported by 10.6% (n = 183, IR:12.2) with the majority being mild or moderate in severity and 0.3% (n = 6) being reported as severe. The ISRs were reported by 3.1% (n = 53, IR: 3.3). Adverse events leading to discontinuation were reported by 4.2% (n = 73, IR: 4.5). The overall safety profile for lebrikizumab consisted of AEs that were mostly nonserious, mild or moderate in severity, and did not lead to treatment discontinuation. Safety profile was similar in both adults and adolescents.

Pharmacokinetics of SPR206 in Plasma, Pulmonary Epithelial Lining Fluid, and Alveolar Macrophages following Intravenous Administration to Healthy Adult Subjects.

SPR206 is a next-generation polymyxin being developed for the treatment of multidrug-resistant (MDR) Gram-negative infections. This Phase 1 bronchoalveolar lavage (BAL) study was conducted to evaluate SPR206's safety and pharmacokinetics in plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AM) in healthy volunteers. Subjects received a 100 mg intravenous (IV) dose of SPR206 infused over 1 h every 8 h for 3 consecutive doses. Each subject underwent 1 bronchoscopy with BAL at 2, 3, 4, 6, or 8 h after the start of the third IV infusion. SPR206 concentrations in plasma, BAL, and cell pellet were measured with a validated LC-MS/MS assay. Thirty-four subjects completed the study and 30 completed bronchoscopies. Mean SPR206 peak concentrations (Cmax) in plasma, ELF, and AM were 4395.0, 735.5, and 860.6 ng/mL, respectively. Mean area under the concentration-time curve (AUC0-8) for SPR206 in plasma, ELF, and AM was 20120.7, 4859.8, and 6026.4 ng*h/mL, respectively. The mean ELF to unbound plasma concentration ratio was 0.264, and mean AM to unbound plasma concentration ratio was 0.328. Mean SPR206 concentrations in ELF achieved lung exposures above the MIC for target Gram-negative pathogens for the entire 8-h dosing interval. Overall, SPR206 was well tolerated; 22 subjects (64.7%) reported at least 1 treatment-emergent adverse event (TEAE). Of the 40 reported TEAEs, 34 (85.0%) were reported as mild in severity. The most frequent TEAEs were oral paresthesia (10 subjects [29.4%]) and nausea (2 subjects [5.9%]). This study demonstrates pulmonary penetration of SPR206 and supports further development of SPR206 for the treatment of patients with serious infections caused by MDR Gram-negative pathogens.

224-OR: The Efficacy and Safety of HSK 16149 in Chinese with Diabetic Peripheral Neuropathic Pain—A Randomized, Double-Blinded, Placebo and Pregabalin-Controlled Phase II/III Study

Background: Chronic diabetic peripheral neuropathic pain (DPNP) is common and difficult to treat. The recommended medications are either inadequate effective or limited by the side effects. This study aims to evaluate the efficacy and safety of HSK16149, a potent, selective ligand of the a2δ subunit of voltage-gated calcium channels (VGCC), as analgesia treatment for DPNP. Materials and Methods: This was a randomized, double-blind, placebo and active-controlled phase II/III study of patients aged ≥18 years with diabetic peripheral neuropathy in China. Firstly, the patients with moderate to severe pain were randomized to receive placebo, HSK 16149 40,80 mg/d without titration, and HSK16149 120, 160mg/d, pregabalin 300mg/d with 1 week titration on average. Then more patients were recruited and randomized to placebo and two HSK16149 dose groups, continued the treatment for up to 13 weeks. The primary endpoint was the change from baseline in average daily pain score (ADPS) at week 13. The secondary endpoint was the responder rates as ≥30% and ≥50% improvement in ADPS. Results: Compared with placebo, the pain was reduced since week 1 in HSK16149 groups. At week 13, the mean ADPS change from baseline was -1.23, -2.24 and -2.16 for placebo (n=177), HSK 16149 40mg/d (n=178) and 80mg/d (n=179), showing statistical significance for both HSK groups versus placebo (P<0.0001). The 30% and 50% responder rate were both significantly greater for two HSK groups versus placebo (≥30%: 57.3%, 51.4% versus 31.6%; ≥50%: 32.0%, 36.3% versus 18.1%) at week 13. Most treatment-emergent adverse events (TEAE) in HSK16149 groups were mild to moderate, and the most frequent TEAEs were dizziness and somnolence, which were always transient and needed no additional treatment. Conclusions: HSK 16149 rapidly improved analgesia without titration and was efficacious in relieving pain in Chinese DPNP patients, and well tolerated. Disclosure X.Guo: None. T.Zhang: None. G.Yuan: None. L.Yukun: None. J.Ma: None. L.Hong-mei: None.

