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Purpose: To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA). Patients and Methods: Patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent. Results: At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8–39.9) in the palbociclib group and 28.0 months (23.5–33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65–0.99). The 6-year OS rate (95% CI) was 19.1% (14.9–23.7) and 12.9% (8.0–19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified. Conclusions: The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2− ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.

Background: The PALOMA clinical trials have shown that palbociclib (PAL) plus endocrine therapy (ET) is a safe and effective treatment for HR+/HER2- ABC. However, Black and Hispanic patients are underrepresented in clinical trials and the efficacy and safety of CDK4/6 inhibitors in these populations have not been reported. This post hoc analysis describes the efficacy and safety of PAL + ET in Black and Hispanic patients with HR+/HER2- ABC enrolled in the PALOMA trials. Methods: Postmenopausal patients were treated with letrozole (LET) + PAL on a 125 mg/d, 3/1 weekly schedule or LET alone (PALOMA-1) or LET + placebo (PBO; PALOMA-2) in the 1st line setting. In PALOMA-3, pre/postmenopausal patients were treated with fulvestrant (FUL) + PAL or PBO, with or without a luteinizing hormone releasing hormone agonist, in the ≥1st-line setting. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Treatment-emergent adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for AEs. Results: In PALOMA-2, Black and Hispanic patients comprised 9.8% of the population and had a median age of 58 yrs (PAL + LET arm; n=47) and 54 yrs (PBO + LET arm; n=18). Patients treated with PAL + LET had more visceral disease (62% vs 50%), lung involvement (51% vs 22%), de novo disease (45% vs 22%) and less prior systemics (55% vs 78%) compared to patients treated with PBO + LET. In PALOMA-3, Black and Hispanic patients comprised 9.2% of the population and had a median age of 57 yrs in both the PAL + FUL (n=29) and PBO + FUL (n=19) arms, with baseline characteristics being generally similar between the two arms. PAL+ ET prolonged median PFS in PALOMA-2 and -3 and prolonged median OS in PALOMA-3 compared to PBO + ET (Table 1). In pooled analyses of these patients from PALOMA 1-3 (n=120), the most common grade 3/4 AEs with PAL + ET were neutropenia (57.7%), leukopenia (24.4%), and anemia (3.8%), similar to the rates in the pooled PALOMA 1−3 overall as-treated population (Table 2). None of these grade 3/4 AEs were reported with PBO + ET in the Black/Hispanic subgroup (Table 2). Febrile neutropenia or pulmonary embolism were not reported in either arm. The rate of dose reduction due to AEs was 37.2% with PAL + ET, similar to the rates of dose reduction across the populations in the PALOMA trials (39.4%−42.2%). Conclusion: In Black/Hispanic pts with HR+/HER2- ABC enrolled in the PALOMA-2 and -3 trials, PAL + ET, in the first or greater lines, was an efficacious treatment option with no increased toxicity rates. These findings support the continued use of PAL + ET as a standard of care in these patients. Considering the substantial burden of breast cancer in Black and Hispanic patients, their relatively small representation in the PALOMA trial program highlights the need to increase diversity in clinical trials. Clinical trial identification: Pfizer (NCT00721409, NCT01740427, NCT01942135) Table 1.Median PFS and OS in the ITT population and Black and Hispanic patients from PALOMA-2 and -3Median (95% CI), moHazard Ratioa (95% CI)PAL + ETPBO + ETPAL + ET vs PBO + ETPFSPALOMA-2ITT [n=666]27.6 (22.4-30.3)14.5 (12.3-17.1)0.56 (0.46-0.69)Black and Hispanic [n=65]27.4 (13.8-NE)13.8 (8.1-30.7)0.61 (0.31-1.2)PALOMA-3ITT [n=521]11.2 (9.5-12.9)4.6 (3.5-5.6)0.50 (0.40-0.62)Black and Hispanic [n=48]11.1 (4.5-12.0)1.9 (1.8-5.7)0.56 (0.28-1.14)OSPALOMA-3ITT [n=521]34.8 (28.8-39.9)28.0 (23.5-33.8)0.79 (0.64-0.97)Black and Hispanic [n=48]35.6 (24.0-58.2)21.0 (14.3-35.4)0.48 (0.23-0.97)ET=endocrine therapy; ITT=intent to treat; NE=not estimable; OS=overall survival; PAL=palbociclib; PBO=placebo; PFS=progression free survival.aEstimated from an unstratified Cox proportional hazards model. Table 2.Grade 3/4 treatment emergent adverse events in the overall as-treated population and Black and Hispanic subgroup pooled from the PALOMA trialsPooled PALOMAPooled Black/HispanicAE, No. (%)PAL + ET (n=872)ETa (n=471)PAL + ET (n=78)PBO + ET (n=42)Any AE662 (75.9)110 (23.4)53 (67.9)12 (28.6)Neutropenia570 (65.4)5 (1.1)45 (57.7)0Leukopenia233 (26.7)2 (0.4)19 (24.4)0Anemia40 (4.6)9 (1.9)3 (3.8%)0Thrombocytopenia17 (1.9)1 (0.2)1 (1.3%)1 (2.4)Infections45 (5.2)12 (2.5)1 (1.3%)1 (2.4)AE=adverse event; ET=endocrine therapy; PAL=palbociclib; PBO=placebo.aEndocrine therapy with placebo (PALOMA-2 and 3) and without placebo (PALOMA-1). Citation Format: Claudine Isaacs, Reshma Mahtani, Filipa Lynce, Bethany Sleckman, Aurelio Castrellon, Sujith Kalmadi, Kathy Puyana Theall, Xin Huang, Eustratios Bananis, Hope S. Rugo. Efficacy and safety of palbociclib plus endocrine therapy in Black and Hispanic patients with hormone receptor positive/human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC) participating in the PALOMA trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-13.

Supplementary Data from Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2− ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study

Purpose:To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA).Patients and Methods:Patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent.Results:At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8–39.9) in the palbociclib group and 28.0 months (23.5–33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65–0.99). The 6-year OS rate (95% CI) was 19.1% (14.9–23.7) and 12.9% (8.0–19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified.Conclusions:The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2− ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.

Objective In the PALOMA-2 trial, palbociclib in combination with letrozole prolonged progression-free survival (PFS) and exhibited an acceptable safety profile in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). This post hoc analysis of PALOMA-2 evaluated the efficacy and safety of palbociclib plus letrozole in patients with preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Methods Postmenopausal patients without prior treatment for ABC were randomized 2:1 to receive palbociclib (125 mg/d on a 3 weeks on/1 week off schedule) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. Patients were grouped by the following MedDRA SOC preexisting conditions: gastrointestinal, musculoskeletal, metabolic, and vascular/cardiac. Median PFS was estimated by the Kaplan-Meier method, and treatment emergent adverse events (AEs) were compared between treatment arms within each preexisting condition subgroup. Results At baseline, 276 (41.4 %) patients had preexisting gastrointestinal disorders, 390 (58.6 %) had musculoskeletal disorders, 259 (38.9 %) had metabolic disorders, and 382 (57.4 %) had vascular/cardiac disorders. Baseline characteristics were similar between subgroups and between each arm within subgroups. Regardless of baseline preexisting condition, palbociclib plus letrozole prolonged PFS compared with placebo plus letrozole. Treatment-emergent AEs associated with palbociclib plus letrozole and dose modifications due to AEs were similar across preexisting condition subgroups. Conclusion This post hoc analysis of PALOMA-2 demonstrated a favorable effect of palbociclib on PFS and a safety profile consistent with previous observations, regardless of underlying preexisting condition. Pfizer Inc (NCT01740427)., Highlights • Preexisting conditions can affect the safety and efficacy of breast cancer therapies. • This is a post hoc analysis of patients with preexisting conditions from PALOMA-2. • Palbociclib prolonged median PFS, regardless of preexisting condition. • Within each treatment arm, AEs were similar regardless of preexisting condition.

