P154 SAFETY AND TOLERABILITY OF ONCE-DAILY ORAL KALLIKREIN INHIBITOR BCX7353 IN PHASE 3 APEX-2 HAE STUDY

BackgroundAntitumor activity with pembrolizumab + enzalutamide was observed in cohort C of the phase 1b/2 KEYNOTE-365 (NCT02861573) study of abiraterone acetate–pretreated patients with mCRPC and in a phase 2 study (NCT02312557) of patients with mCRPC who experienced progression with enzalutamide alone. In KEYNOTE-365 cohort C, prostate-specific antigen (PSA) response rate was 22%, objective response rate (ORR) was 20%, and 12-month PFS and OS rates were 24.6% and 72.8%, respectively. Safety and tolerability of the combination was consistent with individual profiles of each agent. In the phase 2 study of enzalutamide-pretreated patients, 5 of 28 patients (18%) had a PSA decline of ≥50%, and 3 of 12 patients (25%) with measurable disease achieved objective response. KEYNOTE-641 (NCT03834493) is a randomized, phase 3 trial to assess efficacy and safety of pembrolizumab + enzalutamide versus placebo + enzalutamide in patients with mCRPC.MethodsEnrolled patients have biochemical or radiographic progression with androgen deprivation therapy/after bilateral orchiectomy within 6 months of screening, ECOG PS 0/1, ongoing androgen deprivation with serum testosterone <50 ng/dL, and tumor tissue availability for biomarker analysis. The study continues to enroll those who previously had abiraterone acetate therapy; the abiraterone-naive cohort is filled. Exclusion criteria are prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor. Treatment stratification factors are prior abiraterone acetate treatment (yes or no), metastases location (bone only or liver or other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes or no). Response and progression will be determined by imaging (CT/MRI/bone) per PCWG3–modified RECIST v1.1 on visits Q9W during the first year and Q12W thereafter. Approximately 1200 adults will be randomly assigned 1:1 in a double-blind fashion to receive enzalutamide 160 mg orally once daily + pembrolizumab 200 mg IV Q3W or enzalutamide 160 mg orally once daily + placebo for a maximum of 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Coprimary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by blinded independent central review, and OS. The key secondary end point is time to subsequent anticancer therapy or death. Other secondary end points are ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to symptomatic skeletal-related event, time to soft tissue progression, and safety. KEYNOTE-641 is ongoing or planned in 21 countries across Asia, Australia, Europe, and North and South America.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov, NCT03834493Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

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Peginterferon beta-1a every 2 weeks demonstrated better clinical outcomes than glatiramer acetate once-daily in patients with RRMS: Propensity score matching of phase 3 data from ADVANCE and CONFIRM

Revue Neurologique ◽

10.1016/j.neurol.2019.01.269 ◽

2019 ◽

Vol 175 ◽

pp. S96

Author(s):

Thomas Scott ◽

Oksana Mokliatchouk ◽

Carmen Castrillo-Viguera ◽

Adrian Harrington ◽

Maria L. Naylor

Keyword(s):

Propensity Score ◽

Propensity Score Matching ◽

Clinical Outcomes ◽

Glatiramer Acetate ◽

Phase 3 ◽

Once Daily

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Baricitinib inhibits structural joint damage progression in patients with rheumatoid arthritis—a comprehensive review

Arthritis Research & Therapy ◽

10.1186/s13075-020-02379-6 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Paul Emery ◽

Patrick Durez ◽

Axel J. Hueber ◽

Inmaculada de la Torre ◽

Esbjörn Larsson ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Radiographic Progression ◽

