Part 2. Small molecule BTK inhibitor Ibrutinib in the treatment of Chronic Lymphocytic Leukemia (CLL).
November 15, 2013
The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
Note that I’ve defined most of the terms we are using in Part 1, so please refer to that section for help with any abbreviations. In Part 1 is also some background on CLL and the signaling pathways downstream of the B Cell Receptor, which are targeted by these drugs. Finally, I introduced the patient populations typically encountered in CLL clinical trials.
So now we come to the Btk inhibitors and specifically to Ibrutinib, the Pharmacylics compound partnered with the Janssen arm of Johnson & Johnson. This soon-to-be blockbuster drug has been approved for the treatment of Mantle Cell Lymphoma (MCL) at an anticipated cost of 150,000 USD/year.
As mentioned in Part 1, CLL is the most common of the B cell lymphomas, so it is of keen interest to see how Ibrutinib performs in that patient population, especially given the efficacy seen with Idelalisib from Gilead.
Abstract #675 presents data from a 40 patient phase 2 trial in which Ibrutinib (IBRU, 420mg/day) was given with Rituxan anti-CD20 antibody (Rtx). The trial is notable for the inclusion criteria that enrolled patients only if they had high-risk disease: del(17p) or TP53 mutation (treated or untreated), PFS < 36 months after frontline chemotherapy + anti-CD20 treatment, or relapsed CLL with del(11q). Most patients responded well (see the table), very few patients were lost to followup and AEs were well tolerated.
Abstract #525 presents data from a small phase 1b trial in high-risk rrCLL/SLL patients (SLL is a form of CLL called small lymphocytic lymphoma, in which most of the cancer cells are located in lymph nodes). In this trial patients received IBRU + Rtx + B (bendamustine, see part 1). The response rate was very high (see the table) although the authors do note that 30% of patients eventually discontinued treatment, 10% due to progressive disease. Responses appeared to be independent of specific high-risk cytogenetic factors. Grade 3 or higher AEs were GI related, cytopenias (including 6.7% febrile neutropenia), and infections. The data from these 2 abstracts are shown below, and compared to published data (Byrd et al. 2013 NEJM 369:32-42). Note the caveats described above when reading these response percentages.
It is a little hard to directly compare these results with the Idelalisib data, partially reproduced here from Part 1, with one correction to the table (column 3: DOT = median duration of treatment):
It is tempting to conclude that the response rates with Ibrutinib are a little higher, but such comparisons will required much larger data sets. At the moment it is fair to say that these therapeutics both provide superb novel options for rrCLL patients.
Returning to Ibrutinib, there will be additional data from monotherapy studies shown at ASH. Abstract #4163 reports on an extension study of Ibrutinib monotherapy in treatment-naive CLL and in rrCLL patients. An important parameter of this study is that it included treatment-naive (likely newly diagnosed) patients; the data for discontinuation due to disease progression (PD) shows that nearly all of these early-treated patients maintain a response for at least the DOT.
After 2.5 years, 76% of this patient population was still alive, an impressive number.
Abstract #673 also examined the impact of Ibrutinib monotherapy, in this case in elderly patients with or without the del(17p) cytogenetic factor indicating high risk for progression. In this study there was a significant difference in the PR percentage, with 81% of patients with wild-type 17p responding while only 53% of patients with a deletion of 17p responded (p = 0.04). This suggests more (or larger) studies will be required to sort out the best patients for Ibrutinib therapy.
A very nice study will be presented by investigators at The Ohio State University (Abstract # 2872). Using multivariate analyses of patient response, progression and survival, these investigators compare Ibrutinib monotherapy to checkpoint-inhibitor therapy (alvocidib, dinaciclib, or TG02) to “other” therapy, in del(17p) rrCLL patients. “Other” is unfortunately not identified, but must include standard-of-care, which would normally be chemotherapy plus Rituxan. Here is a snapshot of the data at 24 months (the analysis is beautiful and I won’t reproduce their graphs here):
These data really drive home the importance of the new therapeutics and new therapeutic combinations, where we are seeing improvement in PFS.
There are a swarm of newer small molecule drugs coming up, and these will be covered in Part 3.