SAT0149 EXPOSURE-RESPONSE RELATIONSHIPS FOR EFFICACY AND SAFETY OF FILGOTINIB AND ITS METABOLITE GS-829845 IN SUBJECTS WITH RHEUMATOID ARTHRITIS BASED ON PHASE 2 AND PHASE 3 STUDIES

Background:Filgotinib is an orally administered small molecule that provides selective inhibition of JAK1, a signaling molecule that helps drive inflammatory pathways underlying rheumatoid arthritis (RA).Objectives:Exposure-response (ER) analyses were performed for efficacy following completion of Phase 2 studies over a wide range of doses to support evaluation of 200mg and 100 mg once daily in Phase 3 studies. ER analyses were subsequently performed by using Phase 3 efficacy data to support selection of the proposed registrational dose. ER analyses for safety based on pooled Phase 2 and Phase 3 studies were conducted to examine the safety of evaluated doses.Methods:Population PK analyses were conducted to estimate plasma exposures of filgotinib and GS-829845 (major circulating active metabolite of filgotinib) in both Phase 2 (DARWIN 1 and DARWIN 2) and Phase 3 studies (FINCH 1, FINCH 2, and FINCH 3) encompassing a dose range of 25 to 100 mg twice daily and 50 to 200 mg once daily. As both filgotinib and GS-829845 contribute to efficacy via JAK1 inhibition, their exposures were combined into single parameters, AUCeff and Ctau-eff (effective area under the curve and effective concentration at trough, by accounting for relative inhibition potency and molecular weight) in the ER analyses for various efficacy endpoints (e.g ACR20/50/70 responses) at Week 12 and Week 24. The ER analyses for safety endpoints (the 5 most frequent treatment-emergent adverse events [TEAEs] and Grade 3 or 4 laboratory abnormalities, serious TEAEs, and serious infections) were performed separately for filgotinib and GS-829845 exposures to characterize the individual safety profile of each analyte. The 5 evaluated TEAEs were nausea, nasopharyngitis, upper respiratory tract infection, headache, and hypertension; the 5 Grade 3/4 laboratory abnormalities included lymphocytes decrease, glucose increase, phosphate decrease, triacylglycerol lipase increase, and creatine kinase increase.Results:In the ER analyses for efficacy based on Phase 2 studies, high response rates were demonstrated in ACR20/50/70 across all octile groups in subjects with RA receiving filgotinib and the ER supported further evaluation of both 200 mg and 100 mg once daily doses in Phase 3 clinical studies. Similarly, ER relationships based on pooled Phase 3 studies across various endpoints (e.g ACR20/50/70) consistently revealed high response rates across the exposure range for both the filgotinib 200 mg and 100 mg doses. A trend of increasing response with increasing exposure was observed over the exposure range for multiple secondary efficacy endpoints including ACR50 and ACR70 with the effective exposures at filgotinib 200 mg primarily residing on the plateau of the ER curves.Filgotinib was generally well-tolerated with no individual TEAE or Grade 3 or 4 laboratory abnormality > 5% in the filgotinib 200 mg once daily group up to Week 12. No relationships were observed between filgotinib and GS-829845 exposures (AUC0-24 and Cmax) and the most frequent TEAEs, Grade 3/4 laboratory abnormalities, serious TEAEs, or serious infections up to Week 52.Conclusion:ER analyses demonstrate that both the 200 mg and 100 mg once daily filgotinib doses are efficacious in subjects with moderately to severely active RA without clear dose-dependent effects on safety. The trend towards greater efficacy with higher exposures for some secondary endpoints (ACR50 and ACR70) and a lack of exposure-safety relationship supports a dose of 200 mg once daily over 100 mg once daily since it presents the best benefit/risk ratio among the doses tested.Disclosure of Interests: :Amy Meng Shareholder of: Gilead Sciences, Employee of: Gilead, Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Sciences, Cara Nelson Shareholder of: Gilead, Employee of: Gilead, Brian Kirby Shareholder of: Gilead, Employee of: Gilead, Liyun Ni Shareholder of: Gilead, Employee of: Gilead, Shu-Min Chuang Shareholder of: Gilead, Employee of: Gilead, Brian Kearney Shareholder of: Gilead, Employee of: Gilead, Anita Mathias Shareholder of: Gilead, Employee of: Gilead

