Entospletinib Plus Obinutuzumab Shows Early Efficacy, Tolerability in High-Risk Relapsed/Refractory CLL

The combination of entospletinib (GS-9937) and obinutuzumab (Gazyva) demonstrated an acceptable safety profile with encouraging efficacy—even in high-risk subsets of patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to Alexey Danilov, MD, PhD.

Results from a phase 1/2 trial (NCT03010358), which were presented during the 2021 International Workshop on CLL (iwCLL), showed that the doublet elicited an overall response rate (ORR) of 67% (95% CI, 43%-85%) in 21 evaluable patients with CLL.

Of those who responded to treatment, 14% (95% CI, 3%-36%) achieved a complete response (CR) and 53% experienced a partial response. Of 3 patients who had a confirmed CR, 2 also had undetectable minimal residual disease (MRD) in the bone marrow. Moreover, the median event-free survival [EFS] with the regimen was 27.5 months (95% CI, 16–not reached).

In a subset of 13 patients with high-risk CLL, entospletinib plus obinutuzumab elicited an ORR of 54%, which included 2 CRs and 5 PRs. In 8 patients who received prior kinase inhibitors, the ORR with the doublet was 62.5%, and all these patients experienced PRs.

“This is a very promising pathway. One of the big highlights [from this work] is safety,” Danilov said. “The issue with BTK inhibitors [is the] atrial fibrillation and hypertension [that we see]; those risks never disappear. Also, [these agents] do not combine well with anticoagulants because of bleeding risks. With PI3K inhibitors, we [see] autoimmune toxicities. With venetoclax [Venclexta], there is tumor lysis syndrome. Although we have excellent therapies for CLL, each of them [comes with its own challenges]. The great benefit of this [approach] is that it is very safe.”

In an interview with OncLive^®, Danilov, associate director, Toni Stephenson Lymphoma Center and professor, Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, discussed the data on entospletinib/obinutuzumab in patients with R/R CLL and suggests further research directions with this drug combination.

OncLive^®: What was the rationale to evaluate entospletinib in combination with obinutuzumab in patients with relapsed/refractory CLL?

Danilov: Entospletinibis an inhibitor of B-cell receptor signaling and [these] inhibitors have made significant strides in the [treatment] of CLL—particularly BTK inhibitors such as ibrutinib [Imbruvica] and acalabrutinib [Calquence] in the past few years. Spleen tyrosine kinase [SYK] is a cornerstone kinase in the B-cell receptor signaling pathway; without activation of SYK, [B-cell receptor] signaling cannot happen.

We have done quite a bit of preliminary work in this space. For instance, we have shown in our laboratory that SYK not only transmits signals to the B-cell receptor, but it also cooperates with BAFF, or B-cell activation factor, which transmits signals from the CLL microenvironment. [SYK] sits at the crossroads of multiple pathways and is responsible for the survival of CLL cells in the microenvironment.

Therefore, [there was a] very strong rationale for targeting SYK with this selective inhibitor called entospletinib. [We] also [had] preclinical rationale to combine the drug with obinutuzumab [because] it is a second-generation, CD20-targeted antibody that has performed very well in studies with minimal [toxicity].

What was the design of the study?

The study included mostly patients with R/R CLL, [plus] a couple of patients with lymphoma. It was designed as a phase 1/2 study. In the phase 1 component, which followed a standard 3 + 3 design, patients were treated at 2 dose levels.

We found that the second dose level, in which entospletinib [was given] at a dose of 400 mg twice daily in combination with obinutuzumab, was safe. No dose-limiting toxicities [DLTs] reported at that dose level. Obinutuzumab was given for 6 months, or standard dosing, whereas oral entospletinib continued at 400 mg twice daily until progression or intolerable [toxicity].

What were some of the key efficacy findings?

The efficacy [with entospletinib] was very good. [It’s important] to highlight that this study enrolled quite an unfavorable patient population. Specifically, 62% of patients had a p53 aberration; some had complex karyotype [or a] NOTCH1 or SF3B1 mutation. Two-thirds of patients had an unfavorable cytogenetic abnormality. The majority of [patients] had a p53 pathway aberration, which is a high-risk abnormality in CLL.

[Bearing] that [in mind], the overall response rate in the phase 2 portion of the study was close to 80% at the maximum tolerated dose. The median EFS, which is the most important, was 27.5 months.

For this patient population with high-risk, complex karyotype and p53 abnormalities, I would consider this to be a very good result. [Although] we didn't see that many complete responses, [which is] expected with B-cell receptor–signaling inhibitors, the PFS was very good. Moreover, many patients came off [of treatment because of disease] progression rather than adverse effect [AEs].

How did the combination perform in terms of safety?

[The regimen] turned out to be very safe. We only had 1 DLT [observed with] a lower dose of entospletinib, interestingly, and that was laboratory abnormalities of aspartate aminotransferase [AST] and alanine aminotransferase [ALT]; this has previously been reported with SYK inhibitors. [The patient] was asymptomatic; however, because of recurrent AST and ALT abnormalities, [they] had to discontinue treatment. This was the only patient out of 23 patients enrolled to this study who had to discontinue because of an AE.

[Beyond that case], minimal toxicities [were reported] with entospletinib. With obinutuzumab, as expected, we saw some [patients experience] cytopenia early on and some infusion-related reactions. Overall, however, this regimen has been very well tolerated.

What are the clinical implications of these findings? What are the next steps for entospletinib?

In terms of future development, [entospletinib] has been licensed by Gilead Sciences, Inc. to another company, so we will see whether there will be opportunities to develop this drug further. I cannot say more than that at this point, but I do believe that targeting this pathway does have a future in [this disease].

Did any other interesting research read out during the 2021 iwCLL that you would like to spotlight?

A few interesting abstracts [were shared] during the meeting. Currently, there is a great interest in selective BTK inhibitors such as acalabrutinib and zanubrutinib [Brukinsa]. [Data from the] phase 3 ELEVATE-RR trial [NCT02477696] with acalabrutinib, as well as the phase 3 ALPINE trial [NCT03734016] with zanubrutinib, [were] presented. [The trials are] highlighting the safety of second-generation BTK inhibitors in comparison with ibrutinib.

[Findings with] the U2 regimen [of ublituximab and umbralisib (Uknoiq)] from [the phase 3] UNITY-CLL study [NCT02612311] were also presented during the meeting. CAR T-cell data were also shared. Those are the impactful studies that I expect will change practice in the future. Another interesting abstract [looked at] MRD monitoring by using cell-free DNA. I have not seen those data yet, but that's also [an area of interest in the field].

Reference

1. Danilov AV, Lam V, Thurlow B, et al. Final results of a phase 1/2 study of SYK inhibitor entospletinib in combination with obinutuzumab in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 2021 International Workshop on CLL; September 17-20, 2021; virtual. Poster 1083511. https://bit.ly/3FAGPpD