Database Lock Research Articles

A randomized phase II trial comparing switch to nivolumab with TKI continuation after 12 weeks of TKI induction therapy in metastatic renal cell carcinoma patients (NIVOSWITCH).

678 Background: Tyrosine kinase inhibitors (TKI) and Nivolumab (NIVO) are standard treatment options for mRCC. We tested whether TKI followed by early switch to NIVO improved outcome in mRCC patients (pts). Methods: Main inclusion criteria: measurable advanced or metastatic clear cell RCC, ECOG PS 0-2, adequate organ function, PR or SD to induction therapy with sunitinib (50 mg, 4-2 regime) or pazopanib (800 mg OD). 1:1 randomization at 12 wks.: TKI continuation vs. switch to NIVO (240 or 480 mg IV q2-4wks). Strata were MSKCC risk, TKI used and response to TKI. Imaging was performed q12w. 49 of 244 planned pts were randomized between Dec 2016 and Aug 2018, which led to premature closure of the trial. We report the second interim analysis with data base lock on 31.07.19. ORR was assessed according to RECIST 1.1. Efficacy and safety analyses were performed in ITT and safety population, respectively. Log-Rank analyses were used for survival analyses. Results: 25 and 24 pts received NIVO or TKI, respectively. Median age was 65 y (range: 35-79), 82% were male and 4% had ECOG PS 2. Metastases occurred predominantly in lung (47%), lymph nodes (27%) and liver (24%). MSKCC risks were: favorable (31%), intermediate (65%), and poor (4%), which were balanced between arms. 55% received sunitinib. ORR for NIVO vs. TKI differed when assessed from start of induction therapy (64 vs. 70%, P=0.76) or from time of randomization (16 vs. 48%; P=0.032). Accordingly, PFS from randomization was 3.0 vs. 11.9 mo. (HR = 1.72 [95% CI: 1.19 – 2.48]; P=0.0026) in favor of TKI continuation. At a median follow-up of 12.9 mo. median OS was not reached, but HR = 1.86 (95% CI: 0.85 – 4.07) P=0.10 showed a trend for TKI continuation. All grades AE for NIVO vs. TKI occurred in 96% vs. 100%, grade 3-5 48% vs. 71% and serious AE 40% vs. 46%. Conclusions: In TKI-sensitive pts, continuation of TKI is more efficacious than early switch to NIVO. The major limitation of our trial is the premature closure and its limited sample size. Clinical trial information: NCT02959554.

The Impact of COVID-19 on the Conduct of Clinical Trials for Medical Products in Korea.

BackgroundThe number of clinical trials conducted in Korea continues to increase and an increasing proportion focus on severe and rare incurable diseases. After the start of the severe acute respiratory syndrome, coronavirus disease 2019 (COVID-19), Korea Centers for Disease Control and Prevention (KCDC) developed guidelines to prevent the spread of infection. This study evaluated the impact of COVID-19 and the KCDC guideline on the conduct of clinical research in Korea. The purpose was to develop recommendations on how to minimize the risk of infection while enabling subjects to take part in the trials if no better alternative treatment options were available.MethodsThe impact on subject's scheduled visits and major milestones of clinical trials in Korea were measured by conducting a survey among clinical project manager (CPMs) working at global clinical research organization. The policy on monitor's access to hospital and site initiation meetings was investigated through correspondence with clinical trial center of 39 hospitals. The Top 25 pharmaceutical companies' official press and public clinical trial registry database were used to analyze companies' trial strategy during the pandemic and COVID-19 clinical research status, respectively.ResultsOf 85 CPMs, 12% reported that trial subjects' scheduled visits had been affected in their project. Monitors' access to hospital for source data verification was restricted at all sites in February 2020. Accordingly, 43% of 105 CPMs reported that the COVID-19 epidemic had an effect on study major milestones and data cleaning and database lock accounted for > 60% of milestones affected. In addition, 87% sites advised not to have site initiation meetings and 52% pharmaceutical companies suspended recruitment or new study start-up due to the pandemic. On the other hands, the number of COVID-19 related clinical trials increased rapidly in Korea and worldwide, with investigator-initiated trials accounting for 47% and 63% of all trials locally and globally, respectively. Most trials were phase 2 and were in the recruitment stage.ConclusionThe COVID-19 and the KCDC guideline influenced all parties involved in clinical trials in Korea. In order to ensure the safety and well-being of trial subjects during the pandemic, new approaches are required for clinical trials to respond to the impact actively. Method of non-contact is developed to replace and supplement the face-to-face contact and alternatives to reduce the travel is introduced to decrease the risk of infection for all trial participants in whole trial process. The relevant regulations should be developed and the guidelines for foreign countries need to be adopted in accordance with the situation in Korea. COVID-19 trial is rapidly increasing worldwide and continuous support of health authorities, regulation, and facilities is required for developing the treatments with protecting all trial participants.

