Alexey Danilov, MD, PhD, discussed the data on entospletinib/obinutuzumab in patients with R/R CLL and suggests further research directions with this drug combination.
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.
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].
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].
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].
[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.
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].
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].