The story of a promising cancer treatment that was lost, then found again

CURE invited Diane Gambill, PhD, a CURE advisory board member, to share her thoughts on advancements in blood cancers highlighted at the 2014 annual meeting of the American Society of Clinical Oncology.Several years ago, I heard the early results of a new drug being studied in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). The drug (PCI-32765, an inhibitor of Bruton's tyrosine kinase) generated a lot of excitement, but might not have made it to the clinic.Like the stories behind Viagra and penicillin, the development of PCI-32765 is a classic example of scientists developing a compound for one thing and finding out, almost by accident, that it might be useful for something else. PCI-32765 was developed by a company called Celera engaged in the Human Genome Project as a tool to help find new drugs – not as a potential new drug itself, but the head of Celera resigned after the 2006 completion of sequencing the human genome and progress on their new drug portfolio ground to a halt.In 2007, Pharmacyclics acquired the intellectual property of Celera including PCI-32765, what was to later become "Imbruvica." PCI-32765 was not among the acquired compounds that was initially pursued; however, it took less than seven years for Imbruvica to enter the clinic for treatment of MCL (2013), and in February 2014, the FDA granted accelerated approval of Imbruvica for patients with previously treated CLL based on a small phase 2 trial that showed an impressive response rate in 48 heavily pretreated patients [NEJM 2013;369:32). To gain full approval from the FDA, these results need to be confirmed and shown to improve long-term outcomes in phase 3 trials. Seven trials are underway and the preliminary findings of one of them (a trial called RESONATE) were announced at the 2014 annual meeting of the American Society for Clinical Oncology.The RESONATE trial compared Imbruvica to Arzerra (ofatumumab), another treatment for CLL. Patients with CLL that had relapsed following response to prior treatment or was refractory to treatment were randomized to daily oral Imbruvica or 12 doses of intravenous Arzerra. The goal of the trial was to determine if the 195 patients treated with Imbruvica had longer progression-free survival (PFS) than the 196 patients treated with Arzerra. The trial included patients with poor prognostic characteristics such as bulky disease (about half of the patients) and a third of patients had chromosome 17p deletions. The majority (86 percent) of patients on the Imbruvica regimen remain on therapy while all but one of the Arzerra patients had completed therapy. Of note, patients who progressed on Arzerra were allowed to cross over to the Imbruvica arm as of August 2013.The overall response rate was substantially higher for Imbruvica (48 percent) than for Arzerra (4 percent), and the gap was even larger if patients who had a partial response with lymphocytosis were included (63 percent vs. 4 percent). This is consistent with the phase 2 results. According to the investigators, more than 80 percent of the patients receiving Imbruvica are in remission at one year – more than twice the number expected from standard therapy. More importantly, patients who were treated with Imbruvica had significantly better PFS and overall survival compared with those who were treated with Arzerra. With Imbruvica, the risk of progressive disease or death decreased by 78 percent and 57 percent, respectively. The advantage in overall survival was seen despite patients receiving Imbruvica after progressing on Arzerra.Probably the most impressive result was that the data was positive in all subgroups, including disease that was refractory to fludarabine or had poor prognostic markers such as 17p deletions, both of which tend to limit the efficacy of traditional therapies.Both treatments were relatively safe and there were no unexpected toxicities. Diarrhea and mild infection were more common with Imbruvica. Serious infections were similar between the two treatments. Atrial fibrillation (a heart rhythm disorder) was more frequent with Imbruvica (10 patients versus 1 with Arzerra) but caused only treatment discontinuation. Bleeding was also more common with Imbruvica; however, there were no serious events. Infusion reactions and neuropathy were more common with Arzerra. These preliminary results suggest that Imbruvica will achieve full approval; but, final results of this and other phase 3 trials currently underway are needed to see if the impressive results seen in the earlier clinical trials hold up... so look for final data in 2015.