Effects of the Therapeutic Armamentarium on Survival and Time to Next Treatment in CMML Subtypes: An International Analysis of 950 Cases Coordinated By the AGMT Study Group

Effects of the Therapeutic Armamentarium on Survival and Time to Next Treatment in CMML Subtypes: An International Analysis of 950 Cases Coordinated By the AGMT Study Group

Impact of Elotuzumab Plus Pomalidomide and Dexamethasone on Health-Related Quality of Life in Patients with Relapsed/Refractory Multiple Myeloma Enrolled in the ELOQUENT-3 Study

Impact of Elotuzumab Plus Pomalidomide and Dexamethasone on Health-Related Quality of Life in Patients with Relapsed/Refractory Multiple Myeloma Enrolled in the ELOQUENT-3 Study

Obinutuzumab Alone or Combined with Chemotherapy in Previously Untreated (Fit or Unfit) or Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Patients: Final Results from the Phase IIIb GREEN Safety Study with a Focus on Efficacy

Obinutuzumab Alone or Combined with Chemotherapy in Previously Untreated (Fit or Unfit) or Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Patients: Final Results from the Phase IIIb GREEN Safety Study with a Focus on Efficacy

Cytogenetic and Molecular Response with First- and Second-Generation Tyrosine Kinase Inhibitor (TKI) Therapy in Simplicity: An Observational Study of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML)

Introduction: SIMPLICITY (NCT01244750) is an ongoing observational study of patients (pts) with CP-CML receiving first-line (1L) imatinib (IM), dasatinib (DAS), or nilotinib (NIL) in routine clinical practice in Europe and the United States (US). The study aimed to assess the effectiveness and safety of TKIs for pts with CP-CML outside the clinical trial setting. Here, we analyze the clinical outcomes (complete cytogenetic response [CCyR] and major molecular response [MMR]) associated with the CML risk level in SIMPLICITY pts with CP-CML receiving first-generation (1G: IM) or second-generation (2G: DAS/NIL) TKI therapy. Methods: Clinical outcomes after 1L TKI initiation were assessed by CyR (karyotype analysis or fluorescence in situ hybridization) and polymerase chain reaction MR tests. Proportions of pts achieving CCyR and MMR are presented for those with at least one recorded response test during 1L TKI therapy. Outcomes were stratified by CML risk level (Hasford scoring; low [≤780] and intermediate/high risk [≥781]), and the differences between 1L 1G and 2G TKI cohorts analyzed. Statistical comparisons for continuous variables were made using t-tests and the Mann-Whitney U test, and chi-square test for categorical variables. Multivariate logistic regression models, adjusted for age, gender, region, risk level (low vs intermediate/high), and baseline (BL) comorbidities, were used to determine if generation of TKI therapy (1G/2G) was associated with clinical response (CCyR or MMR) after start of 1L TKI. Performance and timing of CyR and MR tests were at the discretion of oncologists, limiting the analysis of outcomes and comparisons of CCyR and MMR rates. Results: There were 1,241 pts (IM: n=416; DAS: n=417; NIL: n=408) at database lock (October 2018); only 391 (31.5%) pts with CP-CML receiving 1L TKI were identified to have the elements needed for a Hasford risk assessment documented at diagnosis (IM: n=140; DAS: n=119; NIL: n=132). CML risk assessment (Hasford score) was significantly more common in Europe (68.7% vs 11.7% in the US, p<0.0001). No significant difference in risk score was observed across the different 1L TKI groups (p=0.7012). Of the 130 (33.2%) pts with recorded CyR test results, no significant differences in BL demographics were observed except for median age at start of 1L TKI and BL cardiovascular and gastrointestinal (GI) comorbidities (Table 1). A higher percentage of pts on 2G TKIs achieved CCyR compared with 1G TKI in both low (88.1% vs 79.2%) and intermediate/high (73.0% vs 44.4%) CML risk categories, with statistical significance reached in the intermediate/high-risk group (p=0.0209). Multivariate logistic regression analysis (Figure 1) showed that pts were approximately 3 times more likely to achieve CCyR if receiving 2G TKIs (odds ratio [95% confidence interval]: 2.93 [1.21, 7.13] vs 1G, p=0.0177). Other predictors of CCyR were low baseline CML risk (5.75 [2.00, 16.50] vs intermediate/high CML risk, p=0.0011) and treatment at European centers (2.72 [1.03, 7.18] vs US centers, p=0.0431). MR test results were recorded in 358 (91.6%) pts; median number of MR tests was significantly higher in Europe (8 vs 5 in the US, p<0.0001). No significant differences in pt demographics were observed except for age at start of 1L TKI and BL GI comorbidities (Table 1). A higher percentage of pts on 2G TKIs achieved MMR compared with 1G TKI in the low (82.0%vs 74.6%) and intermediate/high (87.0% vs 72.4%) CML risk groups, with significance reached in the latter cohort (p=0.0185). Multivariate logistic regression analysis showed that TKI generation was the sole predictor of MMR achievement; pts were approximately twice as likely to achieve MMR with 2G TKIs as with 1G TKI (OR: 2.13 [1.23, 3.70], p=0.0070) (Figure 1). Conclusions: Despite treatment guidelines recommending 2G TKI therapy for pts with higher CML risk, our analysis of SIMPLICITY pts showed no differences in 2G versus 1G TKI use in low and intermediate/high risk groups. Here, the use of 2G TKIs, compared with 1G TKI, was a significant predictor for achieving either CCyR or MMR, thereby validating the clinical response benefits of 2G TKIs regardless of BL CML risk. These findings emphasize the importance of adhering to treatment guidelines when making decisions on the generation of TKI, first (IM) or second (DAS/NIL), to be used in the 1L treatment of pts with CP-CML, particularly in higher risk pts. Disclosures Cortes: Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; BiolineRx: Consultancy. Chen:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment, Equity Ownership. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy. Mauro:Bristol-Myers Squibb: Consultancy; Novartis Oncology: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy.