Background Previous studies demonstrated the tolerability of palbociclib plus endocrine therapy (ET). This analysis evaluated safety based on more recent cutoff dates and a longer palbociclib treatment exposure. Patients and Methods Data were pooled from three randomized studies of patients with hormone receptor‐positive/human epidermal growth factor receptor 2‐negative (HR+/HER2−) advanced breast cancer (ABC), including postmenopausal women who had not received prior systemic treatment for advanced disease (PALOMA‐1/‐2) and pre‐ and postmenopausal women who had progressed on prior ET (PALOMA‐3). Results Updated cutoff dates were December 21, 2017 (PALOMA‐1), May 31, 2017 (PALOMA‐2), and April 13, 2018 (PALOMA‐3). Total person‐years of treatment exposure were 1,421.6 with palbociclib plus ET (n = 872) and 528.4 with ET (n = 471). Any‐grade neutropenia and infections were more frequent with palbociclib plus ET (82.1% and 59.2%, respectively) than with ET (5.1% and 39.5%). The hazard ratios were 1.6 (p = .0995) for grade 3/4 infections, 1.8 (p = .4358) for grade 3/4 viral infections, 1.4 (p = .0001) for infections, and 30.8 (p < .0001) for neutropenia. Febrile neutropenia was reported in 1.4% of patients receiving palbociclib plus ET. Cumulative incidence of all‐grade hematologic adverse events in both arms peaked during the first year of treatment and plateaued over the 5 subsequent years. Interstitial lung disease was reported in 13 patients receiving palbociclib plus ET and 3 receiving ET. Conclusion This 5‐year, long‐term analysis demonstrated that palbociclib plus ET has a consistent and stable safety profile and is a safe treatment for patients with HR+/HER2− ABC. Implications for Practice Several treatments for patients with breast cancer are associated with long‐term or latent adverse events. This long‐term, 5‐year analysis demonstrated that palbociclib plus endocrine therapy has a consistent and stable safety profile without cumulative or delayed toxicities. These results further support palbociclib plus endocrine therapy as a safe and manageable treatment in clinical practice for patients with hormone receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer., This updated analysis based on data pooled from the three PALOMA studies is the largest long‐term analysis, to date, of the safety of a CDK4/6 inhibitor in combination with endocrine therapy for the treatment of advanced breast cancer.

Background: In the PALOMA-2 trial, PAL + letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + LET in pts with ER+/HER2– ABC. This post hoc analysis assessed efficacy and safety of PAL + LET in pts from PALOMA-2 with baseline preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Methods: Postmenopausal pts with ER+/HER2– ABC received PAL (125 mg/d, 3/1 schedule) + LET (2.5 mg/d, continuous) or PBO + LET. Pts were grouped by the following MedDRA SOC preexisting conditions: Gastrointestinal, Musculoskeletal, Metabolism, and Vascular/Cardiac. Baseline characteristics, PFS, and safety were assessed. Results: At baseline, 41.4% of pts had preexisting gastrointestinal disorders, 58.6% musculoskeletal disorders, 38.9% metabolism disorders, and 57.4% vascular/cardiac disorders. Baseline characteristics were similar between treatment arms within each subgroup and also between subgroups. Within each subgroup, ≥40% of pts also had ≥1 of the other coexisting conditions. Median PFS (mPFS) was significantly longer with PAL + LET vs PBO + LET regardless of preexisting condition (Table). In general, adverse events (AEs) were more frequent with PAL + LET in all subgroups; neutropenia was most common. Within each treatment arm, AEs and dose modifications due to AEs were similar regardless of preexisting condition. Conclusion: PAL + LET showed prolonged PFS and a consistent safety profile regardless of baseline preexisting condition in pts with ER+/HER2– ABC. Clinical trial identification: Pfizer Inc (NCT01740427) TablePreexisting ConditionPAL + LETPBO + LETPAL + LET vs PBO + LETnmPFS (95% CI)nmPFS (95% CI)HR (95% CI)P ValueGastrointestinal17627.6 (17.5–33.1)10013.6 (11.0–18.5)0.57 (0.42–0.78) Citation Format: Karen Gelmon, Janice M Walshe, Reshma Mahtani, Anil A Joy, Meghan Karuturi, Patrick Neven, Dongrui Ray Lu, Sindy Kim, Patrick Schnell, Eustratios Bananis, Lee Schwartzberg. Efficacy and safety of palbociclib (PAL) in patients (pts) with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with preexisting conditions: A post hoc analysis of PALOMA-2 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-14.

PurposePalbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, approved in combination with endocrine therapy for the treatment of women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). In the phase 2, open-label, PALOMA-1 trial, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) versus letrozole alone (hazard ratio, 0.488; 95% CI 0.319‒0.748;P = 0.0004; median PFS, 20.2 vs 10.2 months, respectively) in postmenopausal women with estrogen receptor–positive (ER+)/HER2− ABC. Here, we present the final overall survival (OS) and updated safety results.MethodsPostmenopausal women with ER+/HER2− ABC were randomized 1:1 to receive either palbociclib (125 mg/day, 3/1 schedule) plus letrozole (2.5 mg/day, continuous) or letrozole alone (2.5 mg/day, continuous). The primary endpoint was investigator-assessed PFS; secondary endpoints included OS and safety.ResultsA total of 165 patients were randomized. At the data cutoff date of December 30, 2016 (median duration of follow-up, 64.7 months), the stratified hazard ratio for OS was 0.897 (95% CI 0.623–1.294;P = 0.281); median OS in the palbociclib plus letrozole and letrozole alone arms was 37.5 and 34.5 months, respectively. The median time from randomization to first subsequent chemotherapy use was longer with palbociclib plus letrozole than letrozole alone (26.7 and 17.7 months, respectively). The most frequently reported adverse event in the palbociclib plus letrozole arm was neutropenia (any grade, 75%; grade 3 or 4, 59%).ConclusionsPalbociclib plus letrozole treatment led to a numerical but not statistically significant improvement in median OS.Pfizer Inc (NCT00721409)

Background In PALOMA-2, palbociclib + letrozole significantly prolonged progression-free survival (PFS) versus placebo + letrozole in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2−) advanced breast cancer (ABC). We investigated clinical outcomes of patients who achieved or did not achieve a confirmed objective response (OR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (data cutoff: May 31, 2017). Patients and Methods Postmenopausal patients untreated for ER+/HER2− ABC were randomized 2:1 to palbociclib + letrozole or placebo + letrozole. Median PFS, median duration of OR, baseline characteristics, and palbociclib exposure were compared in patients with or without OR by treatment arm. Results In the intent-to-treat population, OR was achieved by 194 (44%) of 444 and 77 (35%) of 222 patients in the palbociclib and placebo arms, respectively (odds ratio, 1.5; 95% confidence interval [CI], 1.0-2.1; P = .0156). Regardless of treatment, more OR than non-OR patients had de novo metastatic disease (47%-50% and 28%-31%, respectively) and no prior endocrine therapy (55% and 35%-37%, respectively). Rates of palbociclib dose reduction owing to adverse events were similar regardless of OR (41% and 38%, respectively). Among the patients with OR during the study, approximately 50% achieved OR within the first 3 months regardless of treatment. The median PFS was significantly prolonged with palbociclib + letrozole versus placebo + letrozole in patients with measurable disease in both OR (37.2 months; 95% CI, 28.1 months to not estimable vs. 27.4 months; 95% CI, 22.2-31.1 months; hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .009) and non-OR groups (10.9 months; 95% CI, 8.2-11.2 months vs. 5.6 months; 95% CI, 5.3-8.3 months; hazard ratio, 0.72; 95% CI, 0.54-0.97; P = .016). Conclusions Palbociclib + letrozole provided significant clinical benefit versus placebo + letrozole to patients with ER+/HER2− ABC regardless of achieving RECIST-defined OR. Pfizer; ClinicalTrials.gov : NCT01740427

