Abstract
Background FL, a highly heterogenous and incurable malignancy, is the second most common NHL subtype and the most common indolent NHL (Freedman & Jacobsen. Am J Hematol. 2020;95:316-27). Despite effectiveness of first-line chemoimmunotherapy, relapses occur in most patients and remissions shorten with each recurrence. No well-defined standard of care exists for patients with R/R FL. There is a substantial need to identify new approaches that offer innovative options for high-risk patients, can overcome disease resistance, avoid cumulative toxicities from successive therapies, reduce transformation risk, and raise the prospect of cure (Hübel, et al. Hemasphere. 2018;2:6).
Large-scale, patient-level, real-world (RW) evidence studies can provide a better understanding of outcomes with currently available therapies in routine clinical practice and contextualize results from uncontrolled clinical trials. In the FLORA study, we aim to identify a large cohort of approximately 450 patients from over 30 clinical sites in 13 countries across North America, Europe, and Asia to characterize RW treatment patterns and outcomes in adults with Grade 1-3a R/R FL. Among them, we will create an analytic cohort with approximately 165 patients who have measurable disease at baseline and PET/CT scans during follow-up, unless they died.
Study Design and Methods FLORA (NCT05338879) is an electronic medical record-based observational, retrospective cohort study evaluating treatment patterns and outcomes in patients with R/R FL who initiate currently available systemic therapies after at least 2L of systemic therapies including an anti-CD20 antibody and an alkylator. The study population will be selected based on similar eligibility criteria as the FL Grade 1-3a arm of the odronextamab ELM-2 trial (NCT03888105) (Figure). Patients must have measurable disease on cross sectional imaging and must have initiated at least 1 additional line of systemic therapy (salvage therapy) for FL Grade 1-3a between Jan 01, 2015 and Dec 31, 2020 (indexing period) after meeting the criteria for R/R FL Grade 1-3a.
FLORA aims to contextualize outcomes from patients with R/R FL enrolled in contemporaneous single-arm studies. To estimate RW objective response rate (ORR) by independent central review (ICR), analytic cohorts will be created from the FLORA population based on data requirements and matching feasibility. Patients eligible for inclusion in FLORA will be propensity score matched and/or weighted to each patient in the ELM-2 trial (anticipated cohort, n=128). To identify variables for inclusion in the propensity score model, a systematic literature review (Prognostic Factors and Effect Modifiers in Patients with Relapsed or Refractory FL Who Failed at Least 2 Lines of Therapy; registered on PROSPERO as CRD42022307561) was conducted. Three key opinion leaders categorized prognostic variables as being of "very high importance", "high importance", "mild importance", "low importance", and "not important" and ranked them for inclusion in the propensity score model. The most important prognostic variables identified include progression of disease within 24 months, chemoimmunoresistance, refractory to last line of therapy, number of prior treatment lines, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, FL International Prognostic Index, age, and Ann Arbor Stage.
The primary endpoint of FLORA is ORR according to Lugano classification of malignant lymphoma and as assessed by ICR. Secondary endpoints include ORR according to the Lugano classification and as assessed by the treating physician, as well as complete response rate, progression-free survival, duration of response, and disease control rate as assessed by ICR and treating physicians. Time to next treatment, overall survival, and histological transformation will also be evaluated. Subgroups of interest will include historical (Jan 01, 2015 through Nov 12, 2019) versus contemporary treatment (Nov 13, 2019 through Dec 31, 2020) and geographic region. Sensitivity analyses will be conducted in expanded cohorts to assess the impact of eligibility criteria and availability of scans.
When complete, FLORA will provide important information on the RW outcomes of patients with FL with high unmet need and provide a valuable source of control data for comparative studies in R/R FL.
Disclosures
Bachy:Amgen, BMS: Research Funding; Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, Sanofi: Honoraria; Roche, Gilead, ADC Therapeutics, Takeda, Novartis, Incyte: Membership on an entity's Board of Directors or advisory committees; Hospices Civils de Lyon: Current Employment. Damaj:Blueprint Medicines Corporation: Consultancy; AbbVie: Other: Travel, accommodation, expenses; Thermofisher: Consultancy; Takeda: Consultancy, Other: Travel, accommodation, expenses; Pfizer: Other: Travel, accommodation, expenses. Ma:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Hampp:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Harnett:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Pfizer Inc.: Current equity holder in publicly-traded company. Sobel:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Pfizer: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Jalbert:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Quek:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Wei:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Wu:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Mastey:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Wang:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Bajwa:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Maissenhaelter:IQVIA: Current Employment; Regeneron Pharmaceuticals, Inc.: Consultancy. Aggarwal:IQVIA: Current Employment; Amgen: Ended employment in the past 24 months. Chaudhry:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Mohamed:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Ambati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Thieblemont:Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda: Consultancy, Honoraria, Other: Travel Support; Incyte: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support; Novartis: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel Support; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support.
OffLabel Disclosure:
Off-Label Drug Purpose: The abstract describes the study design and methods of an observational, retrospective cohort study of real-world treatment patterns and outcomes in adults with Grade 1-3a R/R FL (FLORA), which aims to contextualize outcomes in contemporaneous single-arm studies such as the ELM-2 trial of odronextamab.