A Multi-Center, Multinational, Prospective Observational Registry Study of Defibrotide in Patients Diagnosed with Severe Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT)

Severe hepatic VOD/SOS is a potentially life-threatening complication of HCT conditioning that may also develop after high-dose chemotherapy. The most severe form of VOD/SOS is often accompanied by multi-organ failure (MOF) and is associated with a mortality rate of >80% when managed with supportive care alone. As part of the marketing authorization in Europe, there was an obligation to set up a disease registry of patients with severe VOD/SOS post-HCT who were treated with defibrotide. The goal of this registry was to collect safety and outcome data and assess patterns of defibrotide utilization in the post-approval setting. This multicenter, multinational, prospective observational study (NCT03032016) was performed by the European Society for Blood and Marrow Transplantation (EBMT). The study included patients with severe VOD/SOS post-HCT who were treated with defibrotide and enrolled from April 2015 to July 2018. Participating centers were members of the EBMT. Physicians registered patients diagnosed with severe VOD/SOS, as assessed by the investigator using classical/standard criteria (including but not limited to hyperbilirubinemia, hepatomegaly, ascites, and weight gain >5%), who consented to participate in the study. In addition, patients who were prescribed defibrotide for purposes other than the approved indication (eg, VOD/SOS prophylaxis, treatment of non-severe VOD/SOS or thrombotic microangiopathy) and consented to participate were registered and information collected. There were no specific exclusion criteria; however, treating physicians were alerted to contraindications, special warnings, and precautions detailed in the defibrotide summary of product characteristics. After inclusion, patient information was collected from participating centers at 100 days, 6 months, and 12 months post-HCT. The primary objective was to assess the incidence of specific serious adverse events (SAEs) of interest, which were hemorrhage and site of bleeding, hypotension, coagulopathy, allergic or hypersensitivity reactions, injection-site reaction, infection and septicemia, and thromboembolic events. Secondary endpoints included Day 100 survival, and overall rate of VOD/SOS (and MOF, if present) resolution (based on standard criteria). Summary statistics were calculated for baseline data and safety variables; outcome analyses are descriptive. Here we report an analysis of data with a cutoff of June 18, 2019. Database lock is planned for October 2019, and the presentation will be updated to include the final data. A total of 61 patients with severe VOD/SOS were included; MOF was diagnosed at registration in 34 (56%) patients. The median age of patients with severe VOD/SOS was 14.4 (range: 0-68) years, 34 (56%) aged <18 years and 27 (44%) aged ≥18 years. A total of 54 (89%) patients received allogeneic HCT. Primary diseases included acute myeloid leukemia (26%), acute lymphoid leukemia (13%), solid tumor (12%), and myelodysplastic syndrome (8%). The median length of defibrotide exposure was 17 (IQR: 11-25) days. An SAE of interest occurred in 19 (31%; 95% confidence interval [CI]: 20%-43%) patients with severe VOD/SOS. The most common SAEs of interest by category were infection (n = 13 [21%; 95% CI: 11%-32%]) and bleeding events (n = 8 [13%; 95% CI: 5%-22%]). The most common individual SAEs of interest (≥5% of patients) were pneumonia (8%), gastrointestinal bleeding (8%), and sepsis (5%). Death occurred in 30 (49%) patients within 1 year, with VOD/SOS indicated as a cause of death in 13/30 (43%) patients. The Kaplan-Meier-estimated survival rate at Day 100 for patients diagnosed with severe VOD/SOS post-HCT who were treated with defibrotide was 74% (95% CI: 61%-83%). At latest follow-up, the survival rate was 51%, with median Kaplan-Meier-estimated survival post-HCT not yet reached. VOD/SOS resolved in 46 (75%) patients; the cumulative rate of VOD/SOS resolution at Day 100 was 87% (95% CI: 72%-94%). Resolution of MOF was achieved in 19/34 (56%) patients who had MOF at VOD/SOS diagnosis. In conclusion, among patients with severe VOD/SOS post-HCT (with/without MOF), the incidence of SAEs of interest was consistent with that observed in previous defibrotide clinical trials. Treatment with defibrotide resulted in high rates of Day 100 survival and VOD/SOS resolution. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Blaise:Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Pierre Fabre medicaments: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Hanvesakul:Jazz Pharmaceuticals: Employment, Equity Ownership. Ryan:Jazz Pharmaceuticals: Employment, Equity Ownership. Lawson:Jazz Pharmaceuticals: Consultancy, Honoraria.

Updated Progression-Free Survival (PFS) and Overall Survival (OS) with Melflufen and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Phase 2 Study O-12-M1

