Jennifer A. Woyach, MD

In the treatment of patients with chronic lymphocytic leukemia (CLL), the CD19-directed antibody MOR208 is being explored in combination with lenalidomide (Revlimid) or ibrutinib (Imbruvica) across various patient subgroups.

Lead study author Jennifer A. Woyach, MD, discussed an ongoing phase II trial of MOR208 during the 2016 ASH Annual Meeting. The study includes cohorts of patients with relapsed/refractory CLL, treatment-naïve disease, Richter’s transformation, and those with CLL who have been treated with ibrutinib.

OncLive: Could you provide an overview of your study?

In an interview with OncLive at ASH, Woyach, an associate professor of Medicine in the Division of Internal Medicine at The Ohio State University Comprehensive Cancer Center, spoke on the preliminary results of this ongoing trial and offered in-depth insight on acquired resistance to ibrutinib in CLL.Woyach: MOR208 is a CD19-targeted antibody that is clinically engineered to improved Fc-gamma receptor binding. In a phase I study at Ohio State University, it was previously established that it was effective in CLL and was also safe.

We decided to take this a step further by combining it with lenalidomide because there are preclinical data showing that lenalidomide can increase natural killer cells in antibody-dependent cell-mediated cytotoxicity (ADCC). Therefore, we hypothesized that this would make the antibody even more effective in this disease.

The study we are conducting has 4 different cohorts. We are treating patients with relapsed/refractory CLL, those with treatment-naïve CLL, a cohort of patients with Richter's transformation, and then we have 1 group of patients who had been on ibrutinib. The cohort on ibrutinib have developed mutations that would render them resistant to ibrutinib at some point without having clinical progression—so mutations in BTK—and then we are adding more of MOR208 to ibrutinib.

What are your expectations for this study?

In the first 2 cohorts—the relapsed/refractory and treatment-naïve patients—there will be 20 patients each. So far, we have enrolled 11 patients in each of the 2 cohorts. The Richter's transformation cohort is going to enroll up to 10 patients. Then, for the patients with ibrutinib-resistance mutations, we may enroll up to 25. However, at the moment, there are only 7 patients. We haven't really reported the efficacy yet, as it is ongoing, but what we've seen so far is that the combination does appear to be safe in this patient population. With the combinations of MOR208 plus lenalidomide and MOR208 plus ibrutinib, we have seen anecdotal preliminary efficacy in the CLL population, as well as the Richter's group.

The thing that is of most interest, though, is the group of patients who have those ibrutinib resistance mutations. Whereof the 7 patients, most them have either stable clonal size—which we tend to not see—or they show a very rapid decrease in the frequency of those mutations.

Could you provide more information on ibrutinib resistance in CLL?

We are continuing to enroll and are hoping to use this as a proof of concept for lenalidomide to help the antibody be more effective, but we also might be able to take it a step further into a more definitive study in the future. At Ohio State University, we have a very large cohort of patients treated with ibrutinib. We have a group of 308 patients treated in 4 clinical trials. We have been following these trials to study drug discontinuation and to look at mechanisms of resistance in those patients, with a median follow-up of 3.4 years. In that time, we have had 27 patients with Richter's transformation progress and 55 progressed with CLL. Richter's tends to be an earlier phenomenon, usually occurring within the first 18 months and is rare after 2 years. On the other hand, people with CLL progressing on ibrutinib tend to do so after 2 years of treatment.

We found that, of 46 patients, 87% of them had developed mutations in either BTK or PLCG2 at the time of relapse. Therefore, this kind of verifies that these are really the most predominant mechanisms by which people relapse.

The majority of patients did have mutations at the binding site of ibrutinib. Also, since we know the patients who developed these mutations at relapse, we can go back and look at serial samples that we saved. We found that we can actually detect those clones prior to the development of clinical relapse at a median of 9.3 months. Therefore, there is a pretty long time between when we can first develop and detect a clone and when they relapse, suggesting that there might be a potential for targeting that time period.

What is this significance of this study moving forward?

We also looked at this prospectively and determined that we can detect these clones in a clinical setting. Like I mentioned on the MOR208 study, for some of those patients that develop these resistant subclones, we are then adding MOR208 to ibrutinib. We're using this to inform our practice for the future and inform other clinical trials. We have this hypothesis now and, since we have this time period of asymptomatic clonal expansion, we may be able to add a second therapy onto ibrutinib and potentially prolong the time people will have remission.

Woyach JA, Ruppert AS, Awan FT, et al. Updated results from a phase II study of the Fc engineered CD19 antibody MOR208 in combination with lenalidomide for patients with chronic lymphocytic leukemia (CLL) and Richter’s transformation or ibrutinib for patients with ibrutinib-resistant clones. Presented at: 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 4386.