SIDEBAR: The Ethical Imperative of Clinical Equipoise 


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In her editorial about the RESONATE trial (page 1), Dr. O’Brien raises the issue of equipoise in this phase III clinical trial that compares the efficacy of ibrutinib and ofatumumab (Arzerra) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are not appropriate candidates for treatment or retreatment with purine analog-based therapy.

In the latest update of a phase Ib/II study of ibrutinib in 116 patients presented in December 2012, Byrd et al reported that 85 patients with relapsed or refractory CLL had a 71% overall response rate (or 89% if patients with a partial response with lymphocytosis are included) and a progression-free survival rate of 75% at 26 months.1 In 31 elderly, treatment-naive patients, overall response rate was 68% (or 81% if patients with a partial response with lymphocytosis are included) with a progression-free survival rate of  96% at 26 months.1

In contrast, Wierda et al had previously reported overall response rates for ofatumumab of 58% with median progression-free survival of 5.7 months in fludarabine- and alemtuzumab (Campath)-refractory CLL patients and 47% with median progression-free survival of 5.9 months in fludarabine-refractory CLL patients with bulky lymphadenopathy.2 Thus, as Dr. O’Brien notes, the phase II data for ibrutinib presented at the American Society of Hematology Annual Meeting appear spectacular, especially with respect to progression-free survival, and the magnitude of benefit of ibrutinib over ofatumumab should be impressive.

Interim Results Due in 2014

The phase III RESONATE trial should provide the “substantial evidence” required by the FDA to establish the effectiveness of ibrutinib. On April 3, 2013, the enrollment target of 350 patients for the RESONATE trial was achieved. Based on estimates of progression-free survival events for each arm, we should expect the results of the planned interim analysis in the first quarter of 2014.

If what we expect is confirmed—ie, the interim analysis shows sufficient evidence of benefit in progression-free survival for patients receiving ibrutinib—we are obligated to uphold the ethical imperative of clinical equipoise. All patients who participated in the study should be allowed early access to ibrutinib. We will watch closely to see that this responsibility to our patients is fulfilled. ■

Disclosure: Dr. Schuster receives research support from Pharmacyclics.

References

1. Byrd JC, Furman RR, Coutre S, et al: The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: New and updated results of 116 Patients in a phase Ib/II study. 2012 ASH Annual Meeting. Abstract 189. Presented December 9, 2012.

2. Wierda WG, Kipps TJ, Mayer J, et al: Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 28:1749-1755, 2010.

Dr. Schuster is Robert and Margarita Louis-Dreyfus Associate Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research and Director, Lymphoma Program, Abramson Cancer Center of the University of Pennsylvania, Philadelphia.


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