Background: Patients with multiple myeloma (MM) who have relapsed after conventional treatment have limited therapeutic options for long-term disease control. Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. In the first report of efficacy and safety for the phase 1/2 study O-12-M1 (median follow-up, 28 months), melflufen and dexamethasone demonstrated an overall response rate of 31%, a median PFS of 5.7 months, and a median OS of 20.7 months, with acceptable safety for patients with RRMM (Richardson PG, et al. Blood. 2017; Abstract 3150). Here, updated OS and PFS results from the O-12-M1 study are reported, with 18 months of additional follow-up of the patients who were still participating in long-term follow-up at the time of the final database lock in November 2017. Methods: Eligible patients had RRMM, measurable disease, and ≥2 prior lines of therapy, including bortezomib and lenalidomide. Patients must have had progressive disease (PD) on or within 60 days of completion of last therapy. Patients received melflufen 40 mg intravenously on day 1 of each 28-day cycle and oral dexamethasone 40 mg weekly for up to 8 cycles or longer at the discretion of the investigator and sponsor. Treatment continued until PD or unacceptable toxicity. Patients were followed up for 2 years after PD or start of subsequent therapy. PFS and OS were secondary end points in this study. Time to next treatment (TTNT), an exploratory end point defined as the time from start of melflufen and dexamethasone to first subsequent therapy or death, was retrospectively reviewed. Results: As of 15 May 2019, 45 patients were treated. Median age was 66 years (range, 47-78); 60% of patients had International Staging System stage II/III at study entry, and 44% had high-risk cytogenetics [del(17p), t(14;16), t(4;14), t(14;20), or gain(1q)]. The median time since initial diagnosis was 5.0 years (range, 1-21). Patients received a median of 4 prior lines of therapy (range, 2-14). All patients were exposed to IMiDs, 98% to proteasome inhibitors (PIs), 93% to alkylators (any dose of melphalan, cyclophosphamide, or bendamustine), and 80% to melphalan; 87% were refractory to last line of therapy, and 91%, 67%, and 7% were single (IMiD or PI), double (IMiD and PI), and triple (IMiD, PI, and daratumumab) refractory, respectively. After a median follow-up of 30.1 months, median PFS was 5.7 months (95% CI, 3.7-9.3; 98% events). Median OS was 20.7 months (95% CI, 13.6-not reached; 58% events; Figure). Updated PFS, OS, and TTNT data will be presented. No new adverse events (AEs) were reported. Conclusion: Melflufen and dexamethasone resulted in sustained long-term benefits (median OS, 20.7 months) and no new AEs with 1.5 years of additional follow-up of patients with late-stage, heavily pretreated RRMM who have relapsed on conventional therapy including bortezomib and lenalidomide. Further trials are ongoing to evaluate efficacy and safety of melflufen, including the phase 3 study OCEAN (OP-103; NCT03151811) of melflufen plus dexamethasone versus pomalidomide plus dexamethasone in patients with RRMM refractory to lenalidomide. Figure Disclosures Bringhen: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Voorhees:Novartis: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TeneoBio: Consultancy, Research Funding; Amgen: Research Funding; GSK: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Plesner:AbbVie: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy; Janssen: Consultancy, Research Funding. Mellqvist:Amgen, Janssen, Oncopeptides, Sanofi, Sandoz, Takeda: Honoraria. Reeves:Celgene: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria. Byrne:Oncopeptides: Consultancy; Takeda: Consultancy. Nordström:Oncopeptides: Employment, Equity Ownership. Harmenberg:Oncopeptides: Consultancy, Equity Ownership. Obermüller:Oncopeptides: Employment. Richardson:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a Phase 1/2 investigational study of melflufen in RRMM

ACTR-11. SECOND INTERIM AND 1ST MOLECULAR ANALYSIS OF THE EORTC RANDOMIZED PHASE III INTERGROUP CATNON TRIAL ON CONCURRENT AND ADJUVANT TEMOZOLOMIDE IN ANAPLASTIC GLIOMA WITHOUT 1p/19q CODELETION

Abstract BACKGROUND The 1st interim analysis of the CATNON trial showed benefit from adjuvant (adj) temozolomide (TMZ) on overall survival (OS) but remained inconclusive about concurrent (conc) TMZ. A 2nd interim analysis was planned after 356 events. METHODS The 2x2 factorial design phase III CATNON trial randomized 751 patients with newly diagnosed non-codeleted anaplastic glioma to either 59.4 Gy radiotherapy (RT) alone; the same RT with concTMZ; the same RT and 12 cycles of adjTMZ or the same RT with both concTMZ and adjTMZ (doi: 10.1016/S0140-6736(17)31442–3). MGMT promoter methylation (MGMTmeth) status was re-assessed with the Infinium Methylation EPIC Beadchip. Isocitrate dehydrogenase 1 and 2 (IDH) mutation (mt) status was assessed with a glioma targeted next generation sequencing panel. At the time of molecular analysis, a 3rd database lock was done. RESULTS At the 2nd IDMC (median follow-up 56 months, 356 events observed) the hazard ratio (HR) for OS adjusted for stratification factors after concTMZ was 0.968 (99.1% CI 0.73, 1.28. An IDHmt was found in 368 of 528 assessed cases (70%). After median follow-up of 67 months and with 367 events observed median OS was 19 mo (95% CI 16.3, 22.3) in IDHwt tumors and 116 mo (95% CI 82.0, 116.6) in IDHmt tumors. IDHmt was predictive of benefit from adjTMZ (IDHmt HR: 0.46, 95% CI 0.32, 0.67; IDHwt: HR 1.03, 95% CI 0.73, 1.44; interaction test p = 0.002) and from concTMZ (HR(IDHmt HR: 0.63, 95% CI 0.43, 0.91; IDHwt: HR 1.16, 95% CI 0.83, 1.63; interaction test p = 0.017). MGMTmeth was found in 401 of 478 assessed cases (69%), interaction tests for concTMZ and adjTMZ did not reach statistical significance. CONCLUSIONS In IDHmt tumors adjuvant and concurrent temozolomide improves survival, no effect was observed in IDHwt tumors. Further follow-up and molecular analyses are required for mature analyses.