Joint Damage ◽

Janus Kinase ◽

X Rays ◽

Phase 3 ◽

Once Daily ◽

Positive Effects ◽

Damage Progression ◽

Structural Joint

AbstractBaricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 that has proved effective and well tolerated in the treatment of rheumatoid arthritis (RA) in an extensive programme of clinical studies of patients with moderate-to-severe disease. In a phase 2b dose-ranging study of baricitinib in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in RA patients, magnetic resonance imaging showed that baricitinib 2 mg or 4 mg once daily provided dose-dependent suppression of synovitis, osteitis, erosion and cartilage loss at weeks 12 and 24 versus placebo. These findings correlated with clinical outcomes and were confirmed in three phase 3 studies (RA-BEGIN, RA-BEAM and RA-BUILD) using X-rays to assess structural joint damage. In patients naïve to DMARDs (RA-BEGIN study), baricitinib 4 mg once daily as monotherapy or combined with methotrexate produced smaller mean changes in structural joint damage than methotrexate monotherapy at week 24. Differences versus methotrexate were statistically significant for combined therapy. In patients responding inadequately to methotrexate (RA-BEAM study), baricitinib 4 mg plus background methotrexate significantly inhibited structural joint damage at week 24 versus placebo, and the results were comparable to those observed with adalimumab plus background methotrexate. In patients responding inadequately to conventional synthetic DMARDs (csDMARDs; RA-BUILD study), baricitinib 4 mg again significantly inhibited radiographic progression compared with placebo at week 24. Benefits were also observed with baricitinib 2 mg once daily, but the effects of baricitinib 4 mg were more robust. The positive effects of baricitinib 4 mg on radiographic progression continued over 1 and 2 years in the long-term extension study RA-BEYOND, with similar effects to adalimumab and significantly greater effects than placebo. Findings from the phase 3 studies of patients with RA were supported by preclinical studies, which showed that baricitinib has an osteoprotective effect, increasing mineralisation in bone-forming cells. In conclusion, baricitinib 4 mg once daily inhibits radiographic joint damage progression in patients with moderate-to-severe RA who are naïve to DMARDs or respond inadequately to csDMARDs, including methotrexate, and the beneficial effects are similar to those observed with adalimumab.

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P134 Radiographic progression of structural joint damage over 5 years of baricitinib treatment in patients with RA: results from RA-BEYOND

Rheumatology ◽

10.1093/rheumatology/keab247.130 ◽

2021 ◽

Vol 60 (Supplement_1) ◽

Author(s):

Désirée M F M van der Heijde ◽

Cynthia E Kartman ◽

Li Xie ◽

Scott Beattie ◽

Douglas E Schlichting ◽

...

Keyword(s):

Radiographic Progression ◽

Joint Damage ◽

Extension Study ◽

Categorical Variables ◽

Stock Ownership ◽

Phase 3 ◽

Once Daily ◽

Smallest Detectable Change ◽

Structural Joint

Abstract Background/Aims Baricitinib (BARI) is an oral, reversible, selective JAK1/2 inhibitor. Treatment with once-daily oral BARI resulted in low rates of radiographic progression for up to 2 years in patients with rheumatoid arthritis (RA). Here, we evaluate the radiographic progression of structural joint damage in patients with RA over 5 years of treatment with BARI. Methods This included patients who completed three Phase 3 trials, RA-BEGIN (DMARD-naive), RA-BUILD (csDMARD-IR), or RA-BEAM (MTX-IR), and enrolled in long-term extension study, RA-BEYOND. Patients receiving blinded BARI at the conclusion of Phase 3 trials remained on that dose (2mg/4mg, once daily) in RA-BEYOND. At 52 weeks, DMARD-naive patients receiving methotrexate(MTX) or combination therapy(BARI 4mg+MTX) were switched to BARI 4mg monotherapy; MTX-IR patients receiving adalimumab(ADA) were switched to BARI 4mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo(PBO) were switched to BARI 4mg on background csDMARD. Analysis population included patients who had baseline and at least one radiograph collected after 2 years. Radiographic progression of structural joint damage (Years 3-5) was determined by changes from baseline in van der Heijdemodified Total Sharp Score(ΔmTSS), erosion score, and joint space narrowing. Proportion of patients showing no progression was assessed based on change from baseline mTSS(ΔmTSS) from originating study, using thresholds of 0.5 or smallest detectable change(SDC). Mixedmodel repeatedmeasures and logistic regression models were used to analyze continuous variables and categorical variables, respectively; linear extrapolation was used for imputation of missing data(maximum of 1 year). Results 82.6% (2125/2573) of patients entered long-term extension study. Among DMARD-naive patients, those on initial BARI monotherapy or in combination with MTX had significantly slower radiographic progression(ΔmTSS) versus those on initial MTX at Years 3, 4, 5 (p ≤ 0.05). They had significantly fewer erosions at these time points (p ≤ 0.05). A greater proportion of patients who received initial BARI therapy and BARI+MTX had no radiographic progression versus initial MTX monotherapy using thresholds of 0.5 (p ≤ 0.05). Among MTX-IR patients, those on initial BARI treatment had slower radiographic progression compared to PBO and results were comparable to those on initial ADA treatment at Years 3, 4, 5. A greater proportion of patients who received initial BARI therapy had no radiographic progression versus initial PBO using thresholds of SDC (p ≤ 0.05). Among csDMARD-IR patients, although differences between groups were small, patients on initial BARI 4mg had slowest radiographic progression compared to initial PBO and initial BARI 2mg. At least 74% of the structure data used in the analyses are based on observed data. Conclusion Treatment with once-daily oral BARI maintained low rates of radiographic progression for up to 5 years in different patient populations with RA. Disclosure D.M.F.M. van der Heijde: Consultancies; AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi Sankyo, Eli Lilly and Company, Galapagos NV, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB Pharma. C.E. Kartman: Shareholder/stock ownership; Eli Lilly and Company. L. Xie: Shareholder/stock ownership; Eli Lilly and Company. S. Beattie: Shareholder/stock ownership; Eli Lilly and Company. D.E. Schlichting: Shareholder/stock ownership; Eli Lilly and Company. P. Durez: Member of speakers’ bureau; Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, and Sanofi. Y. Tanaka: Member of speakers’ bureau; AbbVie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, Takeda, UCB, and YL Biologics. Grants/research support; AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, and Taisho-Toyama and Takeda. R. Fleischmann: Consultancies; AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB.