Background Palbociclib (PAL) in combination with endocrine therapy (ET) was shown to be tolerable in a previous pooled analysis of the 3 PALOMA clinical trials. This new pooled, post hoc analysis examines the safety profile of PAL + ET using data from more recent data cutoff dates with longer drug exposure. Methods Data were pooled from 3 randomized phase 2 and 3 studies of patients with hormone receptor-positive/human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2- ABC). Postmenopausal first-line patients were randomized to receive letrozole (2.5 mg/d, continuously) +/- PAL (125 mg/d, 3/1 schedule) in PALOMA-1 or letrozole (2.5 mg/d, continuously) + PAL (125 mg/d, 3/1 schedule)/placebo in PALOMA-2. In PALOMA-3, pre/peri- and postmenopausal patients with prior endocrine resistance received intramuscular fulvestrant (500 mg every 14 days for the first 3 injections, then every 28 days) + PAL (125 mg/d, 3/1 schedule)/placebo. The cumulative rates of adverse events (AEs) were assessed over time. Results Updated data cutoff dates used for this analysis were December 21, 2017 (PALOMA-1), May 31, 2017 (PALOMA-2), and April 13, 2018 (PALOMA-3). The total number of person-years of exposure was 1950 (1422 PAL + ET, 528 ET). In the ET arm (n=471), 20.2% of patients were treated for ≥24 months and 10.2% were treated for ≥36 months. In the PAL + ET arm (n=872), 36% of patients were treated for ≥24 months and 22.4% for ≥36 months. The majority of patients treated for ≥24 and ≥36 months in the PAL + ET arm were from PALOMA-2. As expected, neutropenia and infections (any grade) were more frequent with PAL + ET (82.1% and 59.2%, respectively) than in the ET arm (5.1% and 39.5%). Febrile neutropenia was reported in 1.4% of patients in the PAL + ET arm. The incidence of hematologic AEs in the PAL + ET arm peaked during the first year of treatment and then plateaued over the subsequent 5 years. Serious AEs were reported in 22.8% of patients in the PAL + ET arm and 15.5% in the ET arm. Selected cumulative grade 3/4 event rates through 5 years were neutropenia (68.3% in PAL + ET; 0.8% in ET), leukopenia (29.9%; 0.2%), infections (6.4%; 2.8%), anemia (5.3%; 2.1%), fatigue (2.9%; 1.3%), alanine aminotransferase increased (2.2%; 0.2%), aspartate aminotransferase increased (2.9%; 1.3%), diarrhea (1%; 1.1%), nausea (0.6%; 1.3%), vomiting (0.7%; 1.1%), and QTc prolongation (0.3%; 0.2%). After adjusting for treatment exposure, incidence rates of venous thromboembolism and pulmonary embolism were 0.0225 (PAL + ET) and 0.0246 (ET) per person-year and 0.0127 (PAL + ET) and 0.0132 (ET) per person-year, respectively. Conclusion This 5-year, long-term safety analysis of PAL + ET showed a consistent profile with no new safety signals, and no cumulative/delayed toxicities. PAL + ET remains a safe and manageable treatment for patients with HR+/HER2- ABC. Pfizer (NCT00721409, NCT01740427, NCT01942135) Citation Format: Richard S Finn, Hope S Rugo, Karen Gelmon, Massimo Cristofanilli, Marco Colleoni, Sherene Loi, Patrick Schnell, Dongrui R Lu, Kathy P Theall, Ave Mori, Eric Gauthier, Eustratios Bananis, Nicholas C Turner, Véronique Diéras. Long-term pooled safety analysis of palbociclib in combination with endocrine therapy for hormone receptor-positive/human epidermal growth factor receptor 2–negative advanced breast cancer: An updated analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-16.

Background This analysis investigated whether baseline characteristics affect the survival benefit derived from palbociclib‐fulvestrant and the optimal timing of cyclin‐dependent kinase 4/6 inhibitor therapy for advanced breast cancer (ABC) in patients from PALOMA‐3. Patients and Methods In total, 521 patients were randomized 2:1 to receive palbociclib (125 mg/day, 3/1 schedule)–fulvestrant (500 mg, intramuscular injection, on days 1 and 15 of cycle 1, and then day 1 of each subsequent cycle) or matching placebo‐fulvestrant. Median overall survival (OS) and progression‐free survival were estimated using the Kaplan‐Meier method. Results Multivariable analysis identified endocrine sensitivity, nonvisceral disease, no prior chemotherapy for ABC, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 as significant prognostic factors for OS. Patients without chemotherapy for ABC had fewer prior lines of treatment in any setting and in the ABC setting versus patients with prior chemotherapy for ABC (two or fewer prior systemic therapies: 69% vs. 42%; no more than one prior line for ABC: 82% vs. 33%, respectively). Median OS was prolonged with palbociclib‐fulvestrant in patients without prior chemotherapy for ABC (39.7 vs. 29.5 months; hazard ratio, 0.75; 95% confidence interval [CI]: 0.56–1.01) and was similar in patients with prior chemotherapy for ABC (25.6 vs. 26.2 months; hazard ratio, 0.91 [95% CI: 0.63–1.32]) versus placebo‐fulvestrant. Conclusion Prognostic factors for OS included endocrine sensitivity, nonvisceral disease, ECOG PS of 0, and no prior chemotherapy for ABC. Exploratory analyses suggest improved OS with palbociclib‐fulvestrant versus placebo‐fulvestrant in patients with no prior chemotherapy for ABC, prior endocrine sensitivity, and fewer prior regimens of systemic therapy. (Clinical trial identification number: NCT01942135). Implications for Practice Prognostic factors for overall survival in HR+/HER2− advanced breast cancer (ABC) include the absence of prior chemotherapy in the advanced setting, endocrine sensitivity, nonvisceral disease, and an ECOG performance status of 0. Improved overall survival benefit was observed with palbociclib‐fulvestrant versus placebo‐fulvestrant in patients (regardless of menopausal status or visceral involvement) with no prior chemotherapy for ABC, with prior endocrine sensitivity, and fewer prior regimens of systemic therapy. Progression‐free survival was prolonged with palbociclib across subgroups (regardless of chemotherapy exposure in ABC). These exploratory findings suggest that patients may receive greater clinical benefit from palbociclib‐fulvestrant if they receive the combination before chemotherapy in the advanced setting., This article focuses on whether baseline characteristics affect the survival benefit derived from palbociclib‐fulvestrant and the optimal timing of cyclin‐dependent kinase 4/6 inhibitor therapy for advanced breast cancer in patients from the PALOMA‐3 clinical trial.

Aim: Palbociclib (PAL), ribociclib (RIB) and abemaciclib (ABM), in combination with fulvestrant (FUL), are approved for the treatment of hormone receptor-positive, HER2-negative advanced breast cancer. This study aims to determine relative efficacy of PAL+FUL versus RIB+FUL and ABM+FUL using matching-adjusted indirect treatment comparisons. Patients & methods: Anchored matching-adjusted indirect treatment comparisons were conducted using individual patient data from PALOMA-3 and published summary-level data from MONARCH 2 and MONALEESA-3. The primary outcome was overall survival (OS). Results: OS was similar for PAL+FUL versus ABM+FUL (hazard ratio: 0.87; 95% CI: 0.54–1.40) and RIB+FUL (hazard ratio: 0.89; 95% CI: 0.48–1.63). Conclusion: Adjusting for cross-trial differences suggests similar OS between treatments, underscoring the importance of accounting for these differences when indirectly comparing treatments.

