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Ibrutinib as Treatment for Patients With Relapsed/Refractory Follicular Lymphoma: Results From the Open-Label,
Ajay K Gopal1, Stephen J Schuster1, Nathan H Fowler1
1Ajay K. Gopal, The University of Washington; Ajay K. Gopal, Fred Hutchinson Cancer Research Center, Seattle, WA; Stephen J. Schuster, Abramson Cancer Center of the University of Pennsylvania, Philadelphia; Jing-Zhou Hou, University of Pittsburgh Medical Center; Jing-Zhou Hou, University of Pittsburgh Cancer Institute, Pittsburgh; Rajendra N. Damle, Michael Schaffer, and Sriram Balasubramanian, Janssen Research & Development, Spring House, PA; Nathan H. Fowler, The University of Texas MD Anderson Cancer Center, Houston, TX; Judith Trotman, Concord Hospital, University of Sydney, Sydney, New South Wales; Andrew Spencer, Alfred Hospital-Monash University, Melbourne, Victoria; James Morton, Haematology and Oncology Clinics of Australia, Milton, Queensland, Australia; Georg Hess, Johannes Gutenberg-University, Mainz, Germany; Abdulraheem Yacoub, Kansas University Medical Center, Kansas City, KS; Michael Lill, Cedars-Sinai Medical Center, Los Angeles, CA; Peter Martin, Weill Cornell Medical College, Cornell University, New York, NY; Umberto Vitolo, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; John Radford, University of Manchester; John Radford, Christie National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; Wojciech Jurczak, Jagiellonian University, Kraków, Poland; Dolores Caballero, Hospital Clínico Universitario, Salamanca, Spain; Sanjay Deshpande, Gary J. Gartenberg, and Shean-Sheng Wang, Janssen Research & Development, Raritan, NJ; Jessica Vermeulen, Janssen Research & Development, Leiden, the Netherlands; Bruce D. Cheson, Georgetown University Hospital, Washington, DC; and Gilles Salles, Hospices Civils de Lyon-Université de Lyon, Pierre-Bénite cedex, Lyon, France.
Purpose The Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee-assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle 3) and cytokines/chemokines (baseline/cycle 2) were performed for available samples. Results Between March 2013 and May 2016, 110 patients with a median of three prior lines of therapy were enrolled. At median follow-up of 27.7 months, ORR was 20.9% (95% CI, 13.7% to 29.7%, which did not meet the 18% lower-bound threshold for the primary end point). Twelve patients achieved a complete response (11%; 95% CI, 5.8% to 18.3%). Median duration of response was 19.4 months (range, 1 to ≥ 33 months), with a median progression-free survival of 4.6 months and a 30-month overall survival of 61% (95% CI, 0.51% to 0.70%). Lymphoma symptoms resolved in 67%. Seven of 32 patients who experienced initial radiologic progression responded upon continuing therapy (pseudoprogression). The most common adverse events were diarrhea, fatigue, cough, and muscle spasms; 48.2% of patients reported serious adverse events. In patients who experienced a response, regulatory T cells were downregulated at C3D1 ( P = .02), and Th1-promoting (antitumor) cytokines interferon-γ and interleukin-12 increased ( P ≤ .035). Conclusion With an ORR of 20.9%, ibrutinib failed to meet its primary efficacy end point in chemoimmunotherapy in patients with relapsed/refractory FL, although responses were durable and associated with a reduction in regulatory T cells and increases in proinflammatory cytokines.
Purpose The Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee-assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle 3) and cytokines/chemokines (baseline/cycle 2) were performed for available samples. Results Between March 2013 and May 2016, 110 patients with a median of three prior lines of therapy were enrolled. At median follow-up of 27.7 months, ORR was 20.9% (95% CI, 13.7% to 29.7%, which did not meet the 18% lower-bound threshold for the primary end point). Twelve patients achieved a complete response (11%; 95% CI, 5.8% to 18.3%). Median duration of response was 19.4 months (range, 1 to ≥ 33 months), with a median progression-free survival of 4.6 months and a 30-month overall survival of 61% (95% CI, 0.51% to 0.70%). Lymphoma symptoms resolved in 67%. Seven of 32 patients who experienced initial radiologic progression responded upon continuing therapy (pseudoprogression). The most common adverse events were diarrhea, fatigue, cough, and muscle spasms; 48.2% of patients reported serious adverse events. In patients who experienced a response, regulatory T cells were downregulated at C3D1 ( P = .02), and Th1-promoting (antitumor) cytokines interferon-γ and interleukin-12 increased ( P ≤ .035). Conclusion With an ORR of 20.9%, ibrutinib failed to meet its primary efficacy end point in chemoimmunotherapy in patients with relapsed/refractory FL, although responses were durable and associated with a reduction in regulatory T cells and increases in proinflammatory cytokines.
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