AFM13 IN PATIENTS WITH CD30 POSITIVE RELAPSED OR REFRACTORY (R/R) PERIPHERAL T CELL LYMPHOMA (PTCL): RESULTS FROM THE PHASE 2 REDIRECT STUDY

Introduction: PTCLs are aggressive hematologic malignancies often with poor prognoses; there is no standard of care therapy for patients with R/R PTCL. AFM13, a tetravalent, bispecific innate cell engager, binds CD30 when expressed on PTCL cells, and CD16A on innate effector cells, augmenting the innate immune response to CD30+ tumor cells. Phase 1 clinical trials of AFM13 in patients with R/R Hodgkin lymphoma (HL) and cutaneous CD30+lymphomas showed a tolerable safety profile and clinical activity; correlative science data in a small group of AFM13-responsive patients with HL showed increased natural killer (NK) cell activity. Methods: A Phase 2 study (NCT04101331) assessed the efficacy of AFM13 in patients with select R/R PTCL subtypes, exhibiting histologically confirmed CD30+expression in ≥1% tumor cells, who had received ≥1 prior systemic therapy. The primary endpoint was to assess the overall response rate (ORR) by FDG-PET per independent review committee. Secondary endpoints included safety, complete response rate (CRR), and duration of response (DoR). Progression-free survival (PFS) and overall survival (OS) were exploratory endpoints. Patients received 200 mg AFM13 intravenously once weekly until disease progression, intolerable toxicity, consent withdrawal or termination by the investigator. Results: Patients (n = 108; age 21–93; 61% male) received AFM13 with a median (min, max) number of infusions of 9.0 (1, 116). PTCL subtypes assessed (n) were: PTCL not-otherwise-specified (PTCL-NOS, 41); angioimmunoblastic T cell lymphoma (AITL, 30); anaplastic large cell lymphoma (ALCL, 26); other (11). Patients had received a mean of 2.7 prior treatment lines; 46.3% received prior brentuximab vedotin (BV), 17.6% received prior auto-transplant. The ORR was 32.4% (CRR was 10.2%); ORR per subtype was 22.0% (PTCL-NOS), 53.3% (AITL), 23.1% (ALCL), and 36.4% (other). Median DoR, PFS, and OS were 2.3 months, 3.5 months, and 13.8 months, respectively. AFM13-related treatment emergent adverse events (TEAEs) occurred in 79/108 patients (73.1%); 14 events in 9 patients (8.0%) were considered serious. The most frequent TEAE was infusion-related reactions, as reported by the investigator, seen in 34/108 patients (31.5%), including 12 Grade 3 events in 6 patients (5.7%). Neutropenia was the most frequent Grade ≥3 TEAE occurring in 9.3% of patients. Conclusion: AFM13 monotherapy demonstrated robust clinical activity in heavily pretreated patients with R/R PTCL. The safety profile of AFM13 was well managed and consistent with previously reported data from prior and ongoing clinical studies with AFM13. These data support future evaluation of AFM13 in combination with other immunotherapies, including allogeneic NK cells, to further potentiate anti-tumor immune responses to CD30+ lymphomas. Keyword: immunotherapy Encore Abstract—previously submitted to AACR 2023 The research was funded by: Affimed GmbH Conflicts of interests pertinent to the abstract W. S. Kim Research funding: Sanofi; BeiGene; Boryung; Roche; Kyowa Kirin Co., Ltd.; Dong-A Pharmaceutical Co., Ltd. J. Shortt Consultant or advisory role: Bristol Myers Squibb; Novartis; Otsuka; Astellis; Mundipharma; Pfizer Research funding: Astex; Amgen; Bristol Myers Squibb; Novartis P. L. Zinzani Consultant or advisory role: MSD; Eusapharma; Novartis; Celltrion Healthcare; Gilead; Janssen-Cilag; Bristol Myers Squibb; Servier; AstraZeneca; Takeda; Roche; Kyowa Kirin; Incyte; BeiGene; Secura Bio; Sandoz; ADC Therapeutics A. Marin-Niebla Other remuneration: Janssen; Gilead-Kite; Roche; Eli Lilly; Takeda; Kiowa-Kirin; AbbVie; AstraZeneca; BeiGene K. Alexis Employment or leadership position: Affimed Inc. Stock ownership: Affimed Inc. M. Emig Employment or leadership position: Affimed GmbH Stock ownership: Affimed GmbH L. Garcia Employment or leadership position: Affimed Inc. Stock ownership: Affimed Inc. A. Overesch Employment or leadership position: Affimed GmbH Stock ownership: Affimed GmbH K. Pietzko Employment or leadership position: Affimed GmbH Stock ownership: Affimed GmbH S. Horwitz Consultant or advisory role: Affimed; Daiichi Sankyo; Kyowa Kirin; ONO Pharmaceuticals; SecuraBio; Takeda; Shoreline Pharmaceuticals; Yingli Pharma; Abcuro Inc. Tublulis GmbH Research funding: ADC Therapeutics; Auxilius Pharma; Celgene; CRISPR Therapeutics; Millennium/Takeda; Seattle Genetics; C4 Therapeutics; Verastem/SecuraBio

