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3266 Sensitivity Analysis of Overall Response Rate (ORR) with Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis (HLH)

Program: Oral and Poster Abstracts
Session: 704. Immunotherapies: Poster III
Hematology Disease Topics & Pathways:
Biological, antibodies, Diseases, Therapies, Genetic Disorders, red blood cells, Pediatric, Biological Processes, Immune Disorders, immune cells, Young Adult, Lymphocytopenia, immunotherapy, Cell Lineage, Neutropenia, Study Population, Clinically relevant, inflammation
Monday, December 7, 2020, 7:00 AM-3:30 PM

Franco Locatelli, MD, PhD1, Michael B. Jordan, MD2,3, Carl Allen4*, Simone Cesaro, MD5*, Carmelo Rizzari6*, Anupama Rao7*, Barbara Degar, MD8*, Tim Garrington, MD9*, Julian Sevilla, MD, PhD10*, Maria Caterina Putti, MD11*, Franca Fagioli, MD12*, Martina Ahlmann, MD13*, Jose-Luis Dapena Diaz14*, Michael Henry, MD15*, Fabrizio De Benedetti, MD16*, Alexei Grom17*, Anna Stoltenberg18*, Mårten Vågerö18* and Cristina de Min19*

1The Department of Pediatrics, Sapienza, University of Rome, and the Department of Pediatric Hematology–Oncology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
2University of Cincinnati College of Medicine, Cincinnati, OH
3Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
4Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX
5The Pediatric Hematology–Oncology, Woman and Child Hospital, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
6The Pediatric Hematology–Oncology Unit, Department of Pediatrics, University of Milano–Bicocca, Monza Brianza per il Bambino e la sua Mamma Foundation, Monza, Italy
7Department of Hematology, Great Ormond Street Hospital for Children, London, United Kingdom
8Department of Pediatric Hematology–Oncology, Dana–Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA
9The Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO
10The Departments of Pediatric Hematology–Oncology and Hematology and Oncology, Fundación para la Investigación Biomédica, Hospital Infantil Universitario Niño Jesús, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
11The Clinic of Pediatric Hematology–Oncology, University Hospital of Padova, Padua, Italy
12The Division of Pediatric Onco-Hematology, Regina Margherita Hospital, Turin, Italy
13Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
14Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
15The Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ
16Division of Rheumatology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
17The Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
18Swedish Orphan Biovitrum (Sobi) AB, Stockholm, Sweden
19Swedish Orphan Biovitrum (Sobi) AG, Basel, Switzerland

Background: Primary HLH is a rare, life-threatening immune disorder characterized by a hyperinflammatory state. In patients with primary HLH, interferon gamma (IFNy) is often markedly elevated and is considered one of the key cytokine driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation, the only curative therapy. Conventional HLH therapy comprises immunotherapies (namely, dexamethasone and etoposide), which, unfortunately, predispose patients to infections and toxicity. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. Currently, there is no regulatory precedent or validated response criteria for efficacy assessment to guide clinical trials in primary HLH. In the pivotal study of emapalumab in primary HLH, objective response criteria were used to define the primary endpoint of overall response (Locatelli et al NEJM 2020). These response criteria were defined based on the Histiocyte Society HLH diagnostic criteria (Henter et al Pediatr Blood Cancer 2007), clinical considerations from the study’s Scientific Steering Committee, and available experience reported with conventional HLH treatments. We now report on findings of a sensitivity analysis of overall response rate (ORR) to emapalumab using various assessment criteria.

Methods: The open-label pivotal study included patients aged ≤18 years with a diagnosis of primary HLH and active disease (NCT01818492; Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 10 mg/kg if required, based on predefined laboratory and clinical response parameters, for a treatment duration of 8 weeks. In addition to emapalumab, all patients received dexamethasone, and a protocol amendment allowed for concomitant use of other HLH treatments if deemed appropriate by the investigator. ORR at end of treatment was analyzed as per the protocol definition in the 27 patients previously treated with conventional therapies. In addition, several pre-specified and post hoc sensitivity analyses were performed to pressure test the data; including: (i) a pre-specified analysis using a more conservative approach where any patient who received concomitant HLH therapies during the study was imputed as non-responder; (ii) a pre-specified analysis with physician-reported response rates recorded by the study investigators, based on their clinical judgement and previous experience in treating patients with primary HLH; and (iii) a post hoc sensitivity analysis using a previously published definition of overall response (Henter et al Pediatr Blood Cancer 2007).

Results: 63% (95% confidence interval [CI], 0.42, 0.81) of 27 treatment-experienced patients had a response according to the pivotal study protocol definition of ORR (Fig. 1). A pre-specified sensitivity analysis on the primary endpoint where any patient who received concomitant HLH therapy and imputed as non-responders showed a magnitude of response similar to that observed in the protocol-defined primary analysis (59.3%; 95% CI 0.39, 0.78; n=22). Use of the response criteria defined by Marsh et al (Pediatr Blood Cancer 2013) in a retrospective analysis of 27 patients with primary HLH also resulted in a similar ORR to the protocol-defined primary endpoint in treatment-experienced patients (70.4%; 95% CI 0.50, 0.86). When platelet count was added to this analysis, the percentage of responders to emapalumab increased to 74.1% (95% CI 0.54, 0.89). The pre-specified analysis of physician-reported response rates was also in line with the primary analysis, with 70.4% (95% CI 0.50, 0.86) of 27 treatment-experienced patients deemed to have a response to emapalumab.

Conclusion: The current analyses using different definitions of treatment response support the primary analysis results by having a numerically comparable point estimate to the primary endpoint, therefore confirming the positive benefit of emapalumab in patient's refractory or intolerant to conventional HLH therapies. Taken together, these findings also suggest that the clinically objective ORR, utilized in the pivotal emapalumab trial, may be used as a primary endpoint in primary HLH.

Disclosures: Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jordan: Sobi: Consultancy. Allen: Sobi: Other: Scientific Steering Committee, Data And Safety Monitoring. Rizzari: Sobi: Consultancy, Other: Advisory Board. Rao: Sobi: Consultancy, Other: Advisory Board. Sevilla: Amgen: Other: Advisory Board; Rocket Pharma: Consultancy; Sobi: Other: Advisory Board; Novartis: Other: Advisory Board. Henry: Sobi: Consultancy. De Benedetti: Abbvie: Research Funding; F Hoffmann-La Roche AG: Research Funding; Novartis Pharma: Research Funding; Pfizer: Research Funding; Sanofi-Aventis: Research Funding; Sobi: Consultancy, Research Funding. Grom: Sobi: Consultancy; Novartis Pharma: Consultancy; AB2Bio: Consultancy. Stoltenberg: Sobi: Current Employment. Vågerö: Sobi: Consultancy. de Min: Sobi: Consultancy.

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