Both Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson) and idelalisib (Gilead) are generating a lot of excitement as potential treatment options in non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Arzerra® (ofatumumab, Genmab/GSK) is currently approved for use in refractory CLL patients in both the United States and Europe. Although Arzerra is the second most utilized agent in the United States in CLL patients after their second relapse, it is still only used in 14% of U.S. CLL patients.1 This utilization rate highlights the unmet need for more therapies and helps partly explain the level of excitement for new therapies such as Imbruvica and idelalisib.
Imbruvica, an inhibitor of the Bruton’s tyrosine kinase (BTK), has already garnered accelerated approvals as a monotherapy for both mantle cell lymphoma and CLL based on Phase II data. While evaluation of these two applications were ongoing with the FDA, Pharmacyclics initiated a Phase III trial (RESONATE™) that compared Imbruvica versus Arzerra in 391 patients with multiple relapsed/refractory CLL or small lymphocytic lymphoma, with a median of two or three prior therapies, depending upon the treatment arm. In January 2014, the companies announced that the trial met its primary endpoint of progression-free survival (PFS) as well as the secondary OS endpoint. Interim results of the trial were presented in one of the last oral presentations of the American Society of Clinical Oncology (ASCO) 2014 conference.2
The presenter, Dr. Byrd, stated upon presentation of the primary endpoint data (independent review committee-assessed PFS) that “a picture is worth a thousand words,” and the data in this case supported his statement. Imbruvica was far superior to Arzerra, as it was associated with a 78.5% reduction in the risk of disease progression. The median PFS was not reached in the Imbruvica arm and was 8.1 months in the Arzerra arm (HR 0.215, p<0.0001). It also was associated with a 56.6% reduction in the risk of death, with the median overall survival (mOS) not reached in either arm (HR 0.434, p=0.0049). This hazard ratio could have been even more in Imbruvica’s favor, but 29.1% of the patients treated with Arzerra were treated with Imbruvica at crossover after progressive disease. The overall response rate (ORR) was also significantly improved in the Imbruvica arm (42.6% versus 4.1%, p<0.0001). Importantly, Imbruvica’s PFS benefit was also seen in the subsets of patients with del17p (HR 0.25) or purine analog refractory disease (HR 0.18).
Imbruvica was generally well tolerated, but physicians will need to keep note of its associated toxicities. Imbruvica was associated with increases in diarrhea (all grades, 47.7% versus 17.8%) and nausea (26.2% versus 18.3%). However, these few instances of increased toxicities were not associated with an increased drug discontinuation rate (4.1% versus 3.6%). Several toxicities had been of concern with Imbruvica but may be less so given this data. The rate of Grade 3 or higher infections was similar between the two arms (24% versus 22%), but these values must be considered in the context of a much longer time of treatment for patients on Imbruvica. The incidence of any grade of atrial fibrillation was higher among patients on Imbruvica (5% versus 0.5%); however, this caused discontinuation in only one patient. Bleeding-related adverse events of any grade were more common with Imbruvica (44% versus 12%), but most were Grade 1.
However, other data presented at the conference might be of equal interest to clinicians. Dr. O’Brien presented a long-term analysis of the Phase I PCYC-1102 trial of Imbruvica monotherapy in a mixed patient population – both newly diagnosed and relapsed or refractory – with CLL.3,4,5 After three years post-initiation of Imbruvica, 64% of patients remain on the drug (81% of newly diagnosed, 58% of relapsed/refractory). Most of the adverse events were detected in the early stage of treatment and diminish with time. Also, as treatment continued, patients with responses less than a partial response (PR plus lymphocytosis) converted to a true PR, resulting in an updated response rate of 85%.
As noted above, these data are presented in a disease that has very strong competition. In particular, these data come after release of Phase III data for the PI3Kδ inhibitor idelalisib, in which the efficacy of idelalisib to Rituxan® (MabThera® in Europe, rituximab, Biogen Idec/Roche) was evaluated in 220 relapsed or refractory CLL patients. As presented at the 2013 American Society of Hematology (ASH) conference, idelalisib significantly improved PFS (HR 0.15, p<0.0001) and OS (HR 0.28, p-0.018).6 These data are expected to support FDA approval shortly, which will put Imbruvica and idelalisib in direct competition in the relapsed/refractory CLL setting. In the absence of a head-to-head trial, it might be hard for physicians to choose between these two highly effective and very tolerable agents. In this case, first-to-market may play a role, and this factor favors Imbruvica, which has been approved since February 2014. Other new targeted therapies, such as Gilead’s SYK inhibitor GS-9973 or AbbVie’s Bcl-2 inhibitor ABT-199, are further behind in development.
Although as the discussant (Dr. Lamanna) noted that there might be instances where cytotoxic chemotherapy will still be preferable in relapsed CLL patients, we have entered a new era of targeted therapy in CLL. Doctors will need to choose between many effective therapies, but in the view of patients this will be a good problem. As all of these agents have already or will soon initiate further Phase III trials in earlier lines of CLL, future competition between these agents is expected to be fierce. We look forward to seeing more cases where a “picture is worth a thousand words.”
By Arnold DuBell, Ph.D., Consultant, and Stephanie Hawthorne, Ph.D., Senior Director, Kantar Health
 Kantar Health, CancerMPact® Treatment Architecture United States, accessed June 3, 2014.
 Byrd, Abstract LBA7008, ASCO 2014
 O’Brien, Lancet Oncology, 2013
 Byrd, NEJM, 2013
 O’Brien, Abstract 7014, ASCO 2014
 Furman, Abstract LBA6, ASH 2013
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