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Exposure-Response Relationships for Efficacy and Safety of Filgotinib and its metabolite GS-829845 in Subjects with Rheumatoid Arthritis Based on Phase 2 and Phase 3 Studies

10.22541/au.162418885.56100410/v1 ◽

2021 ◽

Author(s):

Amy Meng ◽

Kacey Anderson ◽

Cara Nelson ◽

Liyun Ni ◽

Shu-Min Chuang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Therapeutic Effects ◽

Phase 2 ◽

Phase 3 ◽

Two Phase ◽

Once Daily ◽

Exposure Response ◽

Daily Dose

Aims:Filgotinib is a potent, oral, JAK1-preferential inhibitor for the treatment of rheumatoid arthritis (RA). This report describes exposure-response (ER) analyses of filgotinib for dose confirmation based on three Phase 3 and two Phase 2 studies in moderate to severe RA patients. Methods:The PK exposures used in ER analyses were derived from population pharmacokinetic analysis. The relationship between filgotinib exposures and various efficacy endpoints (ACR20/50/70 and DAS28) was assessed over octile groups of exposures by using combined exposures of filgotinib and GS-829845 (major, active metabolite). For the ER analyses of safety, exposures were examined between subjects who experienced and who did not experience the evaluated safety events, which was conducted separately for filgotinib and GS-829845. Results:Exposure efficacy relationships consistently revealed high response rates across the exposure range for filgotinib 200 mg once daily dose. A trend of increasing response with increasing exposure was observed over the exposure range for the primary and multiple secondary efficacy endpoints, with exposures associated with the 200 mg dose primarily residing on the curve plateau. For exposure-safety analyses, filgotinib and GS-829845 exposures were similar irrespective of presence/absence of the evaluated safety endpoints, indicating no exposure-safety relationship for common TEAEs, common laboratory abnormalities, serious TEAEs, or serious infections. Conclusions:ER analyses confirmed that filgotinib produced more robust therapeutic effects across the exposure range observed at 200 mg once daily compared to lower doses. The positive exposure-efficacy relationship and a lack of exposure-safety relationship on the evaluated safety endpoints supported the 200 mg once daily dose for commercialization.

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POS1054 UPADACITINIB PHARMACOKINETICS AND EXPOSURE-RESPONSE RELATIONSHIPS FOR EFFICACY AND SAFETY IN PSORIATIC ARTHRITIS – ANALYSES OF THE PHASE 3 SELECT-PsA STUDIES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2182 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 805.2-806

Author(s):

E. Muensterman ◽

B. Engelhardt ◽

S. Gopalakrishnan ◽

J. Anderson ◽

M. E. Mohamed

Keyword(s):

