Combination of Ibrutinib and Buparlisib Shows Promise in MCL and other NHLs

Connie Batlevi, MD, PhD

A phase I/Ib trial of ibrutinib (Imbruvica) and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL) is being conducted to demonstrate synergy between the BTK and PI3-kinase inhibitors.

As of December 16, 2016, 13 patients were enrolled and evaluated for toxicities. Results were reported at this year’s ASCO annual meeting.

The combination of ibrutinib and buparlisib showed promising efficacy in MCL, with 4 patients achieving a complete response and 2 experiencing a partial response. Two patients with follicular lymphoma and 1 patient with DLBCL achieved stable disease.

The combination was considered to be well tolerated with standard toxicities associated with BTK and PI3-kinase inhibitors. The trial continues to enroll for all 3 cohorts.

OncLive: Could you provide an overview of your study?

In an interview with OncLive, Connie Batlevi, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discussed the trial and its implications in MCL.Batlevi: The data that we are presenting here at ASCO are from the phase I dose escalation portion of the combination therapy including buparlisib and ibrutinib in MCL, FL, and DLBCL. Buparlisib is a pan-PI3 kinase inhibitor and ibrutinib is a BTK inhibitor. Both of these are given as oral drugs, daily on a 28-day cycle.

What do you think the next steps would be following these findings?

Can you speak to the synergy between ibrutinib and buparlisib?

In terms of the findings of this combination, it is relatively safe—although we do see the expected toxicities associated with both drugs. For example, hypoglycemia is seen because it is a PI3K-alpha effect, although grade 3 hyperglycemias are relatively infrequent at about 10%. Other toxicities include anorexia, loose stool, as well as central nervous system effects related to the buparlisib, which include mood changes, anxiety, and depression.We are continuing to phase Ib and phase II dose expansion cohorts in MCL, FL, and DLBCL. So, we will see where that leads. At least based on very small numbers, which is difficult to say, the overall response rate is very intriguing for MCL.This is based on 2 preclinical studies, one of them in large cell lymphoma and the other one was in CLL, I believe. It looked at large-scale pharmacologic data and essentially, with the combination of ibrutinib and buparlisib, the cell kill rate was higher in DLBCL compared to each individual agent alone. So, based on that evidence of synergy, it made sense to combine the two.

Is there any reasoning behind this effect in MCL?

Similarly, in CLL and MCL, there could be a reliance on an alpha effect—and as you know, buparlisib is an alpha inhibitor, so that could contribute to why it is having such an effect in MCL.For sure. Ibrutinib has been approved by the FDA for MCL, and clearly it has responses in this disease. But, I think what we are seeing in small numbers of patients is that we can possibly deepen the response. There is preclinical data that suggest that the combination of PI3 kinase inhibitors and BTK inhibitors in these lymphomas is synergistic in nature.

Ibrutinib is an oral agent for MCL that is fairly well tolerated. I think it has definitely opened new lines of therapy for this disease, but because we think of MCL as a less curable disease, I think we need to continue to develop new therapies and combination therapies with it.

Batlevi CL, Hamlin PA, Matasar M, et al. Phase I dose escalation of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). J Clin Oncol 35, 2017 (suppl; abstr 7544).