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FRI0138 THE IMPACT OF UPADACITINIB VERSUS METHOTREXATE OR ADALIMUMAB ON INDIVIDUAL AND COMPOSITE DISEASE MEASURES IN PATIENTS WITH RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1426 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 651.1-652

Author(s):

R. Van Vollenhoven ◽

A. Ostor ◽

E. Mysler ◽

N. Damjanov ◽

I. H. Song ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Selective Inhibitor ◽

Response Criteria ◽

Research Support ◽

Phase 3 ◽

Once Daily ◽

Composite Measures ◽

Treatment Responses ◽

The Impact ◽

Mean Time

Background:In Phase 3 trials, upadacitinib (UPA), an oral JAK1-selective inhibitor, has been assessed as monotherapy vs MTX (SELECT-EARLY1) and in combination with MTX vs adalimumab + MTX (ADA; SELECT-COMPARE2) in RA pts who were MTX naïve or with inadequate responses to MTX (MTX-IR), respectively.Objectives:In this analysis we assessed individual and composite measures of disease activity in SELECT-EARLY and SELECT-COMPARE.Methods:In SELECT-EARLY, MTX-naïve pts received UPA 15 mg or 30 mg monotherapy once daily (QD), or MTX monotherapy, for 12 wks. In SELECT-COMPARE, MTX-IR pts on stable background MTX received UPA 15 mg QD, PBO, or ADA 40 mg every 2 wks for 12 wks. For this analysis, responses at Wk 12 were defined as ≥50% improvement in the 7 components of the ACR response criteria. Among ACR50 responders, the proportions of pts with ≥50% improvement in all 7 components of the ACR criteria was assessed. The proportion of pts achieving TJC68=0 and SJC66=0 was also determined. All analyses were based on observed data without imputation.Results:947 pts were randomized in SELECT-EARLY, and 1629 pts in SELECT-COMPARE. Mean time since RA diagnosis was 2.7 years in SELECT-EARLY (median 6 months) and 8.2 years in SELECT-COMPARE; mean DAS28(CRP) was 5.9 and 5.8, respectively. In SELECT-EARLY, significantly more MTX-naïve pts receiving UPA 15 mg or 30 mg monotherapy achieved ≥50% improvements in all ACR components at Wk 12 compared with MTX (Figure 1a,Figure 1b). In SELECT-COMPARE, significantly more MTX-IR pts on UPA 15 mg + MTX achieved ≥50% improvement in the ACR components vs PBO (all components) and ADA + MTX (all components except SJC and PhGA). Among pts with ACR50 responses at Wk 12, approximately half of the MTX-naïve pts on UPA 15 mg and 30 mg in SELECT-EARLY had ≥50% improvements in all 5 remaining ACR components (pain, PtGA, PhGA, HAQ-DI, hsCRP) compared with 28% with MTX. Corresponding proportions in MTX-IR pts in SELECT-COMPARE were 34% for UPA 15 mg + MTX, 28% for ADA + MTX, and 17% for PBO. UPA treatment also significantly increased the proportions of pts achieving both TJC68=0 and SJC66=0 vs PBO or MTX, and SJC66=0 vs ADA + MTX (Figure 1a,Figure 1b).Conclusion:In MTX-naïve and MTX-IR pts, treatment responses at 12 wks occurred in significantly higher proportions of pts receiving UPA monotherapy vs MTX and UPA + MTX vs PBO for all 7 components of the ACR response criteria, and for 5 of 7 ACR components for UPA + MTX vs ADA + MTX. Favorable outcomes with UPA treatment were evident both in composite and individual parameters.References:[1]van Vollenhoven R, et al. Arthritis Rheumatol 2018;70(Suppl. 10): Abstract 891[2]Fleischmann R, et al. Arthritis Rheumatol 2018;70(Suppl. 10): Abstract 890Disclosure of Interests:Ronald van Vollenhoven Grant/research support from: AbbVie, Arthrogen, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, and UCB, Consultant of: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, GSK, Janssen, Lilly, Medac, Merck, Novartis, Pfizer, Roche, and UCB, Andrew Ostor Consultant of: MSD, Pfizer, Lilly, Abbvie, Novartis, Roche, Gilead and BMS, Speakers bureau: MSD, Pfizer, Lilly, Abbvie, Novartis, Roche, Gilead and BMS, Eduardo Mysler Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Roche, Eli Lilly, Novartis, Janssen, Sanofi, and Pfizer., Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Roche, Eli Lilly, Novartis, Janssen, Sanofi, and Pfizer, Nemanja Damjanov Grant/research support from: from AbbVie, Pfizer, and Roche, Consultant of: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Speakers bureau: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, In-Ho Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jessica Suboticki Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB

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Phase 3 comparison of high-dose once-daily (QD) thoracic radiotherapy (TRT) with standard twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC): CALGB 30610 (Alliance)/RTOG 0538.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8505 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8505-8505

Author(s):

Jeffrey A Bogart ◽

Xiaofei F. Wang ◽

Gregory A. Masters ◽

Junheng Gao ◽

Ritsuko Komaki ◽

...

Keyword(s):

Regional Lymph Node ◽

Performance Status ◽

Lymph Node Involvement ◽

High Dose ◽

Phase 3 ◽

Ecog Performance Status ◽

Once Daily ◽

Concomitant Boost ◽

Significant Difference ◽

Grade 3

8505 Background: Although level 1 evidence is lacking, the majority of patients (pts) with LSCLC are treated with a high dose QD TRT regimen in clinical practice. CALGB 30610/RTOG 0538 was designed to determine if administering high dose TRT would improve overall survival (OS), compared with standard 45 Gy BID TRT, in LSCLC pts treated with chemoradiotherapy. Methods: Eligible pts had LSCLC, ECOG performance status (PS) 0-2 and regional lymph node involvement excluding contralateral hilar or supraclavicular nodes. This phase 3 trial was conducted in 2 stages. In the first stage, pts were randomized 1:1:1 to 45 Gy BID over 3 weeks, 70 Gy QD over 7 weeks, or 61.2 Gy concomitant boost (CB) over 5 weeks. For the second stage, the study planned discontinuation of one high dose arm based on interim toxicity analysis with patients then randomized 1:1 in the two remaining arms. TRT was given starting with either the 1st or 2nd (of 4 total) chemotherapy cycles. The primary endpoint was OS measured from date of randomization. Results: The trial opened 03/15/2008 and closed 12/01/2019 upon completing accrual, with the CB arm discontinued 3/11/2013 after interim analysis. This analysis includes 638 pts randomized to 45 Gy BID TRT (n = 313) or 70 Gy QD TRT (n = 325). Median age was 63 years (range 37-81), the majority of pts were Caucasian (86%), female (52%), and with ECOG PS 0-1 (95%). After median follow-up of 2.84 years (IQR:1.35 -5.61) for surviving pts, QD compared to BID did not result in a significant difference in OS (HR 0.94, 95% CI: 0.76-1.2, p = 0.9). Median, 2- and 4-year OS for QD were 30.5 months (95% CI: 24.4-39.6), 56% (95% CI: 0.51-0.62), and 39% (95% CI: 0.33-0.45), and for BID 28.7 months (95% CI: 26.2-35.5), 59% (95% CI: 0.53-0.65), and 35% (95% CI: 0.29-0.42). QD also did not result in a significant difference in PFS (HR 0.96, 95% CI: 0.78-1.18, p = 0.94). Most grade 3+ hematologic and non-hematologic adverse events (AEs) were similar between cohorts. Rates of grade 3+ febrile neutropenia, dyspnea, esophageal pain and dysphagia for QD were 12.6%,7%, 11.6% and 11.3%, and for BID 13.6%, 4%, 11.2 % and 9.5%. Grade 5 AEs were reported in 3.7% and 1.7% of the QD and BID cohorts, respectively. Results will be updated at presentation. Conclusions: High dose QD TRT to 70 Gy did not significantly improve OS compared with standard 45 Gy BID TRT. Nevertheless, favorable outcomes on the QD arm provide the most robust evidence available supporting high dose once-daily TRT as an acceptable option in LSCLC. Outcomes from this study, the largest conducted in LSCLC to date, will help guide TRT decisions for this patient population. Support: U10CA180821, U10CA180882; Clinical trial information: NCT00632853.

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