PCN181 ACCELERATING EARLY COST-EFFECTIVENESS MODELING IN ONCOLOGY USING AN INDICATION-AGNOSTIC WEB-BASED PLATFORM: A RETROSPECTIVE CASE STUDY OF NIVOLUMAB PRE-TREATED METASTATIC SMALL-CELL LUNG CANCER POPULATION

To demonstrate the value of a generic cost-effectiveness (CE) modeling platform in oncology for early market access strategy development. With limited clinical data, strategy-making is based on uncertain outcomes and several assumptions. To assess the accuracy in predictive modeling and in identifying key drivers of results, an early analysis based on an initial trial database lock (DBL1) was compared with later, more mature data (DBL2). An internally-developed R/Shiny oncology modeling platform was used for the CE analyses simulating the market access strategy-informing process. The case study, using only published data, compared scenarios using nivolumab data from CheckMate032-DBL1 (“early scenario”) and CheckMate032-DBL2 (“final scenario”) in pre-treated small cell lung cancer (SCLC). The comparator treatment was topotecan, the predominantly-prescribed treatment in pre-treated SCLC. Progression-free and overall survival (PFS, OS), digitized from literature for both treatments, were extrapolated over a 20-year time horizon using parametric survival models. Time on treatment (ToT) was assumed equal to PFS. Model projected nivolumab mean PFS and OS were 4.8 and 26.4 months, respectively, in the early scenario, and 6.9 and 21.7 months in the final scenario. The ICERs differed by 32% between scenarios, mainly due to different OS and ToT. Key inputs affecting differences between-scenarios were ToT and OS. OS differences were expected as DBL1 and DBL2 considered second- and third- or later-line patients, respectively. Between-scenario results variations are expected due to different patient populations, and data maturity levels. Notwithstanding those differences and limitations in including disease-specific elements, the generic modeling platform proves helpful in performing analyses timely, which can guide prioritization of evidence generation by identifying key drivers of results with sparse data (ToT in this case study), assess the impact of parameter variations and alternative modeling approaches for future reimbursement submission-ready models at early stages.

PCN227 A PARTITIONED SURVIVAL MODEL TO DETERMINE COST-EFFECTIVENESS OF THIRD-LINE NIVOLUMAB MONOTHERAPY FOR SMALL CELL LUNG CANCER

To present a cost-effectiveness analysis of nivolumab monotherapy versus commonly prescribed third-line (3L) treatment in small cell lung cancer (SCLC). A partitioned survival model with 3 health states (progression-free [PF], progressed disease [PD], and death) was developed from a US payer perspective. A systematic literature review identified no randomised controlled or single-arm trials that reported outcomes separately for 3L SCLC patients for any treatment. As topotecan was frequently prescribed in real-world clinical practice (SEER and Flatiron electronic health database) for 3L SCLC patients, it was chosen as the comparator. Clinical inputs for topotecan were derived from Flatiron data (January 2011 to September 2017) with inclusion/exclusion criteria matched to 3L+ nivolumab-treated patients in CheckMate 032 (January 2018 database lock). Clinical efficacy of IV and oral topotecan were assumed equivalent. The base-case analysis used a 20-year lifetime horizon. Patients entered the model in the PF health state. Cost-effectiveness of treatments were calculated by combining estimated time spent in the PF and PD states with the costs and health utilities assigned to those states based on parametric survival curves. An annual discount rate of 3% for costs and outcomes was applied. Incremental cost per quality adjusted life-year (QALY) gained with nivolumab was US$153,312 versus IV topotecan and US$123,003 versus oral topotecan. When results were disaggregated, nivolumab-related costs were mainly driven by drug acquisition cost and topotecan-related costs were primarily due to treatment of adverse events. Deterministic sensitivity analysis showed that changes in discount rate for costs, outcomes, and body weight had the greatest impact on the results. Based on the literature on willingness-to-pay for a QALY in metastatic cancer, nivolumab monotherapy represents a cost-effective option for 3L+ treatment of SCLC compared with IV and oral topotecan.

LBA11 - Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): The phase III ATTRACTION-3 study

LBA11 - Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): The phase III ATTRACTION-3 study

683P - FOLFIRINOX in locally advanced (LA) and borderline resectable (BR) pancreatic adenocarcinoma: Update of the AGEO cohort

