Enzastaurin Combo Under Exploration in High-Risk, DGM1+ DLBCL

Grzegorz S. Nowakowski, MD

Investigators are evaluating the efficacy of enzastaurin, a PCKß inhibitor, in combination with standard rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with high-risk Denovo Genomic Marker 1 (DGM1)–positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 ENGINE trial (NCT03263026).

“This will be an important study for several reasons,” Grzegorz S. Nowakowski, MD, the lead author of the study, said. “We are trying to improve outcomes for patients in the up-front setting, so this has the potential to change clinical practice. There are also implications to what we do with our research and subsequent studies, as well.”

In the double-blind, placebo-controlled, multicenter study, approximately 235 patients in the United States and China with high-risk DLBCL will be randomized 1:1 to receive enzastaurin in combination with R-CHOP or R-CHOP plus placebo. Specifically, those in the investigational arm will receive R-CHOP as directed plus a 1125-mg loading dose of enzastaurin on day 2 followed by 500 mg daily. Those in the control arm will receive R-CHOP as directed, plus an identical number of placebo tablets.

The primary end point of the trial is overall survival (OS). Although OS has been the gold standard, it is challenging to achieve, according to Nowakowski. Because ENGINE investigators hope to capture high-risk patients in real-world situations, they hope to observe a difference in OS; if successful, this could impact the design of other trials, added Nowakowski.

In an interview with OncLive^®, Nowakowski, an associate professor of medicine and oncology, and a consultant in the Division of Hematology of the Department of Internal Medicine at Mayo Clinic, discussed the current treatment landscape of DLBCL and provided key insight to the ongoing ENGINE study.

OncLive^®: Could you provide a brief overview of what the current treatment paradigm of DLBCL looks like?

Nowakowski: DLBCL is an aggressive subtype of non-Hodgkin lymphoma. What we see in this disease is a dichotomy of the end outcome. Essentially, approximately 60% of patients are cured with R-CHOP chemotherapy. However, 40% of patients are not cured; they will typically relapse within 2 years following induction chemotherapy. The majority of these patients will succumb to their disease despite recent progress made in the relapsed/refractory setting.

If you look at the proportion of patients who relapse with a high International Prognostic Index (IPI) [score], the risk [of death due to DLBCL] is even higher. Therefore, there is still an unmet need to advance frontline therapy in DLBCL, as well as to build on the backbone of R-CHOP to improve [outcomes].

Obviously, in the relapsed/refractory setting, there is also a need to improve treatment. There has been some progress with the recent approval of tafasitamab (Monjuvi) [plus lenalidomide (Revlimid)], CAR T-cell therapy, and polatuzumab vedotin (Polivy) in this space. However, the majority of patients will still succumb to their disease, so an unmet need remains.

What was the rationale for the ENGINE study?

In this study, investigators compared standard treatment with R-CHOP versus the combination of R-CHOP and enzastaurin in patients with newly diagnosed DLBCL. It builds on the idea that the addition of a novel agent can improve results compared with what has been seen with R-CHOP alone and focuses on patients with high-risk disease.

In previous studies, we observed that patients with the biomarker DGM1 experienced a significant benefit with the addition of enzastaurin. In this patient group, the addition of targeted agents resulted in improved OS.

What is interesting about the design of the ENGINE study is that the primary end point is OS. In most other phase 3 studies, we see progression-free survival as the primary end point. The rationale for having OS as an end point in the ENGINE study is because if the strong data with enzastaurin that have been reported in previous studies. Those findings demonstrated an OS benefit with the addition of enzastaurin to R-CHOP in this patient population.

What is the prevalence of patients with DLBCL who are DGM1 positive?

In terms of prevalence, DGM1 varies significantly by race and country. It is present in about 90% of Caucasians and 60% of African Americans in the United States. If you go farther east, about 95% of patients in China will be positive for the biomarker.

Could you expand on the trial design and the population of patients examined?

We focused on high-risk patients who have high IPI scores. IPI helps us identify patients who are at a high risk of disease recurrence. The study is focused on improving outcomes for the patients who have the biggest clinical need. What is nice about this study is that the biomarker is built into the trial; it is not required for patient inclusion or initial selection. This is very important because we struggle with the patients who have rapidly progressing disease who require urgent initiation of therapy. These patients often cannot enter studies [because they are] waiting for biomarkers or other assessments. The ENGINE study does not have this barrier, so patients can be efficiently enrolled to the trial earlier on.

What is the anticipated safety profile of the combination?

In the past, the addition of enzastaurin to R-CHOP concomitantly or in the maintenance setting was shown to be safe and well tolerated. In the ENGINE study, our experience so far has been very positive, and we have not seen any new safety signals.

Efficacy analysis will be completed after the study is completed, but we are anticipating that accrual will complete later in 2020.

Could you speak to the importance of this study? What is your hope for the combination?

I mentioned that the study is trying to capture those high-risk patients without delay. This is an important concept and proof of principle that this strategy may capture those patients and improve outcomes.

The study is also looking at OS as the primary end point, which is different from other studies; this is quite innovative. OS has been the gold standard for a long time, but it has been difficult to achieve. Because the ENGINE study is capturing high-risk patients in real-world situations, we may be able to observe a difference in OS. This could potentially impact the design of other studies.

Obviously, if the [combination] shows promise, we will probably move it to other lines of therapy in DLBCL. Some data from other tumor types, including those with brain tumors, suggest enzastaurin could show efficacy in those areas, as well. Additional studies with this agent are expected.

Is there anything else that you would like to highlight about the study?

What is interesting about the ENGINE study is that the concept is trying to revitalize an older drug that was already studied in this space using new technology.

Other studies [with this combination] have previously been done. One was a maintenance study, which examined enzastaurin after R-CHOP; this was negative. The other was a randomized phase 2 study of enzastaurin concomitant with R-CHOP versus R-CHOP, which was also negative.

Now, we've revived the whole concept of the study by looking at this new biomarker. DGM1 is a germline biomarker that you are born with. By looking at the dataset with this new biomarker we saw evidence that in a subset of patients, the addition of enzastaurin could be associated with benefit.

It is an interesting concept. We have many other studies which failed for different reasons and did not show improvement with other drugs. [Harnessing] a biomarker that can identify patients who have benefit from this treatment is an important and interesting concept in drug development.

Reference

Nowakowski GS, Zhu J, Zhang Q, et al. ENGINE: a phase III randomized placebo-controlled study of enzastaurin/R-CHOP as frontline therapy in high-risk diffuse large B-cell lymphoma patients with the genomic biomarker DGM1. Future Oncol. 2020;16(15):991-999. doi:10.2217/fon-2020-0176