LBA1003 Background: PAL was the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for ER+/HER2– ABC based on the randomized, phase 2 PALOMA-1 study. PALOMA-2 is a randomized, double-blind, phase 3 trial in first-line ER+/HER2– ABC that confirmed a clinically and statistically significant improvement in progression-free survival (PFS) with PAL+LET versus PBO+LET (median PFS, 27.6 vs 14.5 months; hazard ratio, 0.56 [95% CI, 0.46–0.69]; P12 months, median OS (95% CI) was 66.3 months (52.1–79.7) in the PAL+LET arm (n=179) and 47.4 months (37.7–57.0) in the PBO+LET arm (n=93); hazard ratio, 0.728 (95% CI, 0.528-1.005). No new safety findings were observed. Conclusions: PALOMA-2 met its primary endpoint of improving PFS but not the secondary endpoint of OS. Pts receiving PAL+LET had numerically longer OS compared to PBO+LET, but the results were not statistically significant. Funding: Pfizer Inc (NCT01740427) Clinical trial information: NCT01740427.

Objective This post-hoc, pooled analysis of Phase 3 studies of tofacitinib examined the safety of tofacitinib 5 and 10 mg twice daily (BID) when used as monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA). Methods Pooled data from six double-blind, randomized controlled Phase 3 studies of tofacitinib 5 and 10 mg BID in patients with RA were analyzed for safety and stratified by administration as monotherapy (ORAL Solo: NCT00814307 and ORAL Start: NCT01039688) or in combination with csDMARDs (ORAL Sync: NCT00856544, ORAL Standard: NCT00853385, ORAL Scan: NCT00847613, and ORAL Step: NCT00960440), and by glucocorticoid use at baseline. Safety assessments included incidence rates (IRs) for serious adverse events (SAEs), discontinuations due to AEs, serious infection events, and herpes zoster (HZ), and were evaluated throughout the duration of the Phase 3 studies. Results In total, 3881 patients were included in the safety analysis (monotherapy studies: n = 1380; combination therapy studies: n = 2501). IRs for selected AEs of interest were generally numerically lower in patients who received tofacitinib 5 and 10 mg BID as monotherapy than as combination therapy (SAEs: IR [range] 6.21–6.72 versus IR 10.17–13.46; discontinuations due to AEs: IR 5.53–6.18 versus IR 10.80–11.01; serious infections: IR 1.57–1.66 versus IR 3.39–3.56; HZ: IR 1.95–2.93 versus IR 4.37–4.99, respectively), irrespective of tofacitinib dose or glucocorticoid use. There were too few patients and events within the placebo group to fully evaluate effect between combination therapy and monotherapy. Conclusions Safety profiles were generally similar between patients receiving monotherapy and combination therapy; however, selected safety events of interest, including HZ and serious infections, showed lower IRs with non-overlapping 95% confidence intervals for tofacitinib all monotherapy versus combination therapy. Tofacitinib monotherapy may, therefore, have fewer safety events compared with combination therapy, and have a favorable risk-benefit profile in patients with active RA who are intolerant to csDMARDs.

BACKGROUND: Previous findings from the PALOMA-2 study (N=666) demonstrated the efficacy and safety of PAL+LET as first-line ABC therapy versus placebo (PBO)+LET (Finn et al, NEJM. 2016). This analysis evaluated the efficacy and safety of PAL+LET by geographic region (North America [NA], Europe [EU], and Asia Pacific [AP]; data cutoff: Feb 26, 2016). METHODS: Women with ER+/HER2– ABC who had not received prior systemic treatment in the advanced setting were randomized 2:1 to PAL (125 mg/d oral [3 wks on, 1 wk off])+LET (2.5 mg once daily) or PBO+LET. RESULTS: This analysis included 267 patients from NA, 307 from EU, and 92 from AP. At baseline, demographics and disease characteristics generally were similar between regions. In the overall population (Table 1), PAL+LET demonstrated improvements versus PBO+LET in progression-free survival (PFS), objective response rate (ORR), and clinical benefit response rate (CBR). Similarly, PFS was longer and ORR and CBR were higher with PAL+LET versus PBO+LET in NA, EU, and AP subgroups (Table 1). All-grade treatment-emergent adverse events (AEs) (PAL+LET/PBO+LET) occurred in 99%/99% of patients in NA, 98%/92% in EU, and 100%/96% in AP. In the PAL+LET arm, neutropenia (all-grade/grade ≥3) was the most common AE in all regions. The incidence of neutropenia was numerically higher in AP (91%/84%) compared with NA (73%/65%) and EU (81%/62%). Grade 3 or 4 febrile neutropenia occurred in 4 (2%) NA patients, 4 (2%) EU patients, and no AP patients in the PAL+LET arm and in no patients in any of the regions in the PBO+LET arm. CONCLUSIONS: PAL+LET showed improvement versus PBO+LET in PFS, ORR, and CBR in patients with ER+/HER2- ABC in NA, EU, and AP, with comparable magnitude of benefit between regions. With PAL+LET, neutropenia was the most commonly reported AE in all regions, with a numerically higher incidence reported in AP versus NA or EU; the safety profile was similar to previously reported results in the overall population. Funding: Pfizer (NCT01740427) section, copy and paste the following tag, including brackets, where you would like your table to appear Table 1. PFS, ORR, and CBR Median PFSPFS HRORR,* %CBR,* % (95% CI), mo(95% CI)(95% CI)(95% CI)Overall Population PAL+LET24.8 (22.1-NE)0.58 (0.46-0.72); P . Citation Format: Gelmon KA, Castrellon A, Joy AA, Walshe JM, Ettl J, Mukai H, Park IH, Lu DR, Mori A, Bananis E, Diéras V, Finn RS. Efficacy and safety of palbociclib (PAL) + letrozole (LET) as first-line therapy in estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): Findings by geographic region from PALOMA-2 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-25.

Objective.Tofacitinib has been investigated for the treatment of rheumatoid arthritis (RA) in phase III studies in which concomitant glucocorticoids (GC) were allowed. We analyzed the effect of GC use on efficacy outcomes in patients with RA receiving tofacitinib and/or methotrexate (MTX) or conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in these studies.Methods.Our posthoc analysis included data from 6 phase III studies (NCT01039688; NCT00814307; NCT00847613; NCT00853385; NCT00856544; NCT00960440). MTX-naive patients or patients with inadequate response to csDMARD or biological DMARD received tofacitinib 5 or 10 mg twice daily alone or with csDMARD, with or without concomitant GC. Patients receiving GC (≤ 10 mg/day prednisone or equivalent) before enrollment maintained a stable dose throughout. Endpoints included the American College of Rheumatology (ACR) 20/50/70 response rates, rates of Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA; CDAI ≤ 10) and remission (CDAI ≤ 2.8), and changes from baseline in CDAI, 28-joint count Disease Activity Score (DAS28-4)–erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire–Disability Index (HAQ-DI), pain visual analog scale (VAS), and modified total Sharp score.Results.Of 3200 tofacitinib-treated patients, 1258 (39.3%) received tofacitinib monotherapy and 1942 (60.7%) received tofacitinib plus csDMARD; 1767 (55.2%) received concomitant GC. ACR20/50/70 response rates, rates of CDAI LDA and remission, and improvements in CDAI, DAS28-4-ESR, HAQ-DI, and pain VAS with tofacitinib were generally similar with or without GC in monotherapy and combination therapy studies. GC use did not appear to affect radiographic progression in tofacitinib-treated MTX-naive patients. MTX plus GC appeared to inhibit radiographic progression to a numerically greater degree than MTX alone.Conclusion.Concomitant use of GC with tofacitinib did not appear to affect clinical or radiographic efficacy. MTX plus GC showed a trend to inhibit radiographic progression to a greater degree than MTX alone.