BackgroundFOLFIRINOX has shown promising results in LA or BR pancreatic adenocarcinoma (PA) in non-randomized series. We report here an updated large cohort of pts treated with FOLFIRINOX for a LA or BR PA. MethodsThis French retro-prospective multicenter study included all consecutive patients (pts), PS 0/1/2, with non-metastatic, non-resectable, non-pretreated, LA or BR PA treated with FOLFIRINOX. Non-resectability was defined by each center’s multidisciplinary team meeting at diagnosis according to the ISGPS guidelines. FOLFIRINOX chemotherapy (CT) was performed as described in the PRODIGE 4 trial until progression, major toxicity or consolidation treatment radiotherapy (RT) or surgery. ResultsAt the time of database lock, in December 2018, 293 pts were included (42% female, 33% > 65 years, 97% PS<2). Disease was classified as BR (32%) or LA (68%). After a median of 7 (IQR: 5-11) CT cycles, objective response rate was 29% and stable disease 51%. Subsequent RT was performed in 42% and 24% had a curative intent surgery (R0: 72%; ypT0N0: 9%). Resection rates were 40% for BR and 17% for LA pts. Main G3/4 toxicities were: fatigue (14%), neutropenia (12%), nausea (8%) and diarrhea (7%). Oxaliplatin-induced peripheral neuropathy G2/3 was observed in 34%. 13% of pts has stopped chemotherapy for toxicity including 2 toxic deaths. After consolidation RT and/or surgery disease progression occurred in 52% and was mainly metastatic (56%). After a median follow-up of 24 months (mo), median OS (mOS) and PFS were 21 and 12mo, respectively. mOS was 27mo for BR and 19mo for LA pts (p=.002). For pts treated by CT alone, or CT+RT, or CT+/-RT+surgery mOS were 14mo, 22mo and not reached, respectively (p<.0001). A trend to a better survival was seen when RT was performed before surgery (mOS 29mo vs not reached, p=.08). ConclusionsFOLFIRINOX for LA and BR PA seems to be effective with a manageable toxicity profile. However secondary surgery rate and OS were lower than what we previously reported, but similar to the meta-analysis we previously published. These promising results in “real life” pts have now to be confirmed in phase III randomized trial (PRODIGE 29 - NEOPAN). Updated results will be presented at the meeting. Legal entity responsible for the studyAGEO. FundingHas not received any funding. DisclosureE. Francois: Advisory / Consultancy: Roche; Advisory / Consultancy: Servier; Advisory / Consultancy: Amgen; Advisory / Consultancy: MSD; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Novartis. J. Bachet: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi. D. Tougeron: Advisory / Consultancy: Amgen; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: Servier. J. Forestier: Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Ipsen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Honoraria (self): Servier. R. Coriat: Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Keocyt. J. Taieb: Advisory / Consultancy: Amgen; Advisory / Consultancy: Lily; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Servier; Advisory / Consultancy: Sirtex; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Amgen; Advisory / Consultancy: Amgen. All other authors have declared no conflicts of interest.

Anti-influenza immune plasma for the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial

Infection with influenza virus causes substantial morbidity and mortality globally, although antiviral treatments are available. Previous studies have suggested that anti-influenza immune plasma could be beneficial as treatment, but they were not designed as randomised, blinded, placebo-controlled trials. Therefore, we aimed to prospectively evaluate the clinical efficacy of high-titre immune plasma compared with standard low-titre plasma to improve outcomes in patients with severe influenza A infection. We did this randomised, double-blind, phase 3 trial at 41 US medical centres to assess the efficacy of high-titre anti-influenza plasma (haemagglutination inhibition antibody titre ≥1:80) compared with low-titre plasma (≤1:10). Children and adults with PCR-confirmed influenza A infection, a National Early Warning score of 3 or greater, and onset of illness within 6 days before randomisation were eligible. Patients were randomly assigned (2:1) using an interactive web response system to receive either two units (or paediatric equivalent) of high-titre plasma (high-titre group) or low-titre plasma (low-titre group), and were followed up for 28 days from randomisation. High-titre and low-titre plasma had the same appearance. Randomisation was stratified by severity (in intensive care unit, not in intensive care but requiring supplemental oxygen, or not in intensive care and not requiring supplemental oxygen) and age (<18 years and ≥18 years). All participants, site staff, and the study team were masked to treatment allocation until after the final database lock. The primary endpoint was clinical status assessed by a six-point ordinal scale on day 7 (death, in intensive care, hospitalised but requiring supplemental oxygen, hospitalised not requiring supplemental oxygen, discharged but unable to resume normal activities, and discharged with full resumption of normal activities) analysed in a proportional odds model (an odds ratio [OR] >1 indicates improvement in clinical status across all categories for the high-titre vs the low-titre group). The primary analysis was done in the intention-to-treat population, excluding two participants who did not receive plasma. This trial is registered with ClinicalTrials.gov, NCT02572817. Participants were recruited between Jan 26, 2016, and April 19, 2018. Of 200 participants enrolled (177 adults and 23 children), 140 met the criteria for randomisation and were assigned to the high-titre group (n=92) or to the control low-titre group (n=48). One participant from each group did not receive plasma. At baseline, 60 (43%) of 138 participants were in intensive care and 55 (71%) of 78 participants who were not in intensive care required oxygen. 93% of planned plasma infusions were completed. The study was terminated in July, 2018, when independent efficacy analysis showed low conditional power to detect an effect of high-titre plasma even if full accrual (150 participants) was achieved. The proportional OR for improved clinical status on day 7 was 1·22 (95% CI 0·65-2·29, p=0·54). 47 (34%) of 138 participants experienced 88 serious adverse events: 32 (35%) with 60 events in the high-titre group and 15 (32%) with 28 events in the low-titre group. The most common serious adverse events were acute respiratory distress syndrome (ARDS; four [4%] vs two [4%]), allergic transfusion reactions (two [2%] vs two [4%]), and respiratory distress (three [3%] vs none). 65 (47%) participants experienced 183 adverse events: 42 (46%) with 126 events in the high-titre group and 23 (49%) with 57 events in the low-titre group. The most common adverse events were anaemia (four [3%] vs two [4%]) and ARDS (four [3%] vs three [5%]). Ten patients died during the study (six [7%] in the high-titre group vs four [9%] in the low-titre group, p=0·73). The most common cause of death was worsening of acute respiratory distress syndrome (two [2%] vs two [4%] patients). High-titre anti-influenza plasma conferred no significant benefit over non-immune plasma. Although our study did not have the precision to rule out a small, clinically relevant effect, the benefit is insufficient to justify the use of immune plasma for treating patients with severe influenza A. National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Bethesda, MD, USA).

