Beyond a Binary Endpoint: Longitudinal and Individual Symptom Analyses from the Simplify-1 Study Demonstrate Clinically Comparable Symptomatic Benefit of Momelotinib to Ruxolitinib in JAK Inhibitor Naive Myelofibrosis Patients

Author(s)

Mesa R¹, Hudgens S², Floden L², Palmer J³, Gupta V⁴, McLornan DP⁵, McMullin MF⁶, Kiladjian JJ⁷, Foltz L⁸, Platzbecker U⁹, Fox ML¹⁰, Mead AJ¹¹, Ross DM¹², Oh ST¹³, Perkins A¹⁴, Leahy MF¹⁵, Deheshi S¹⁶, Donahue R¹⁷, Klencke BJ¹⁷, Verstovsek S¹⁸
¹UT Health San Antonio MD Anderson, Boerne, TX, USA, ²Clinical Outcomes Solutions, Tucson, AZ, USA, ³Mayo Clinic, Phoenix, AZ, USA, ⁴University Health Network, University of Toronto, Toronto, ON, Canada, ⁵Guy's & St Thomas' NHS Foundation Trust, London, UK, ⁶Queens University, Belfast City Hospital Trust, Belfast, UK, ⁷Hôpital Saint-Louis; Université de Paris, Paris, France, ⁸St Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada, ⁹Leipzig University Hospital, Leipzig, Germany, ¹⁰Hematology Department, Hospital Universitario Vall d'Hebron, Barcelona, Spain, ¹¹MRC Weatherall Institute of Molecular Medicine, Oxford, UK, ¹²Flinders Medical Centre and University, Adelaide, SA, Australia, ¹³Washington University School of Medicine, St. Louis, MO, USA, ¹⁴Monash University, Malvern, SA, Australia, ¹⁵University of Western Australia, Perth, WA, Australia, ¹⁶Sierra Oncology, Vancouver, Canada, ¹⁷Sierra Oncology, Vancouver, BC, Canada, ¹⁸MD Anderson Cancer Center, Houston, TX, USA

OBJECTIVES:

Clinical trials investigating JAK1/JAK2 inhibitors for myelofibrosis subjects have measured symptom improvement as a minimum 50% reduction in total symptom score (TSS) at the end of a 24-week treatment period. However, this landmark response analysis is based on post-baseline score changes occurring only between Week 21 (W21) through W24 and does not account for variation in baseline TSS. To better understand the clinical relevance of TSS improvement we applied individual item analyses and Mixed-effect Models for Repeated Measures (MMRM) to SIMPLIFY-1, a phase 3 study which randomized 432 intermediate and high risk JAK inhibitor-naive MF patients 1:1 to momelotinib or ruxolitinib.

METHODS:

Analyses were conducted in the intention-to-treat (ITT) population and in symptomatic subjects (baseline TSS ≥ 10). The distributions of TSS items were examined at baseline, and shift in scores at W24 (health state shifts) were determined. Odds ratios from generalized estimating equations for improvement on momelotinib relative to ruxolitinib were calculated for each item of the TSS using multiple predictive imputations for missing data. The MMRM compared mean change in TSS from baseline through W24. The meaningful change threshold (MCT) was determined using Patient Global Impression of Change.

RESULTS:

While the prespecified non-inferiority endpoint for TSS response rate was not met for momelotinib (28%) vs ruxolitinib (42%), item-level health state shifts and responder analyses showed similar improvements for momelotinib and ruxolitinib. No significant differences on any items were seen; odds ratios for each between-group comparison ranged from 0.74 to 1.20.

MMRM mean TSS change score at W24 was 6.35 (momelotinib) vs 7.87 (ruxolitinib) in the ITT and 8.80 (momelotinib) vs 10.46 (ruxolitinib) in the symptomatic subset. TSS improvements were near the within-subject MCT of 8 points in the ITT and exceeded the MCT in the symptomatic subset.

CONCLUSIONS:

Item analyses and MMRM showed clinically important and comparable improvements in TSS.

Conference/Value in Health Info

2021-05, ISPOR 2021, Montreal, Canada

Value in Health, Volume 24, Issue 5, S1 (May 2021)

Code

PCN19

Topic

Clinical Outcomes, Methodological & Statistical Research, Patient-Centered Research

Topic Subcategory

Clinical Outcomes Assessment, Patient-reported Outcomes & Quality of Life Outcomes, PRO & Related Methods

Disease

Drugs, Oncology

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