Rheumatoid Arthritis ◽

Psoriatic Arthritis ◽

Inadequate Response ◽

Efficacy And Safety ◽

Phase 3 ◽

Exposure Response ◽

Serious Infections ◽

Grade 3 ◽

Using Data ◽

Compare Study

Background:Upadacitinib (UPA) is an oral, reversible, JAK inhibitor approved for the treatment of rheumatoid arthritis (RA). The efficacy and safety profile of UPA in psoriatic arthritis (PsA) has been established in the SELECT-PsA program which includes two global Phase 3 studies.Objectives:These analyses characterize UPA pharmacokinetics and exposure-response relationships for efficacy and safety endpoints using data from the SELECT-PsA studies.Methods:The SELECT-PsA program enrolled patients with prior inadequate response (IR) or intolerance to ≥1 non-bDMARD1 (N=1705) and prior IR or intolerance to ≥1 bDMARD2 (N=642). Data from both trials was integrated for patients receiving placebo (PBO), UPA 15mg once daily (QD) and UPA 30mg QD; adalimumab data was excluded from this analysis. UPA pharmacokinetics were characterized in PsA patients using Bayesian population pharmacokinetics analyses and utilizing prior information from analyses in healthy subjects and RA patients. Exposure-response analyses were conducted using logistic regression to characterize the relationships between upadacitinib average plasma concentration during a dosing interval (Cavg) and the percentage of patients achieving ACR20/50/70 at Weeks 12 and 24, static Investigator Global Assessment of psoriasis (sIGA) of 0 or 1 (clear or almost clear) and at least a 2-point improvement from baseline, and PASI75 at Weeks 16 and 24 or experiencing selected clinically relevant safety events through week 24.Results:Analyses were conducted using data from 1694 subjects (for pharmacokinetics) and 1916 subjects (for exposure-response analyses). UPA model-estimated plasma exposures in subjects with PsA who received 15mg and 30mg QD doses were comparable to previously estimated exposures in subjects with RA. Body weight and methotrexate use had no clinically relevant effects on UPA exposures. There was a statistically significant relationship between UPA Cavg and the percentage of subjects who achieved Week 12 ACR50/70, Week 16 sIGA 0/1, and Week 24 sIGA 0/1 (Figure 1). No statistically significant exposure-response relationship was observed for Week 12 ACR20, Week 16 PASI75, or Week 24 ACR20/50/70 or PASI75, indicating that the 15mg QD exposures are approximately at the plateau of response for these endpoints. No statistically significant relationships were observed between upadacitinib Cavg and the percentage of subjects experiencing pneumonia, herpes zoster, hemoglobin < 8 g/dL, Grade ≥3 lymphopenia, Grade ≥3 neutropenia. There was a shallow but statistically significant exposure-response relationships with the occurrence of serious infections and decrease in hemoglobin from baseline (>2 g/dL and >2 g/dL in combination with hemoglobin < lower limit for normal).Figure 1.Observed and Model Predicted Efficacy Responses at Week 12 (for ACR50/70) or at Weeks 16 and Week 24 (for sIGA 0/1) Versus Upadacitinib Plasma ExposuresConclusion:Exposure-response analyses demonstrated that plasma exposures associated with UPA 15 mg QD achieves robust efficacy in subjects with PsA with limited effects on the evaluated safety endpoints. UPA plasma exposures associated with UPA 15 and 30mg QD are predicted to provide similar ACR responses by week 24 while a small additional efficacy benefit with UPA 30mg is predicted for the achievement sIGA 0/1.References:[1]van Vollenhoven R, et al. Monotherapy with Upadacitinib in MTX-naïve Patients with Rheumatoid Arthritis: Results at 48 Weeks from the SELECT-EARLY Study. 2019 EULAR; THU0197[2]Fleischmann R, et al. Safety and Effectiveness of Upadacitinib or Adalimumab in Patients with Rheumatoid Arthritis: Results at 48 weeks from the SELECT-COMPARE Study. 2019 EULAR; FRI0147Disclosure of Interests:Elena Muensterman Shareholder of: AbbVie, Employee of: AbbVie, Benjamin Engelhardt Shareholder of: AbbVie, Employee of: AbbVie, Sathej Gopalakrishnan Shareholder of: AbbVie, Employee of: AbbVie, Jaclyn Anderson Shareholder of: AbbVie, Employee of: AbbVie, Mohamed-Eslam Mohamed Shareholder of: AbbVie, Employee of: AbbVie.