The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor–Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy—MONARCH 2

Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated. To compare the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET. MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib plus fulvestrant vs placebo plus fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019. Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary). The primary end point was investigator-assessed progression-free survival. Overall survival was a gated key secondary end point. The boundary P value for the interim analysis was .02. Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus fulvestrant and 37.3 months for placebo plus fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945; P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib. Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy. ClinicalTrials.gov identifier: NCT02107703.

Noninvasive Bimodal Neuromodulation for the Treatment of Tinnitus: Protocol for a Second Large-Scale Double-Blind Randomized Clinical Trial to Optimize Stimulation Parameters.

BackgroundThere is increasing evidence from animal and human studies that bimodal neuromodulation combining sound and electrical somatosensory stimulation of the tongue can induce extensive brain changes and treat tinnitus.ObjectiveThe main objectives of the proposed clinical study are to confirm the efficacy, safety, and tolerability of treatment demonstrated in a previous large-scale study of bimodal auditory and trigeminal nerve (tongue) stimulation (Treatment Evaluation of Neuromodulation for Tinnitus - Stage A1); evaluate the therapeutic effects of adjusting stimulation parameters over time; and determine the contribution of different features of bimodal stimulation in improving tinnitus outcomes.MethodsThis study will be a prospective, randomized, double-blind, parallel-arm, comparative clinical trial of a 12-week treatment for tinnitus using a Conformité Européenne (CE)–marked device with a pre-post and 12-month follow-up design. Four treatment arms will be investigated, in which each arm consists of two different stimulation settings, with the first setting presented during the first 6 weeks and the second setting presented during the next 6 weeks of treatment. The study will enroll 192 participants, split in a ratio of 80:80:16:16 across the four arms. Participants will be randomized to one of four arms and stratified to minimize baseline variability in four categories: two separate strata for sound level tolerance (using loudness discomfort level as indicators for hyperacusis severity), high tinnitus symptom severity based on the Tinnitus Handicap Inventory (THI), and tinnitus laterality. The primary efficacy endpoints are within-arm changes in THI and Tinnitus Functional Index as well as between-arm changes in THI after 6 weeks of treatment for the full cohort and two subgroups of tinnitus participants (ie, one hyperacusis subgroup and a high tinnitus symptom severity subgroup). Additional efficacy endpoints include within-arm or between-arm changes in THI after 6 or 12 weeks of treatment and in different subgroups of tinnitus participants as well as at posttreatment assessments at 6 weeks, 6 months, and 12 months. Treatment safety, attrition rates, and compliance rates will also be assessed and reported.ResultsThis study protocol was approved by the Tallaght University Hospital/St. James’s Hospital Joint Research Ethics Committee in Dublin, Ireland. The first participant was enrolled on March 20, 2018. The data collection and database lock are expected to be completed by February 2020, and the data analysis and manuscript submission are expected to be conducted in autumn of 2020.ConclusionsThe findings of this study will be disseminated to relevant research, clinical, and health services and patient communities through publications in peer-reviewed journals and presentations at scientific and clinical conferences.Trial RegistrationClinicalTrials.gov NCT03530306; https://clinicaltrials.gov/ct2/show/NCT03530306International Registered Report Identifier (IRRID)DERR1-10.2196/13176

Safety and efficacy of a docetaxel-5FU-oxaliplatin regimen with or without trastuzumab in neoadjuvant treatment of localized gastric or gastroesophageal junction cancer: A retrospective study.

BACKGROUNDTriplet chemotherapy, with docetaxel-5FU-oxaliplatin FLOT regimen recently became the standard perioperative treatment for localized gastric cancer (GC). An adapted regimen called TeFOX was recently tested in metastatic setting and gave promising results.AIMTo determine safety and efficacy of TeFOX perioperative regimen.METHODSThis monocentric retrospective study aims to test efficacy and safety of the perioperative TeFOX regimen given alone or in combination with trastuzumab in patients with localized GC. TeFOX consist in docetaxel (50 mg/m²) with oxaliplatin 85 mg/m² and and leucovorin (400 mg/m2) 5 FU bolus (400 mg/m2) on day 1, followed by continuous infusion of 5FU for 46 h (2400 mg/m2) every 2 wk.RESULTSThirty-three consecutive patients were included in this retrospective study. Eighteen patients have a gastroesophageal junction cancer and 11 have a GC. Median follow-up of surviving patients was 32 mo. R0 resection was obtained in 30 (91) patients. Twelve patients (36) had a pathological complete response and 8 (24) patients a nearly complete pathological response. Median OS and PFS were not reached at data base lock. We have observed 6 metastatic relapses and 1 localized relapse. No relapse was observed in patients with pathological complete responses. The most common grade 3-4 adverse events were peripheral neuropathy (21) and asthenia (20).CONCLUSIONTeFOX regimen could be safely administrated in perioperative treatment of localized GC. TeFOX and the FLOT regimen have comparable efficacy and safety profiles.

