Vincent Ribrag1, Seung Tae Lee2, David Rizzieri3, Martin J S Dyer4, Luis Fayad5, Razelle Kurzrock5, Leslie Andritsos6, Reda Bouabdallah7, Amjad Hayat8, Larry Bacon9, Yu Jiang10, Kowser Miah10, Bruno Delafont10, Oday Hamid10, Stephanie Anyanwu10, Pablo Martinez10, Brian Hess11. 1. Department of Hematology, Early Drug Development, Institut Gustave Roussy, Villejuif, France. Electronic address: vincent.ribrag@igr.fr. 2. Department of Medicine, University of Maryland, Baltimore, MD. 3. Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC. 4. The Ernest and Helen Scott Hematological Research Institute, University of Leicester, Leicester, UK. 5. Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX. 6. Division of Hematology/Oncology, University of New Mexico, Albuquerque, NM. 7. Department of Hematology, Institut Paoli-Calmettes Unicancer, Paris, France. 8. Department of Haematology, University Hospital Galway, Galway, Ireland. 9. Department of Haematology, St James' Hospital, Dublin, Ireland. 10. AstraZeneca, Gaithersburg, MD. 11. Division of Hematology & Oncology, MUSC Health Hollings Cancer Center, Charleston, SC.
Abstract
BACKGROUND: Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti-cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity. PATIENTS AND METHODS: In this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. RESULTS: As of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks). CONCLUSION: The primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.
BACKGROUND: Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti-cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity. PATIENTS AND METHODS: In this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. RESULTS: As of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks). CONCLUSION: The primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.