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Exposure-Response of Quizartinib Efficacy in Patients with Relapsed/Refractory AML

Blood ◽

10.1182/blood-2019-122582 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1263-1263

Author(s):

Dongwoo Kang ◽

Julie Passarell ◽

Malaz A Abutarif ◽

Jeanne Mendell ◽

Ophelia Yin

Keyword(s):

Complete Remission ◽

Phase 2 ◽

Dosing Regimen ◽

Phase 3 ◽

Once Daily ◽

Exposure Response ◽

Phase 2 Study ◽

Quartile Group ◽

Cyp3a Inhibitor ◽

To Receive

Introduction: Quizartinib is a once-daily, oral, highly potent and selective FLT3 inhibitor that has shown clinical activity in patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3 internal tandem duplications in the phase 3 QuANTUM-R trial (Cortes et al, Lancet Oncol 2019; NCT02039726). In this analysis, exposure-response relationships of select efficacy endpoints of quizartinib were evaluated. Methods: Analysis was conducted for the following 2 studies separately: phase 2 study APS2689-CL-2004 and phase 3 QuANTUM-R study. Phase 2 study APS2689-CL-2004 enrolled 76 patients who were randomized to receive quizartinib 30 or 60 mg once daily (26.5 and 53.0 mg free base, respectively). Dose escalation was allowed and no dose reduction for strong cytochrome P450 3A (CYP3A) inhibitors was made in this study. In QuANTUM-R, 245 patients were randomized to receive quizartinib. The quizartinib dosing regimen was 30 mg/day and then escalated to 60 mg/day after 2 weeks if QTcF was ≤ 450 ms. Patients receiving a concurrent strong CYP3A inhibitor initiated quizartinib at 20 mg/day, with an increase to 30 mg/day, because concomitant use of a strong CYP3A inhibitor approximately doubles quizartinib exposure. Efficacy endpoints included in the analysis were rate of composite complete remission (CRc; complete remission (CR) + complete remission with incomplete platelet recovery + complete remission with incomplete hematologic recovery), duration of CRc, and overall survival (OS). Exposure measures in individual patients, such as average daily area under the curve (AUC), maximum concentration, and trough concentration, were obtained from a population pharmacokinetic analysis of quizartinib plasma concentration data (Kang et al, EHA 2019) and then used for correlating with the efficacy endpoints. Logistic regression analysis was used for CRc rate, and time-to-event analysis was performed for the duration of CRc and OS. The effect of quizartinib exposure on the percentage of subjects achieving bone marrow (aspirate) blasts of < 5% in QuANTUM-R was also assessed. Results: Patients were divided into 4 quartile groups according to average daily quizartinib AUC for the investigation of exposure-response relationships for OS and the duration of CRc. The lowest exposure quartile group showed shorter OS than the higher 3 quartile groups. The overall median OS from the intent-to-treat (ITT) population was 6.2 months in the phase 3 study; the median OS in the lowest exposure quartile group (Q1) was 4.5 months, whereas the median OS in the highest exposure quartile group (Q4) was 9.6 months (Fig. 1). Analysis of OS for the phase 2b study APS2689-CL-2004 demonstrated a similar trend, in which the lower AUC quartile demonstrated decreased OS. The overall OS from the ITT population was 5.2 months in the phase 2 study, and the median OS in Q1 and Q4 was 4.6 and 6.9 months, respectively (Fig. 2). Consistent with analyses for OS, the duration of CRc showed a trend of shorter duration of response in the lower AUC quartiles in both studies. Additionally, the lower AUC quartile appeared to result in a smaller proportion of subjects who achieved blast reduction of < 5% (ie, 33.3% in Q1 vs 45.6% to 52.6% in Q2 to Q4). However, no apparent trend of exposure-response relationship was shown for CRc (P > .05 from logistic regression analysis). Conclusions: Exposure-response analysis suggests a consistent trend for reduced clinical benefit at lower quizartinib AUC quartiles across various efficacy endpoints (but not CRc) in both the phase 2 and phase 3 studies. Current analysis supports the recommended dosing regimen of 30-mg starting dose with escalation to 60 mg as the target clinical dose. Figure Disclosures Kang: Daiichi Sankyo: Employment. Passarell:Cognigen Corporation: Employment. Abutarif:Daiichi Sankyo: Employment, Equity Ownership. Mendell:Daiichi Sankyo, Inc.: Employment. Yin:Daiichi Sankyo: Employment.