Patient-reported outcomes and final overall survival results from the randomized phase 3 PENELOPE trial evaluating pertuzumab in low tumor human epidermal growth factor receptor 3 (HER3) mRNA-expressing platinum-resistant ovarian cancer

IntroductionThe PENELOPE trial evaluated pertuzumab added to chemotherapy for biomarker-selected platinum-resistant ovarian cancer. As previously reported, pertuzumab did not statistically significantly improve progression-free survival (primary end point: HR 0.74, 95%...

A pre-specified statistical analysis plan for the VERIFY study: Vildagliptin efficacy in combination with metformin for early treatment of T2DM.

AimsTo ensure the integrity of the planned analyses and maximize the clinical utility of the VERIFY study results by describing the detailed concepts behind its statistical analysis plan (SAP) before completion of data collection and study database lock. The SAP will be adhered to for the final primary data analysis of the VERIFY trial.Materials and MethodsVildagliptin efficacy in combination with metformin for early treatment of T2DM (VERIFY) is an ongoing, multicentre, randomized controlled trial aiming to demonstrate the clinical benefits of glycaemic durability and glucose control achieved with an early combination therapy in newly‐diagnosed type 2 diabetes (T2DM) patients.ResultsThe SAP was initially designed at the study protocol conception phase and later modified, as reported here, in collaboration between the steering committee members, statisticians, and the VERIFY study leadership team. All authors were blinded to treatment allocation. An independent statistician has additionally retrieved and presented unblinded data to the independent data safety monitoring committee. An overview of the trial design with a focus on describing the fine‐tuning of the analysis plan for the primary efficacy endpoint, risk of initial treatment failure, and secondary, exploratory and pre‐specified subgroup analyses is provided here.ConclusionAccording to optimal trial practice, the details of the statistical analysis and data‐handling plan prior to locking the database are reported here. The SAP accords with high‐quality standards of internal validity to minimize analysis bias and will enhance the utility of the reported results for improved outcomes in the management of T2DM.

PF679 REAL‐WORLD SAFETY DATA FROM A NONINTERVENTIONAL LONG‐TERM POSTAUTHORIZATION SAFETY STUDY OF RUXOLITINIB IN MYELOFIBROSIS

Background:Ruxolitinib (RUX, oral JAK inhibitor) was approved for treatment (Tx) of patients (pts) with myelofibrosis (MF) based on the data from COMFORT I/II (phase 3 registrational studies). At the time of submission of the Marketing Authorization Application in the European Union (EU), a significant number of pts (589) had been exposed to RUX in clinical studies. However, there was a lack of postmarketing exposure data leading to an agreement with the European Medicines Agency to conduct this postauthorization safety study (PASS [ENCePP No. 3296]: per EU Vol. 9a [Rules for Medicinal Products]).Aims:To provide real‐world safety data on pts with MF exposed/nonexposed to RUX.Methods:This was a prospective, multicenter, noninterventional PASS study for adult pts with MF (primary [per WHO criteria]/secondary [per IWG‐MRT criteria]). The primary objective was to study long‐term safety (incidence of adverse drug reactions [ADRs]/serious adverse events [SAEs]) in pts with MF treated with RUX as per prescribing information. The key secondary objectives included the incidence/outcome of events of special interest (EoSI [bleeding events, serious/opportunistic infections, second primary malignancies, and deaths]). The statistical analysis was done after last pt completed 3 years on the study or discontinued early (final database lock, July 5, 2018).Results:Overall, 462 pts were included (prevalent users = 260, new users = 32, nonexposed = 170 [inclusive of RUX‐switch {N = 57}]). The demographic/baseline pt characteristics (representative of pts with MF and well balanced across all types of users) and pt disposition will be described in the presentation. The study duration, RUX‐exposure, summary of dose reductions/interruptions (primary reasons: medical decisions/ADRs across all cohorts), Tx‐emergent ADRs, and Tx‐emergent SAEs are summarized in Table A. The exposure‐adjusted incidence rates of ADRs and SAEs were comparable among the new users’ vs the prevalent users’ cohorts (ADR: 19.3 vs 19.6; SAE: 25.2 vs 25.0; Table A). The most frequently reported ADRs across all types of cohorts included thrombocytopenia, anemia, epistaxis, and herpes zoster. The incidence rates of thrombocytopenia and anemia were higher in the RUX‐switch vs prevalent users’/new users’ cohorts (shorter duration of exposure in the RUX‐switch cohort). Anemia, pneumonia, and general physical health deterioration were the most frequently reported SAEs across all cohorts. The incidence rate of Tx‐emergent SAE (any SAE) was slightly higher in RUX‐switch cohort vs the prevalent users’/new users’ cohorts. The Tx‐emergent EoSIs are presented in Table B. Bleeding events were reported in a larger proportion of pts in the prevalent users’ cohort; while serious/opportunistic infections were reported in a larger proportion of pts in the new users’ cohort (vs other cohorts). The second primary malignancies were reported in a larger proportion of pts in the prevalent users’ cohort (Table B). The incidence rate of on‐Tx deaths (due to any cause [mostly attributed to progression of underlying MF, sepsis, and pneumonia]) is listed in Table B.Summary/Conclusion:The long‐term safety of RUX as assessed in this real‐world PASS study was consistent with the previous findings (COMFORT I/II). Of note, the study comprised of a broader population including pts at lower risk/elderly pts vs the COMFORT I/II study populations. No new or unexpected safety signals were identified with the long‐term Tx. Overall, the observed safety profile of RUX in this PASS study along with the safety findings from COMFORT I/II support the long‐term Tx with RUX in pts with MF.image