Objective Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster (HZ), and the risk appears to be increased in patients treated with tofacitinib. The aim of this study was to evaluate whether concomitant treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with tofacitinib. Methods HZ cases were identified from the databases of 2 phase I, 9 phase II, 6 phase III, and 2 long-term extension studies of tofacitinib in RA patients. Crude incidence rates (IRs) of all HZ events (serious and nonserious) per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated for unique patients. Within phase III studies, we described HZ rates according to concomitant csDMARD treatment and baseline GC use. A multivariable Cox proportional hazards regression model was used to evaluate HZ risk factors across studies. Results Across all studies (6,192 patients; 16,839 patient-years), HZ was reported in 636 tofacitinib-treated patients (IR 4.0, 95% CI 3.7–4.4). In most cases (93%), HZ was classified as nonserious, and the majority of patients (94%) had involvement of only 1 dermatome. HZ IRs varied across regions, from 2.4 (95% CI 2.0–2.9) in Eastern Europe to 8.0 (95% CI 6.6–9.6) in Japan and 8.4 (95% CI 6.4–10.9) in Korea. Within phase III studies, HZ IRs varied according to tofacitinib dose, background csDMARD treatment, and baseline use of GCs. The IRs were numerically lowest for monotherapy with tofacitinib 5 mg twice daily without GCs (IR 0.56 [95% CI 0.07–2.01]) and highest for tofacitinib 10 mg twice daily with csDMARDs and GCs (IR 5.44 [95% CI 3.72–7.68]). Age, GC use, tofacitinib dose, and enrollment within Asia were independent risk factors for HZ. Conclusion Patients receiving treatment with tofacitinib and GCs appear to have a greater risk of developing HZ compared with patients receiving tofacitinib monotherapy without GCs.

Additional file 1 : Table S1. Summary of the PALOMA Clinical Trial Data. Table S2. Schedule of Per Protocol Palbociclib Dose Reductions and Modifications. Table S3. Time Points for Assessing Frequency of AEs Both Before and After Palbociclib Dose Reductions. Table S4. Incidence of Hematologic Adverse Events Before/After Palbociclib Dose Reduction From 125 to 100 mg: Asian/non-Asian. Table S5. Incidence of Hematologic Adverse Events Before/After Palbociclib Dose Reduction From 125 to 100 mg: BMI. Table S6. Incidence of Hematologic Adverse Events Before/After Palbociclib Dose Reduction From 125 to 100 mg: Age. Figure S1. Study Design of PALOMA-1, PALOMA-2, and PALOMA-3.

Palbociclib is a cyclin‐dependent kinase 4/6 inhibitor indicated for treatment of hormone receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer in combination with endocrine therapy. We investigated the efficacy and safety of palbociclib in patients enrolled in North America during two‐phase 3 trials: PALOMA‐2 (n = 267, data cutoff: May 31, 2017) and PALOMA‐3 (n = 240, data cutoffs: April 13, 2018, for overall survival, October 23, 2015, for all other outcomes). In PALOMA‐2, treatment‐naïve postmenopausal patients with advanced breast cancer were randomized 2:1 to palbociclib (125 mg/d; 3 weeks on/1 week off [3/1]) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. In PALOMA‐3, patients who progressed on prior endocrine therapy were randomized 2:1 to palbociclib (125 mg/d; 3/1) plus fulvestrant (500 mg, per standard of care) or placebo plus fulvestrant; pre/perimenopausal patients received ovarian suppression with goserelin. Palbociclib plus endocrine therapy prolonged median progression‐free survival vs placebo plus endocrine therapy in North American patients (PALOMA‐2: 25.4 vs 13.7 months, hazard ratio, 0.54 [95% CI, 0.40–0.74], P

1000 Background: In PALOMA-3, a randomized, double-blind, placebo-controlled, phase 3 study, PAL+FUL significantly prolonged progression-free survival (PFS) compared with placebo (PBO) + FUL (1-sided P6 years of median follow-up in pts with HR+/HER2– ABC who had progressed on prior endocrine treatment. Pfizer (NCT01942135) Clinical trial information: NCT01942135 .[Table: see text]

Despite the demonstrated efficacy of etanercept for the treatment of ankylosing spondylitis (AS), sulfasalazine is often prescribed, especially in countries with limited access to biologic agents. The objective of this subset analysis of the ASCEND trial was to compare the efficacy of etanercept and sulfasalazine in treating patients with AS from Asia, Eastern/Central Europe, and Latin America. A total of 287 patients, 190 receiving etanercept 50 mg once weekly and 97 receiving sulfasalazine 3 g daily, from eight countries were included in this subset analysis. Differences in disease activity and patient-reported outcomes assessing health-related quality-of-life (HRQoL) parameters in response to treatment were analyzed using the Cochran-Mantel-Haenszel test for categorical efficacy endpoints and analysis of covariance model for continuous variables. At week 16, a significantly greater proportion of patients receiving etanercept achieved ASAS20 (79.0 %) compared with patients receiving sulfasalazine (61.9 %; p = 0.002). At week 16, treatment with etanercept also resulted in significantly better responses than sulfasalazine for ASAS40 (64.7 vs. 35.1 %; p < 0.001), ASAS5/6 (48.1 vs. 26.3 %; p < 0.001), proportion of patients achieving 50 % response in Bath AS Disease Activity Index (65.8 vs. 42.3 %; p < 0.001), partial remission (35.3 vs. 17.5 %; p = 0.002), and all HRQoL parameters. Both treatments were well tolerated. Etanercept was significantly more effective than sulfasalazine in the treatment of patients with AS from Asia, Central/Eastern Europe, and Latin America.

In the PALOMA-3 trial, the median progression-free survival (PFS) was longer among patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) treated with palbociclib plus fulvestrant than those treated with placebo plus fulvestrant. This subgroup analysis examined the efficacy and safety of palbociclib among Korean patients enrolled in PALOMA-3 (n = 43 [palbociclib group, n = 24; placebo group, n = 19]). In both groups, > 40% of patients were pre/perimenopausal at enrollment. The median PFS was significantly prolonged with palbociclib vs. placebo (12.3 [95% confidence interval (CI), 9.1–not estimable] vs. 5.4 months [95% CI, 1.9–9.2]; hazard ratio, 0.40 [95% CI, 0.19–0.83]; one-sided p = 0.005), and the confirmed objective response was 21.1% and 11.8%, respectively (odds ratio, 2.0 [95% CI, 0.24–24.8]). Neutropenia was the most common adverse event associated with palbociclib. Overall, palbociclib plus fulvestrant was effective and generally safe among Korean patients with HR+/HER2− ABC, regardless of menopausal status.