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Efficacy and safety of filgotinib in combination with methotrexate in Japanese patients with active rheumatoid arthritis who have an inadequate response to methotrexate: Subpopulation analyses of 24-week data of a global phase 3 study (FINCH 1)

Modern Rheumatology ◽

10.1093/mr/roab030 ◽

2021 ◽

Author(s):

Yoshiya Tanaka ◽

Tsukasa Matsubara ◽

Tatsuya Atsumi ◽

Koichi Amano ◽

Naoki Ishiguro ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Japanese Patients ◽

Incidence Rates ◽

Janus Kinase ◽

Inadequate Response ◽

Efficacy And Safety ◽

Phase 3 ◽

Once Daily ◽

American College Of Rheumatology ◽

Grade 3

ABSTRACT Objectives Evaluate the efficacy and safety of the Janus kinase-1 inhibitor filgotinib in Japanese patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX). Methods Data from 147 Japanese patients in FINCH 1, a 52-week global Phase 3 study, were analysed up to 24 weeks. Patients received once-daily filgotinib 200 or 100 mg, biweekly adalimumab, or placebo, all with stable background MTX. Results In the Japanese population, American College of Rheumatology 20% response rates at Week 12 (primary endpoint) were 77.5%, 65.9%, 53.6%, and 36.8% for filgotinib 200 mg, filgotinib 100 mg, adalimumab, and placebo. Proportions of patients achieving Disease Activity Score with 28 joints <2.6 at Week 24: filgotinib 200 mg, 65.0%; filgotinib 100 mg, 51.2%; adalimumab, 42.9%; and placebo, 5.3%. Incidence rates of serious infections: filgotinib 200 mg, 2.5%; filgotinib 100 mg, 0%; adalimumab, 10.7%; and placebo, 5.3%. Treatment-emergent laboratory abnormalities Grade ≥3 occurred in five (12.5%) filgotinib 200 mg, three (7.3%) filgotinib 100 mg, one (3.6%) adalimumab, and no placebo patients. No deaths were reported among Japanese patients. Conclusions Filgotinib once daily combined with MTX was effective and generally safe and well tolerated up to Week 24 in Japanese patients with RA and inadequate response to MTX.

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Pharmacokinetics and exposure–response analysis of venetoclax+obinutuzumab in chronic lymphocytic leukaemia: phase 1b study and phase 3 CLL14 trial

10.22541/au.163253527.70781921/v1 ◽

2021 ◽

Author(s):

Divya Samineni ◽

Leonid Gibiansky ◽

Bei Wang ◽

Shweta Vadhavkar ◽

Richa Rajwanshi ◽

...

Keyword(s):

Steady State ◽

Chronic Lymphocytic Leukaemia ◽

Lymphocytic Leukaemia ◽

Response Analysis ◽

Parameter Estimates ◽

Phase 3 ◽

Once Daily ◽

Exposure Response ◽

Phase 1B ◽

Grade 3

Aims: To investigate pharmacokinetics (PK) and exposure-response of the 400 mg once daily venetoclax dose regimen in combination with obinutuzumab in the phase 3 CLL14 study approved for the treatment of first-line (1L) chronic lymphocytic leukaemia (CLL). Methods: Parameter estimates and uncertainty estimated by a previously developed population PK (popPK) model were used as informative priors for this analysis. They were re-estimated, then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using CLL14 data, with steady-state exposure at the nominal target dose (C) as the predictor variable. Exposure-safety analyses were conducted using logistic regression for selected treatment-emergent grade ≥3 adverse events (AEs) and serious AEs (SAEs). Dose intensities were summarized by tertiles of C. Results: PK data from 274 patients (CLL14, n=194; phase 1b dose-finding study GP28331, n=80) were included. The final model provided good fit of observed data. Obinutuzumab co administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥3 neutropenia, grade ≥3 thrombocytopenia, grade ≥3 infections and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles. Conclusion: PopPK and exposure efficacy, -safety and -tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab in patients with 1L CLL.

