The RESONATE trial is randomly assigning patients with refractory or relapsed CLL to either ofatumumab (Arzerra) or the investigational oral agent ibrutinib. Ofatumumab is an anti-CD20 monoclonal antibody like rituximab (Rituxan), but is more potent as a single agent. It was approved for refractory CLL about 3½ years ago. Ibrutinib is a novel Bruton’s tyrosine kinase (BTK) inhibitor that has shown promising results in early data for CLL, leading to the current RESONATE trial that just recently completed enrollment.
The primary endpoint is progression-free survival; however, overall survival is one of the secondary endpoints. Once the primary endpoint has been met, not allowing crossover has caused considerable dismay in the oncology community, not to mention among patients. It is my understanding that the FDA strongly opposed allowing crossover. I presume that is because the FDA also wants to see if there is a survival advantage.
In my opinion that’s wrong—the magnitude of benefit of ibrutinib over ofatumumab is going to be spectacular. Where is the equipoise?
Look back several years, and you’ll find a glaring example of what’s now happening with RESONATE. Imatinib (Gleevec) received accelerated FDA approval for chronic myeloid leukemia patients after failure of interferon, which was the standard front-line therapy at the time. Then the IRIS trial compared front-line treatment with interferon to imatinib in randomized fashion. In retrospect, that trial was not reasonable. The data clearly showed that imatinib was an order of magnitude superior to interferon, not to mention significantly less toxic, yet there were very strict crossover criteria that resulted in little crossover.
When that trial ended, imatinib received immediate approval in the front-line setting, and patients on the interferon arm instantly went on imatinib. Thus, there was no improvement in survival with imatinib, but does anyone really think that without a randomized trial you can’t show survival benefit? Just look at published data for survival curves in imatinib compared to any historical control data as well as SEER data. Imatinib has dramatically improved survival for the population at large. We knew that going into the trial.
Here’s the harsh reality: There are people on the control arm of RESONATE who will probably have disease progression and die. Presumably, that is what FDA believes is necessary to document improved survival. As I’ve pointed out, the magnitude of ibrutinib’s benefit obviates the need for this. I think it’s unfortunate, and most people in the CLL community feel the same way.
This is an important issue that needs open discussion. ■
Disclosure:Dr. O’Brien receives research support from Pharmacyclics.
Dr. O’Brien is Ashbel Smith Professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston.
Editor’s note: Ibrutinib is currently being studied in a randomized phase III trial called RESONATE [A Randomized, Multicenter, Open-label, Phase III Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib vs Ofatumumab in Relapsed or Refractory CLL/SLL]. There is no crossover for patients who show disease progression on treatment. The ASCO Post invited leukemia experts Susan O’Brien, MD, and Stephen J. Schuster, MD, to share their opinions on the issue. We invite you to share your opinions on this subject. Write to editor@ASCOPost.com.
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...