Introduction Here we examine the relationship between achieving different levels of disease activity with tofacitinib (an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis), long-term structural progression, and patient-reported physical function. Methods This was a post hoc analysis of two 24-month, phase III randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder (IR) patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily as either monotherapy or with background MTX. The modified total Sharp score (mTSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were analyzed at month 24 according to disease activity at month 6 defined by the Clinical Disease Activity Index (CDAI) or the Disease Activity Score in 28 joints, C-reactive protein (DAS28CRP). Results Mean changes from baseline in mTSS at month 24 were less in patients with CDAI remission at month 6 than in those with CDAI moderate/high disease activity (MDA/HDA) at month 6. A DAS28CRP of

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We evaluated the relationship between disease activity, according to Routine Assessment of Patient Index Data 3 (RAPID3) after 6-month treatment with tofacitinib, and long-term outcomes at 24 months. This was a post hoc analysis of two 24-month, phase 3, randomized controlled trials in methotrexate (MTX)-naive (ORAL Start [NCT01039688]) or MTX-inadequate responder patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily (BID) as monotherapy or with background MTX. RAPID3 scores were calculated at baseline, month (M)6, and M24, and defined as remission (≤ 3), low (LDA; > 3–≤ 6), moderate (MDA; > 6–≤ 12), or high disease activity (HDA; > 12). Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and radiographic non-progression (modified Total Sharp Scores ≤ 0) at M24 were evaluated by M6 RAPID3 response. Among patients receiving tofacitinib 5 or 10 mg BID, respectively, 42.2 and 51.5% (ORAL Start) and 29.8 and 39.0% (ORAL Scan) achieved RAPID3 remission/LDA at M6. Most patients maintained/improved RAPID3 responses at M24. A higher proportion of patients in RAPID3 remission/LDA versus MDA/HDA at M6 achieved CDAI remission, reported normative HAQ-DI scores (

Objectives Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR). Methods Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed. Results 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs). Conclusions Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations. Trial registration numbers (NCT00413660, NCT0050446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385).

Objective.Investigate the role and relation of disease duration of different factors for achieving clinical remission with anti-tumor necrosis factor (TNF) treatment in patients with active ankylosing spondylitis (AS).Methods.Data pooled from 4 large (n = 1281) clinical trials were used to compare disease duration subgroups for placebo or sulfasalazine (SSZ) versus etanercept (ETN), which, in turn, were analyzed by age of diagnosis ≤ 40 versus > 40 years, HLA-B27 status, and baseline C-reactive protein (CRP) ≤ upper limit of normal (ULN) versus > ULN using chi-square tests, and ANCOVA. The primary efficacy measure was Assessments of SpondyloArthritis international Society (ASAS) partial remission (PR) after 12 weeks of treatment. Also analyzed were Bath AS Disease Activity Index and Functional Index, AS Disease Activity Scores, and ASAS response rates.Results.Overall, a larger percentage of patients achieved ASAS-PR with ETN versus SSZ or placebo. More patients with ≤ 2-year disease duration treated with ETN experienced partial remission (34%) versus longer disease duration (30%, 27%, and 22% for > 2–5, > 5–10, and > 10 yrs, respectively; all p < 0.05). In the subgroup of patients with both disease duration ≤ 2 years and aged ≤ 40 years at diagnosis, the treatment response was even more pronounced. Similar results were seen in HLA-B27–positive patients in the disease duration ≤ 2-year subgroup. Overall, patients with high CRP at baseline had better treatment responses compared with patients with normal CRP.Conclusion.Treatment response under anti-TNF treatment with ETN at 12 weeks was greatest among patients with disease duration ≤ 2 years and even more pronounced in subgroups of patients ≤ 40 years old or HLA-B27–positive at diagnosis.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the effect of concomitant methotrexate (MTX) or glucocorticoid (GC) use on tofacitinib clinical efficacy. Data were pooled from two open-label, long-term extension studies of tofacitinib 5 or 10 mg twice daily in patients with RA. Response according to Clinical Disease Activity Index (CDAI) was assessed separately in patients who discontinued (no MTX/GC use within 30 days prior to year-3 visit; assessment at month 3/year 3) or initiated (on/before year 3; assessment at initiation and year 3) MTX/GC. By year 3, among patients receiving background MTX at baseline, 186/1608 (11.6%) discontinued MTX, and 319/1434 (22.2%) patients receiving GC at baseline discontinued GC. Overall, 70.4/69.1% of patients who discontinued/continued MTX and 72.7/65.9% who discontinued/continued GC achieved CDAI remission or low disease activity (LDA) at year 3. Month 3 remission/LDA rates were maintained at year 3 in the majority of patients, irrespective of MTX/GC discontinuation/continuation. By year 3, 6.2% of patients receiving tofacitinib without MTX at baseline had initiated concomitant MTX, and 25.1% receiving tofacitinib without GC initiated GC; 69.0% and 45.4% initiating MTX or GC, respectively, had a CDAI-defined incomplete response prior to initiation. RA signs/symptoms improved following MTX initiation; only modest improvement was observed with GC initiation. Patients achieving remission/LDA with tofacitinib may discontinue MTX or GC and maintain treatment response. Patients with an incomplete response may benefit from adding concomitant MTX. Pfizer Inc. Study A3921024 [NCT00413699] and Study A3921041 [NCT00661661].

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. ORAL Solo (NCT00814307) and ORAL Sync (NCT00856544) were two Phase 3 index studies that demonstrated the efficacy of tofacitinib in adult patients (pts) with RA who were DMARD inadequate responders (DMARD-IR). Early onset of effect is a clinically meaningful endpoint. Objectives This post hoc analysis examined the magnitude and durability of early response to tofacitinib in ORAL Solo and ORAL Sync. Methods ORAL Solo and ORAL Sync were double-blind, placebo (PBO)-controlled, parallel-group studies in pts with active RA and an inadequate response to ≥1 conventional synthetic (cs) or biologic (b) DMARDs. Pts were randomised to tofacitinib 5 mg BID, tofacitinib 10 mg BID, PBO advanced to tofacitinib 5 mg BID, or PBO advanced to tofacitinib 10 mg BID, either as monotherapy in ORAL Solo or with background csDMARDs in ORAL Sync. In ORAL Solo, pts randomised to PBO were advanced to tofacitinib at Month (M) 3; in ORAL Sync, pts randomised to PBO were advanced to tofacitinib at M3 (non-responders) or M6 (all other pts). In this post hoc analysis, the following clinical efficacy data for pts on tofacitinib or PBO (prior to advancement to tofacitinib) ± csDMARDs, were evaluated at Week 2, M3 and M6 (ORAL Sync only; no M6 PBO comparison in ORAL Solo): change from baseline (CFB) in Clinical Disease Activity Index (CDAI) >12,1 HAQ-DI CFB ≥0.22, CDAI ≥50% improvement from baseline, CDAI ≥70% improvement from baseline, CDAI ≥85% improvement from baseline, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score improvement from baseline ≥4, Pain visual analogue scale (VAS) score CFB ≥10. This analysis was post hoc and multiplicity adjustment was done. Results Clinical efficacy endpoint data are summarised in the Table. At Week 2, more patients receiving tofacitinib 5 or 10 mg BID ± csDMARDs (compared with PBO ± csDMARDs) achieved a CDAI CFB >12, HAQ-DI CFB ≥0.22, CDAI ≥50% improvement from baseline and pain VAS CFB ≥10. By M3, more pts receiving tofacitinib 5 or 10 mg BID ± csDMARDs (compared with PBO ± csDMARDs) achieved the efficacy outcomes measured including improvements from baseline in FACIT-F scores ≥4, CDAI ≥50%, CDAI ≥70% and CDAI ≥85%. Responses attained at M3 were maintained or increased at M6. Conclusions DMARD-IR pts with active RA receiving tofacitinib ± csDMARDs appeared to show greater improvements compared with PBO in clinical disease activity, HAQ-DI, and pain as early as Week 2 (first post-baseline assessment), and improvements in fatigue by M3. Responses were maintained or improved through M3 (monotherapy) or M6 (with background csDMARDs). References Curtis JR et al. Arthritis Care Res (Hoboken) 2015; 67:1345–1353. Acknowledgements Previously presented at ACR 2016 and reproduced with permission. This study was sponsored by Pfizer Inc. Editorial support was provided by AG McCluskey of CMC and was funded by Pfizer Inc. Disclosure of Interest D. Aletaha Consultant for: AbbVie, BMS, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, and UCB, Speakers bureau: AbbVie, BMS, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, and UCB, A. Kivitz Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Genentech, Pfizer Inc, Consultant for: AbbVie, Amgen, Bristol Myers Squibb, Genentech, Pfizer Inc, Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Genentech, Pfizer Inc, G. Valenzuela Speakers bureau: AbbVie, Janssen, Eli-Lilly, Merck, Novartis and Pfizer Inc, J. Tesser Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, S. Hays Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Li Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Bananis Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Soonasra Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. S. Smolen Grant/research support from: AbbVie, Janssen, Lilly, MSD, Pfizer Inc, and Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, and UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, and UCB