A novel abiraterone acetate oral suspension for patients with metastatic prostate cancer: An open-label, phase 3, randomized trial.

5052 Background: Abiraterone acetate (AA) is a first-line oral hormone therapy for metastatic prostate cancer (mPC), but the licensed formulation is limited by large tablet size, requirement to take on an empty stomach, and pharmacokinetic variability. TAVT-45, a novel formulation of AA granules for oral suspension, offers improved oral bioavailability (allowing dose reduction), decreased food effect, and may provide an option for the ~20-30% of patients with dysphagia. This Phase 3, open-label global study (NCT04887506) aimed to establish therapeutic equivalence between TAVT-45 granules and reference AA tablets (R-AA). Methods: Patients with castrate-resistant or castrate-sensitive mPC (mCRPC or mCSPC) were randomized 1:1 to receive TAVT-45 (1 sachet of AA granules [250 mg] in water or juice, twice daily) or R-AA tablets (2 x 500 mg once daily ≥1 h before or ≥2 h after food), plus prednisone (5 mg once [mCSPC] or twice [mCRPC] daily) for 84 days. Efficacy (serum testosterone and prostate-specific antigen [PSA]) and safety were assessed. Average serum testosterone concentrations on Days 9 & 10 (primary endpoint, analyzed via analysis of covariance) were compared to show therapeutic equivalence. The key secondary endpoint was PSA-50 response (patients with ≥50% decrease in PSA from baseline at any time). mCRPC was the primary analysis population. Preliminary results are presented. Results: Of 107 randomized patients, 103 received TAVT-45 (n=54) or R-AA (n=49). The TAVT-45 and R-AA groups were well matched (mean [SD] age: 74.5 [8.45] and 74.9 [8.40] years; mCRPC: 61.1% and 61.2%). In mCRPC, serum testosterone concentrations fell rapidly from mean (SD) baseline of 9.7 (5.19) for TAVT-45 and 10.6 (7.32) ng/dL for R-AA, with all <1 ng/dL by Day 9. Therapeutic equivalence between TAVT-45 and R-AA at Days 9 & 10 was also shown in the full study population: Days 9 & 10 average rounded-up least-squares mean serum testosterone levels were comparable (TAVT-45 [n=52]: 1.004 ng/dL; R-AA [n=47]: 1.015 ng/dL), and the geometric mean ratio between groups was 0.990 (90% CI: 0.978-1.002), with the 90% CI falling within 80.0–125.0% equivalence limits. No statistical difference between TAVT-45 vs R-AA was demonstrated for PSA-50 (mCRPC 85% vs 70%; mCSPC 90% vs 95%). The frequency of treatment-emergent adverse events (TEAEs) was similar between groups; most were mild or moderate. Serious TEAEs occurred in 5 TAVT-45 and 3 R-AA patients. There were two deaths in treated patients due to cardiorespiratory arrest (TAVT-45) and prostate cancer (R-AA); neither was considered related to study drug. Conclusions: This Phase 3 study demonstrates that TAVT-45, a novel AA formulation with improved bioavailability, yields similar testosterone/PSA responses and a comparable safety profile to R-AA, and as an oral solution, may be suitable for mPC patients with dysphagia. Clinical trial information: NCT04887506 .