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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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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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Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4509 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4509-4509

Author(s):

Chung-Han Lee ◽

Martin H Voss ◽

Maria Isabel Carlo ◽

Ying-Bei Chen ◽

Eduard Reznik ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

Clear Cell ◽

Phase 2 ◽

Phase 3 ◽

Cell Renal Cell Carcinoma ◽

Stage Design ◽

Phase 2 Trial ◽

Clear Cell Rcc ◽

Grade 3

4509 Background: Cabozantinib plus nivolumab (CaboNivo) improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) over sunitinib in a phase 3 trial for metastatic clear cell renal cell carcinoma (RCC). (Choueiri, abstract 6960, ESMO 2020) We report the results of a phase 2 trial of CaboNivo in patients (pts) with non-clear cell RCC. Methods: Pts had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given across two cohorts. Cohort 1: papillary, unclassified, or translocation associated RCC; Cohort 2: chromophobe RCC. The primary endpoint was ORR by RECIST; secondary endpoints included PFS, OS, and safety. Cohort 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Cohort 2 was a Simon two-stage design that closed early for lack of efficacy. Correlative analyses by next generation sequencing were performed and to be presented. Results: A total of 40 pts were treated in Cohort 1, and 7 pts were treated in Cohort 2 (data cutoff: Jan 20, 2021). Median follow up time was 13.1 months (range 2.2 – 28.6). In Cohort 1, 26 (65%) pts were previously untreated, and 14 (35%) pts had 1 prior line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR for Cohort 1 was 48% (95% CI 31.5–63.9; Table). Median PFS was 12.5 months (95% CI 6.3–16.4) and median OS was 28 months (95% CI 16.3–NE). No responses were seen among 7 patients in Cohort 2 with chromophobe histology (Table). Grade 3/4 treatment emergent adverse events were consistent with that reported in the phase 3 trial; Grade 3/4 AST and ALT were 9% and 15%, respectively. Cabozantinib and nivolumab were discontinued due to toxicity in 17% and 19% of pts, respectively. Conclusions: CaboNivo had an acceptable safety profile and showed promising efficacy in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies whereas activity in patients with chromophobe RCC was limited. Clinical trial information: NCT03635892. [Table: see text]

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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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Population Pharmacokinetics of Doravirine and Exposure-Response Analysis in Individuals with HIV-1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02502-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 8

Author(s):

Ka Lai Yee ◽

Aziz Ouerdani ◽

Anetta Claussen ◽

Rik de Greef ◽

Larissa Wenning

Keyword(s):

Virologic Failure ◽

Phase 1 ◽

Fixed Dose ◽

Response Analysis ◽

Population Pharmacokinetic ◽

Phase 3 ◽

Once Daily ◽

Intrinsic Factors ◽

Exposure Response ◽

Hiv 1

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1) infection. A population pharmacokinetic (PK) model was developed for doravirine using pooled data from densely sampled phase 1 trials and from sparsely sampled phase 2b and phase 3 trials evaluating doravirine administered orally as a single entity or as part of a fixed-dose combination of doravirine-lamivudine-tenofovir disoproxil fumarate. A one-compartment model with linear clearance from the central compartment adequately described the clinical PK of doravirine. While weight, age, and healthy versus HIV-1 status were identified as statistically significant covariates affecting doravirine PK, the magnitude of their effects was not clinically meaningful. Other intrinsic factors (gender, body mass index, race, ethnicity, and renal function) did not have statistically significant or clinically meaningful effects on doravirine PK. Individual exposure estimates for individuals in the phase 2b and 3 trials obtained from the final model were used for subsequent exposure-response analyses for virologic response (proportion of individuals achieving <50 copies/ml) and virologic failure. The exposure-response relationships between these efficacy endpoints and doravirine PK were generally flat over the range of exposures achieved for the 100 mg once-daily regimen in the phase 3 trials, with a minimal decrease in efficacy in individuals in the lowest 10th percentile of steady-state doravirine concentration at 24 h values. These findings support 100 mg once daily as the selected dose of doravirine, with no dose adjustment warranted for the studied intrinsic factors.

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