Aims: We compared etanercept 50 mg once weekly (ETN50)/methotrexate versus etanercept 25 mg (ETN25)/methotrexate or biologic-free methotrexate after response to ETN50/methotrexate in moderate rheumatoid arthitis patients from central/eastern Europe, Latin America and Asia. Methods: In a 36-week induction phase, methotrexate-resistant patients received ETN50/methotrexate. In a 52-week, double-blind phase, patients who achieved sustained Disease Activity Score in 28 joints low disease activity (LDA) were randomized to ETN50/methotrexate, ETN25/methotrexate or methotrexate. Results: Sustained Disease Activity Score in 28 joints LDA was achieved in 85% at week 36. LDA was achieved in 83, 81 and 50% with ETN50/methotrexate, ETN25/methotrexate and methotrexate and remission in 66, 61 and 31%, respectively, at week 88 (p < 0.0001). Conclusion: Etanercept/methotrexate therapy for 36 weeks effectively induced response in this moderate rheumatoid arthritis subpopulation. Conventional- and reduced-dose etanercept/me...

Background General practitioners/dermatologists may be aware of musculoskeletal symptoms in patients with psoriasis but may have difficulty accurately detecting psoriatic arthritis (PsA). Objective We sought to evaluate 3 PsA screening questionnaires–the Psoriasis and Arthritis Screening Questionnaire (PASQ), Psoriasis Epidemiology Screening Tool (PEST), and Toronto Psoriatic Arthritis Screen (ToPAS)–based on rheumatologist assessment in patients with psoriasis. Methods Consecutive unselected patients with psoriasis, initially evaluated by dermatologists for plaque psoriasis, were randomized to receive 1 of 3 questionnaires. Patients were subsequently evaluated by rheumatologists to establish/exclude clinical PsA diagnosis. Using clinical PsA diagnosis as the standard for comparison, questionnaire accuracy was assessed by calculating sensitivity/specificity and positive/negative predictive values. Results Of 949 patients with psoriasis evaluated by rheumatologists, 285 (30%) received a clinical diagnosis of PsA (95% confidence interval 27%-33%). Probable PsA was detected in 45.1%, 43.0%, and 42.9% of patients using PASQ, PEST, and ToPAS, respectively. Sensitivity ranged from 0.67 to 0.84; specificity, 0.64 to 0.75; positive predictive value, 0.43 to 0.60; and negative predictive value, 0.83 to 0.91. Limitations Not all patients completed all questionnaires; lack of standardized diagnostic criteria introduced possible bias. Conclusion PASQ, PEST, and ToPAS are useful screening tools that can help dermatologists identify patients without PsA and patients with possible PsA who may benefit from rheumatologist assessment.

The aims of this study were to investigate the short-term benefit of etanercept (ETN) + MTX vs conventional synthetic DMARDs (csDMARDs; HCQ, LEF or SSZ) + MTX in subjects with established RA. The effect of disease duration (≤2 years vs2 years) and severity (moderate vs severe) on treatment outcomes was also assessed. Methods. Data from Asian and Latin American subjects with inadequate response to MTX were pooled from the APPEAL (ETN 25 mg biweekly + MTX or csDMARD + MTX; NCT00422227) and Latin RA (ETN 50 mg/week + MTX or csDMARD + MTX; NCT00848354) studies. Endpoints included the 28-joint DAS with ESR (DAS28-ESR) low disease activity (LDA; ≤3.2), DAS28 remission (2.6) and HAQ score ≤0.5.Four hundred seventy-eight subjects received ETN + MTX, 245 subjects received csDMARD + MTX [HCQ + MTX (n = 81), LEF + MTX (n = 69), SSZ + MTX (n = 95)]. At week 16, significantly more subjects receiving ETN + MTX vs subjects on csDMARDs + MTX achieved DAS28-ESR LDA (39% vs 18%, P0.001), remission (18% vs 7%, P0.001) and HAQ ≤0.5 (48% vs 34%, P0.001). For both treatment arms, these endpoints were achieved by a greater proportion of subjects with ≤2 years vs2 years disease duration and with moderate vs severe disease activity.Overall, ETN + MTX was more effective in treating subjects with established RA than csDMARDs + MTX at 16 weeks. More subjects with shorter disease duration and moderate disease activity achieved optimal response regardless of treatment regimen.clinicaltrials.gov, NCT00422227 and NCT00848354.

Background Prompt identification and treatment of psoriatic arthritis (PsA) in patients with psoriasis is critical to reducing the risk of joint damage, disability, and comorbidities. Objective We sought to estimate PsA prevalence in patients with plaque psoriasis in 34 dermatology centers in 7 European and North American countries. Methods Consecutive patients were evaluated by dermatologists for plaque psoriasis and subsequently by rheumatologists for PsA. PsA prevalence was estimated primarily based on rheumatologists' assessment of medical history, physical examination, and laboratory tests. Results Of 949 patients evaluated, 285 (30%) had PsA (95% confidence interval 27-33) based on rheumatologists' assessment. PsA diagnosis changed in 1.2% of patients when diagnostic laboratory tests were added to medical history and physical examination. Of 285 patients given the diagnosis of PsA, 117 (41%) had not been previously given the diagnosis. Limitations Bias may have been introduced by lack of standardized diagnostic criteria and unbalanced recruitment based on country populations. Conclusions In this study, almost a third of patients with psoriasis seen in dermatology centers had PsA as determined by rheumatologists. More than a third of patients with PsA had not been previously given the diagnosis. Clinical evaluation alone is often sufficient basis for PsA diagnosis, but laboratory test results may be helpful in some patients.

Background In most patients with rheumatoid arthritis (RA), Disease Activity Score 28-joint count C reactive protein (DAS28-CRP) is lower than DAS28 erythrocyte sedimentation rate (DAS28-ESR), suggesting that use of the DAS28-ESR cut-off to assess high disease activity (HDA) with DAS28-CRP may underestimate the number of patients with HDA. We determined the DAS28-CRP value corresponding to the validated DAS28-ESR cut-off for HDA. Methods Baseline data were pooled from 2 clinical studies evaluating etanercept (ETN) plus methotrexate (MTX) or MTX in early RA; DAS28-CRP and DAS28-ESR were obtained, allowing the determination of the DAS28-CRP HDA value best corresponding to the DAS28-ESR cut-off of >5.1. Results At baseline, as expected, fewer patients had HDA by DAS28-CRP than DAS28-ESR; DAS28-CRP>5.1 and DAS28-ESR>5.1 had only modest agreement (κ coefficients 0.45–0.54). Mean DAS28-CRP and DAS28-ESR were 5.7 and 6.2, respectively, in the ETN+MTX group (n=571), and 6.0 and 6.5 in the MTX group (n=262). A DAS28-CRP cut-off of 4.6 corresponded to a DAS28-ESR cut-off of 5.1. Conclusions We have shown that a DAS28-CRP of 4.6 corresponds to 5.1 for DAS28-ESR. Since this is substantially lower than the DAS28-ESR cut-off of 5.1, using 5.1 as the cut-off for DAS28-CRP underestimates disease activity in RA. Trial registration number NCT00195494; NCT00913458.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis investigated the effect of methotrexate (MTX) dose on the efficacy of tofacitinib in patients with RA. ORAL Scan (NCT00847613) was a 2-year, randomized, Phase 3 trial evaluating tofacitinib in MTX-inadequate responder (IR) patients with RA. Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo, with low (≤12.5 mg/week), moderate (>12.5 to

Switching among biologic therapies is common practice in patients with rheumatoid arthritis who have an inadequate response or intolerable adverse events. Evidence from observational studies and association guidelines supports the use of sequential biologic therapy for these reasons. Owing to recent economic pressures on healthcare budgets, patients with rheumatoid arthritis who are well controlled on and tolerant of their current biologic therapy may be switched to alternative biologics, despite limited evidence supporting this practice. Clinical research and experience suggest that TNF antagonists are not interchangeable, as meaningful differences have been observed in their efficacy and safety profiles. Additional research is needed to assess the risk:benefit ratio of specific sequences of biologic therapies and the validity of switching biologic therapies for nonclinical purposes.