Phase I study of the mutant IDH1 inhibitor ivosidenib: Long-term safety and clinical activity in patients with conventional chondrosarcoma.

11532 Background: Chondrosarcomas (CS) are rare primary bone malignancies for which there are no approved systemic therapies. 85% of CS are the conventional subtype. Mutations in the isocitrate dehydrogenase 1 ( IDH1) gene occur in ~50% of conventional CS. In a phase 1 study in patients (pts) with IDH1-mutated advanced solid tumors, ivosidenib (IVO), an oral potent inhibitor of mutant IDH1, demonstrated manageable toxicity (without dose-limiting toxicities), suppression of the oncometabolite 2-hydroxyglutarate at dose levels ≥300 mg/day, and disease control in pts with conventional CS. We report long-term safety, tolerability and efficacy of IVO in pts with conventional CS. Methods: In this phase I multicenter open-label dose-escalation and expansion study, IVO was administered orally (100 mg twice/day [BID] to 1200 mg once/day [QD]) in continuous 28-day cycles. Primary outcome was safety and tolerability; secondary outcomes included clinical activity (objective response rates [ORR, defined as complete response (CR) + partial response (PR)], stable disease [SD] and progression-free survival [PFS]). Adverse events (AEs) were assessed every visit and reported per the Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Responses were assessed every other cycle using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Results: 13 pts with advanced conventional CS were included in this analysis (data cut off 15 September 2022; women, n = 4; median age 54.0; AJCC tumor grade I [n = 2], II [n = 8], III [n = 1], unknown [n = 2]; 6 had received prior systemic therapy; received 100 mg IVO BID [n = 1], 400 mg QD [n = 1], 500 mg QD [n = 7], 800 mg QD [n = 2], and 1200 mg QD [n = 2]). Median treatment duration was 11.3 months (range: 0.5-92.6 months). Four pts (30.8%) have continued therapy for > 6 years (two of which were treated for > 7 years). Median relative dose intensity was 100%. The most frequent treatment emergent AEs (in > 4 pts; mostly grade 1/2) were diarrhea (n = 5) and nausea (n = 5). Six pts experienced grade ≥3 AEs. Three pts experienced serious AEs (none considered related to treatment). There were no discontinuations, dose reductions or deaths due to AEs. The ORR was 23.1%. Median duration of response was 42.5 months (range: 25.8-51.8 months). One pt with a base of the skull lesion achieved a CR (1200 mg IVO QD); two achieved PR (one 500 mg and one 1200 mg IVO QD); seven had SD (five received ≥500 mg IVO QD) and two had PD (both received ≥500 mg IVO QD). All responses occurred after > 2 years on treatment. Median PFS was 7.4 months (95% CI: 2.0-61.3). Conclusions: In pts with IDH1 mutated advanced conventional CS, IVO demonstrates manageable toxicity and durable disease control including long-term responses, extending several years for a proportion of pts. Future studies are warranted to better understand the efficacy of IVO in pts with advanced conventional CS. Clinical trial information: NCT02073994 .

