David Hong1, Drew Rasco2, Michael Veeder3, Jason J Luke4, Jason Chandler5, Ani Balmanoukian6, Thomas J George7, Pamela Munster8, Jordan D Berlin9, Martin Gutierrez10, Alain Mita11, Heather Wakelee12, Selda Samakoglu13, Shanhong Guan14, Isaiah Dimery13, Thorsten Graef13, Erkut Borazanci15. 1. Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA, dshong@mdanderson.org. 2. Department of Clinical Research, South Texas Accelerated Research Therapeutics, Houston, Texas, USA. 3. Department of Oncology, Illinois Cancer Care, Peoria, Illinois, USA. 4. Department of Medicine, University of Chicago, Chicago, Illinois, USA. 5. Department of Oncology and Hematology, West Cancer Center, Memphis, Tennessee, USA. 6. Department of Oncology, The Angeles Clinic and Research Institute, Los Angeles, California, USA. 7. Department of Medicine, University of Florida Health Cancer Center, Gainesville, Florida, USA. 8. Department of Medicine, University of California San Francisco, San Francisco, California, USA. 9. Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA. 10. Department of Hematology and Oncology, Hackensack University Medical Center, Hackensack, New Jersey, USA. 11. Department of Experimental Therapeutics, Cedars-Sinai Medical Center, Los Angeles, California, USA. 12. Division of Oncology, Department of Medicine, Stanford University, Stanford, California, USA. 13. Department of Clinical Science, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California, USA. 14. Department of Biostatistics, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California, USA. 15. Department of Clinical Translational Research, HonorHealth/TGen, Scottsdale, Arizona, USA.
Abstract
BACKGROUND: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. METHODS: This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab. RESULTS: The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). CONCLUSIONS: The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.
BACKGROUND:Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. METHODS: This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab. RESULTS: The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). CONCLUSIONS: The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.
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