To the Editor: We thank Professor Boers for his interest1 in our study2 and are grateful for the opportunity to respond to his queries. Our posthoc analysis investigated the effect of concomitant glucocorticoid (GC) use on clinical and radiographic outcomes in phase III studies of methotrexate (MTX)-naive patients receiving tofacitinib or MTX as monotherapy (ORAL Start), disease-modifying antirheumatic drug (DMARD)–inadequate responder (IR) patients receiving tofacitinib or placebo as monotherapy (ORAL Solo), and MTX-IR and DMARD-IR patients receiving tofacitinib or placebo in combination with background conventional synthetic DMARD (ORAL Sync, ORAL Standard, ORAL … Address correspondence to E. Bananis, 235 E. 42nd St., New York, New York 10017, USA. E-mail: stratis.bananis{at}pfizer.com.

1060Background: A previous pooled analysis showed that 36.9% of pts receiving PAL required dose reduction, most occurring during the first 6 mo of treatment and with decreasing frequency during sub...

ObjectivesDisease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) is used instead of erythrocyte sedimentation rate (DAS28-ESR) to assess rheumatoid arthritis disease activity; however, values for remission and low disease activity (LDA) for DAS28-CRP have not been validated. American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) guidelines suggest remission should be calculated by Simplified Disease Activity Index (SDAI) rather than DAS28-ESR. We examined values of remission and LDA of DAS28-CRP that correspond to the respective cut-off points for DAS28-ESR and SDAI from five clinical trials.MethodsDAS28-CRP cut-offs that best correspond to DAS28-ESR remission ResultsPercentage of patients who achieved remission and LDA by DAS28-ESR cut-offs was greater for DAS28-CRP versus DAS28-ESR regardless of patient population or treatment group. Discordance between CRP and ESR cut-offs ranged from 4%–26% and 8%–23% for remission and LDA, respectively, and 19%–40% and 6%–11% for DAS28-CRP versus SDAI, respectively. Estimated (range) remission and LDA thresholds were 2.4 (2.2–2.6) and 2.9 (2.6–3.3), 1.9 (1.6–2.2) and 3.1 (3.1–3.3) and 2.2 (1.1–2.9) and 3.6 (3.4–4.0) for DAS28-CRP versus DAS28-ESR, DAS28-CRP versus SDAI and DAS28-ESR versus SDAI, respectively.ConclusionsDAS28-CRP underestimates disease activity when using cut-off points validated for DAS28-ESR; therefore, DAS28-ESR cut-off values should not be applied to DAS28-CRP. Although DAS28-CRP and DAS28-ESR cut-offs for LDA ≤3.2 correspond to SDAI LDA, neither corresponds well to SDAI remission.

Intracellular trafficking regulates the abundance and therefore activity of transporters present at the plasma membrane. The transporter, Na+-taurocholate co-transporting polypeptide (ntcp), is increased at the plasma membrane upon treatment of cells with cAMP, for which microtubules (MTs) are required and the PI3K pathway and PKCzeta have been implicated. However, trafficking of ntcp on MTs has not been demonstrated directly and the regulation and intracellular localization of ntcp is not well understood. Here, we utilize in vitro and whole-cell immunofluorescence microscopy assays to demonstrate that ntcp is present on intracellular vesicles that bind MTs and move bidirectionally, using kinesin-1 and dynein. These vesicles co-localize with markers for recycling endosomes and early but not late endosomes. They frequently undergo fission, providing a mechanism for the exclusion of ntcp from late endosomes. PI(3,4,5)P3 activates PKCzeta and enhances motility of the ntcp vesicles and overcomes the partial inhibition produced by a PI3-kinase inhibitor. Specific inhibition of PKCzeta blocks the motility of ntcp-containing vesicles but has no effect on late vesicles as shown both in vitro and in living cells transfected with ntcp-GFP. These data indicate that PKCzeta is required specifically for the intracellular movement of vesicles that contain the ntcp transporter.

Our previous studies demonstrated that fluorescent early endocytic vesicles prepared from rat liver after injection of Texas red asialoorosomucoid contain asialoglycoprotein and its receptor and move and undergo fission along microtubules using kinesin I and KIFC2, with Rab4 regulating KIFC2 activity (J. Cell Sci. 116, 2749, 2003). In the current study, procedures to prepare fluorescent late endocytic vesicles were devised. In addition, flow cytometry was utilized to prepare highly purified fluorescent endocytic vesicles, permitting validation of microscopy-based experiments as well as direct biochemical analysis. These studies revealed that late vesicles bound to and moved along microtubules, but in contrast to early vesicles, did not undergo fission. As compared with early vesicles, late vesicles had reduced association with receptor, Rab4, and kinesin I but were highly associated with dynein, Rab7, dynactin, and KIF3A. Dynein and KIF3A antibodies inhibited late vesicle motility, whereas kinesin I and KIFC2 antibodies had no effect. Dynamitin antibodies prevented the association of late vesicles with microtubules. These results indicate that acquisition and exchange of specific motor and regulatory proteins characterizes and may regulate the transition of early to late endocytic vesicles. Flow cytometric purification should ultimately facilitate detailed proteomic analysis and mapping of endocytic vesicle-associated proteins.

We previously established conditions to reconstitute kinesin-dependent early endocytic vesicle motility and fission on microtubules in vitro. The present study examined the question whether motility and fission are regulated in this system. Screening for proteins by immunofluorescence microscopy revealed that the small G protein, Rab4, was associated with 80% of hepatocyte-derived early endocytic vesicles that contain the ligand asialoorosomucoid (ASOR). By contrast, other markers for early endocytic vesicles including clathrin, Rab5 and EEA1 were present in the preparation but did not colocalize with the ASOR vesicles. Guanine nucleotides exchanged into the Rab4 present on the vesicles as shown by solubilization of Rab4 by Rab-GDI; solubilization was inhibited by incubation with GTP-γ-S and promoted by GDP. Pre-incubation of vesicles with GDP increased the number of vesicles moving on microtubules and markedly increased vesicle fission. This increase in motility from GDP was shown to be towards the minus end of microtubules, possibly through activation of the minus-end-directed kinesin,KIFC2. Pre-incubation of vesicles with GTP-γ-S, by contrast, repressed motility. Addition of exogenous GST-Rab4- GTP-γ-S led to a further repression of motility and fission. Repression was not seen with addition of GST-Rab4-GDP. Treatment of vesicles with Rab4 antibody also repressed motility, and repression was not seen when vesicles were pre-incubated with GDP. Based on these results we hypothesize that endogenous Rab4-GTP suppresses motility of ASOR-containing vesicles in hepatocytes and that conversion of Rab4-GTP to Rab4-GDP serves as a molecular switch that activates minus-end kinesin-based motility, facilitating early endosome fission and consequent receptor-ligand segregation.