Darolutamide observational (DAROL) study in patients with nonmetastatic castration-resistant prostate cancer: Second interim analysis.

e17095 Background: In ARAMIS (NCT02200614), darolutamide (DARO) significantly improved metastasis-free survival (MFS) by ~2 years (HR 0.41, 95% CI 0.34–0.50) and reduced the risk of death by 31% (HR 0.69, 95% CI 0.53–0.88) compared with placebo in men with nonmetastatic castration-resistant prostate cancer (nmCRPC), with a favorable tolerability profile. The ongoing DAROL study (NCT04122976) aims to understand the real-world safety and effectiveness of DARO in patients (pts) with nmCRPC. We report results from the pre-planned second interim analysis (IA). Methods: DAROL is a global, open-label, single-arm, non-interventional study in pts aged ≥18 years with confirmed nmCRPC for whom the decision to be treated with DARO is decided pre-enrollment. The primary endpoint is safety, including incidence, severity, and frequency of treatment-emergent adverse events (TEAEs). Secondary endpoints are patient demographics and disease characteristics, treatment duration, MFS, overall survival (OS), time to prostate-specific antigen (PSA) progression, and PSA response. Primary and secondary endpoints are reported after 300 pts completed ≥6 mo of treatment. All treated pts were assessed for safety while efficacy was evaluated in pts who did not violate any eligibility criteria and had ≥1 post-baseline assessment (cut-off October 11, 2022). Results: Of the 300 treated pts, the percentage enrolled in North America/Europe/Asia Pacific/Latin America was 45%/30%/25%/ < 1%, respectively. Median age was 80 years; 51% had a reported Gleason score > 7; 92% had a reported ECOG performance status of 0/1. Median baseline (BL) PSA was 3.9 ng/mL (range 0–248.0), with 21% of pts reporting PSA < 2 ng/mL. Median BL PSA doubling time (PSADT) was 5.3 mo (range 0–36.2), with 42% of pts reporting PSADT > 6 mo. At the data cut-off, median follow-up time was 14.8 mo (interquartile range [IQR] 10.9–19.3) and median treatment duration was 13.4 mo (IQR 9.3–17.8). The incidences of TEAEs and DARO-related TEAEs were generally low (Table), consistent with the safety profile of DARO reported in ARAMIS. Fatigue occurred in ≥5% of pts. For the 263 pts eligible for efficacy analysis, median time to PSA progression was 17.6 mo (95% CI 13.2–19.0); MFS/OS data remain immature. PSA declines from baseline of ≥30%, ≥50%, and ≥90% at any time were observed in 80%, 76%, and 54% of pts, respectively. Conclusions: In the DAROL second IA, under real-world conditions, DARO continued to show a favorable safety profile, consistent with the clinical profile of ARAMIS, with no new safety signals. Clinical trial information: NCT04122976 . [Table: see text]

Real-world efficacy of ribociclib (RIB) + aromatase inhibitor (AI)/fulvestrant (FUL), or endocrine monotherapy (ET), or chemotherapy (CT) as first-line (1L) treatment (tx) in elderly patients (pts; > 75 years) with hormone receptor–positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC): Results of fifth interim analysis (IA) from RIBANNA.

e13050 Background: RIB+ET has demonstrated a statistically significant survival benefit across three phase 3 MONALEESA trials, irrespective of menopausal status, line of therapy, or combination partner. RIBANNA (CLEE011ADE03), a prospective, noninterventional study assessing the efficacy and safety of RIB+ET, or ET alone or CT in 1L setting in pre-, peri- and postmenopausal women with HR+, HER2– ABC is ongoing in Germany since October 2017. In this 5th IA from RIBANNA, efficacy, safety, and tolerability for exclusively elderly pts ( > 75 years) will be presented. Methods: Pts were included in accordance with the German tx guideline. The following analysis will be performed exclusively for pts > 75 years. Effectiveness analysis for PFS will be performed including propensity score matched (PSM) and Cox Proportional Hazards Regression (CPHR) analysis. Data for patient-reported outcomes (PRO) were collected at baseline and every 3 months until the end of treatment and will be evaluated using the Morisky Medication Adherence Scale (MMAS-8), questionnaires related to quality-of-life (EORTC QLQ-C30) and its breast cancer–specific module (EORTC QLQ-BR23) as well as the Hospital Anxiety and Depression Scale (HADS). Results: At data cutoff Sep 6, 2022, 2581 pts were enrolled in the study (RIB+AI/FUL, n = 2163; ET, n = 237; CT, n = 181). For pts > 75 years data from n = 434 (RIB+AI/FUL), n = 83 (ET) and n = 20 (CT) are available. In the overall population at baseline, the mean age (standard deviation [SD]) of patients was 65.5 (11.6), 70.8 (11.3), and 61.8 (11.6) years in the RIB + AI/FUL, ET, and CT cohorts, respectively. The unadjusted KM estimate for median PFS was 32.2 months (95% CI, 29.3–34.8) in the RIB + AI/FUL cohort, 35.2 months (95% CI, 23.9–44.2) in the ET cohort, and 16.7 months (95% CI, 9.9–17.5) in the CT cohort. Multivariate analysis showed that PFS was independently affected by several baseline parameter. After CPHR Analysis RIB + AI/FUL was associated with prolonged PFS compared with ET or CT. These results could be confirmed using PSM. The most frequent treatment-emergent adverse events (AEs) (all grade) in the RIB + AI/FUL cohort were neutropenia (25.8%), nausea (25.1%), fatigue (24.2%), and leukopenia (19.8%). Nausea and fatigue were the most common treatment-emergent AE (all grade) in both the CT and ET cohorts. Conclusions: RIBANNA study showed diverse population characteristics among pts who received RIB tx in a real-world setting. In the overall population Ribociclib showed superiority over ET and CT in the clinical routine, without new safety signals. Data for exclusively elderly pts ( > 75 years) will be presented.

