SYK Inhibitor Shows Promise in CLL

Jeff P. Sharman, MD

Entospletinib (GS-9973) has shown early promise as a treatment for pretreated patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), but further investigation is needed to determine if more patients will benefit from the selective spleen tyrosine kinase (SYK) inhibitor alone or in combination with other agents.

In a phase II study presented at the 2015 ASH Annual Meeting¹, 41 patients with CLL and 15 patients with SLL were treated with entospletinib at 800 mg. The median number of prior therapies was 2.

The median progression-free survival (PFS) was 20.5 months (95% CI, 7.7 months-not reached). PFS at 24 weeks, the trial’s primary endpoint, was 72.3% (95% CI, 57.1-83.0). The median duration of response was 21.3 months (95% CI, 13.2 months-not reached). Results of an independent response assessment are pending.

The agent appeared to be well tolerated. Twenty-four patients (42.9%) experienced adverse events that were mainly grade 1/2 and 22 patients (39%) experienced disease progression. There were 2 patient deaths, 1 due to septic pneumonia and 1 due to pseudomonal infection which was unrelated to entospletinib, according to investigator review.

OncLive: Please provide an overview of the phase II trial examining entospletinib in patients with CLL and SLL.

In an interview with OncLive, lead study author Jeff P. Sharman, MD, medical director of Hematology Research for US Oncology Research, discusses the significance of the phase II study and what lies ahead for entospletinib in patients with CLL and SLL.Sharman: We had the opportunity to study a new molecule called entospletinib, which is a SYK inhibitor. This is one member of the B-cell receptor signaling cascade. Other targets in that pathway include BTK and PI3K delta, so other drugs such as ibrutinib (Imbruvica) and idelalisib (Zydelig) are in this space, but SYK targets another member of the pathway.

What other adverse events were reported?

What are going to be the next steps with investigating this agent?

What we have seen in patients with CLL and SLL is that this molecule has pretty substantial clinical activity. We see good levels of responses and prolonged disease control for a number of patients in a medication that is fairly well tolerated. We have seen signs of liver function test abnormalities but, overall, it has been well tolerated and those side effects have been quite manageable.The liver test function abnormalities have been, for the most part, the most obvious side effect. Outside of that, there has been some mild, infrequent stomach upset, and a little bit of nausea and diarrhea. By and large, the liver function test abnormalities have been the primary side effect we observed in this study.This is all in process. The landscape in CLL and SLL, 5 years ago, would have been completely straightforward for this drug and there would have been a clear route to approval.

However, in light of the new molecules that are available in this space, proceeding as a single agent may be most suitable in patients who are either intolerant or refractory to some of the other medications that are available. We’re currently studying the same drug in patients who have either discontinued ibrutinib or idelalisib for a number of reasons.

What are the biggest unanswered questions with entospletinib?

Alternatively, we could take this into combination studies. There were data presented at the 2015 ASH Annual Meeting showing a unique and interesting combination with microtubule drugs such as vincristine, which is commonly used in lymphoid malignancies, so that exploration is just getting underway, as well.The key question is, “What are the routes to getting this drug approved?” As I said, the landscape would have been very straightforward for this drug 5 years ago. In fact, the very first B-cell receptor signaling inhibitor studied in this space was a SYK inhibitor called fostamatinib.

What changes should be made in the treatment landscape for high-risk patients with relapsed CLL or SLL?

Yet, because entospletinib is now following these other medications, simply doing head-to-head studies and so forth is not a likely viable strategy. Instead, it is better to look at those patients who can’t tolerate those other medications or who have progressed on them. Or, finding suitable combination partners will be the next step. For patients with relapsed CLL, the drugs that we have recently developed are clearly dramatically better than anything we’ve had previously. That being said, there are still patients who could do better on these approved drugs.

For instance, patients on ibrutinib—the most commonly utilized relapsed/refractory drug now in CLL—may not derive the same magnitude or benefit if they have 17p deletions, 11q22.3 deletions, or possibly even TP53 mutations, compared with patients who lack those mutations. So, there is an effort to look at these patients with a variety of new strategies.

We have seen data presented on venetoclax, which is a BCL-2 inhibitor, showing profound activity in this space. There are other ongoing clinical trials looking at the addition of novel antibodies, such as ibrutinib with or without ublituximab, which is a novel CD20 antibody. Another trial is looking at ibrutinib versus ACP-196, which is a different BTK inhibitor.

Where do you envision the treatment paradigm for CLL and SLL in the next 5 to 10 years?

For those patients with relapsed CLL, this is currently an area of active exploration. Multiple new drugs are emerging. Often times, as new drugs emerge, there are logistical barriers to putting them in combination with one another but as those drugs become approved, the ability to start doing combination studies becomes more available.

I think we will be looking at adding these new drugs that really have unprecedented levels of efficacy and tolerability together to see if we can get to treatment conditions where patients have very durable disease control. Perhaps they can have limited therapy or not necessarily be on medication for the rest of their life. That’s what we hope to get to.

Sharman JP, Klein LM, Boxer M, et al. Phase 2 trial of entospletinib (GS-9973), a selective Syk inhibitor, in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Presented at: 2015 ASH Annual Meeting. December 5-8, 2015; Orlando, FL. Abstract 4152.