Pirtobrutinib in covalent BTK-inhibitor (cBTKi) pre-treated mantle cell lymphoma (MCL): Updated results and subgroup analysis from the phase 1/2 BRUIN study with >3 years follow-up from start of enrollment.

7514 Background: Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi. Here, we report updated results of pirtobrutinib in patients (pts) with cBTKi pre-treated relapsed/refractory (R/R) MCL and more than 3 years follow-up from start of enrollment. Methods: Pts with cBTKi pre-treated R/R MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in the prespecified primary efficacy cohort that comprised the first 90 enrolled pts who had measurable disease, had received a prior cBTKi, and had no known central nervous system involvement. The primary endpoint was overall response rate (ORR) as assessed by independent review committee. Secondary endpoints included duration of response (DOR) and safety. A data cut of 29 July 2022 was utilized. Results: Among MCL pts who received a prior cBTKi (n=90), median age was 70 years (range, 46-87), median prior lines of therapy were 3 (range, 1-8), 82% discontinued a prior cBTKi due to disease progression, and 78% had intermediate/high risk sMIPI score. Of samples available, 17/36 (47%) had TP53 mutations and 25/34 (74%) had Ki67 ≥30%. The ORR was 57% (95% CI, 46-67), including 19% complete responses (n=17) and 38% partial responses (n=34). At a median follow-up time of 13 months, the median DOR among the 51 responding pts was 17.6 months (95% CI, 7.3-27.2). The 12- and 18-month estimated DOR rates were 58% (95% CI, 41-72) and 45% (95% CI, 27-61), respectively. ORR and DOR by subgroups are shown in the Table. The median progression-free survival was 7.4 months (95% CI, 5.3–13.3). The median overall survival was 23.5 months (95% CI, 15.9-NE). In the MCL safety cohort (n=166), the most frequent treatment-emergent adverse events (TEAE) were fatigue (31%), diarrhea (22%), and anemia (17%). The most common Grade ≥3 TEAE was neutropenia (15%). Grade ≥3 TEAE of hemorrhage (3%) and atrial fibrillation/flutter (2%) were infrequent. Only 5 (3%) pts discontinued due to a treatment-related AE. Conclusions: Pirtobrutinib continues to show durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. Responses were observed in pts with high-risk disease features including pts with blastoid/pleomorphic variants, elevated Ki67 index, and TP53 mutations. Clinical trial information: NCT03740529 . [Table: see text]

PIRTOBRUTINIB IN COVALENT BTK‐INHIBITOR PRE‐TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS, SUBGROUP ANALYSIS FROM BRUIN WITH >3 YEARS FOLLOW‐UP FROM START OF ENROLLMENT

PIRTOBRUTINIB IN COVALENT BTK‐INHIBITOR PRE‐TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS, SUBGROUP ANALYSIS FROM BRUIN WITH >3 YEARS FOLLOW‐UP FROM START OF ENROLLMENT