Enzastaurin and a Novel Biomarker Spark Optimism for All Risk Levels of DLBCL

Grzegorz S. Nowakowski, MD

Enzastaurin (LY317615), a potent, selective, oral serine-threonine kinase inhibitor of PKCβ, may represent a new option to replace similar drugs that have been discontinued as treatment of patients with diffuse large B-cell lymphoma (DLBCL), based on preclinical research that identified a new biomarker to target, DGM1. The research dates back to 2018 when a poster was presented for the 2018 American Society of Hematology (ASH) Annual Meeting.

In the initial study of enzastaurin (PRELUDE, NCT00332202), 750 patients with DLBCL were randomized to receive enzastaurin monotherapy versus placebo. Overall, the study failed to meet its primary end point of overall survival (HR, 1.04; 95% CI, 0.74-1.50). However, an analysis of patient samples from the PRELUDE study demonstrated an improvement in OS among patients who were positive for the novel biomarker, DGM1 (HR, 0.27; 95% CI, 0.15-0.51; P =.002).

The efficacy of enzastaurin was evaluated further in a phase 2 trial (NCT00451178), of enzastaurin plus R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) versus R-CHOP alone in intermediate or high-risk patients with DLBCL. The study included 101 subjects and concluded similar findings to the prior PRELUDE study. In patients with the DGM1 biomarker, OS was significantly improved (HR, 0.1; 95% CI, 0.02-0.492; P =.005).

Data from these two trials justified a deeper look at enzastaurin plus R-CHOP in DLBCL. The randomized, double-blind, placebo-controlled, multicenter, phase 3 ENGINE study is exploring the efficacy and safety of enzastaurin plus R-CHOP compared with R-CHOP alone in this patient population.

In an interview with Targeted Oncology, Grzegorz S. Nowakowski, MD, associate professor of Medicine and associate professor of Oncology at the Mayo Clinic, discussed the promise of the enzastaurin in the DLBCL treatment landscape and the ongoing phase 3 ENGINE study (NCT03263026).

TARGETED ONCOLOGY: What are the key unmet needs in the current treatment landscape of DLBCL?

Nowakowski: The field is changing quite a bit with a lot of new agents coming and being approved. Those agents are approved mainly in the relapsed or refractory space.I still see an unmet need in the frontline treatment of DLBCL. If you look at patient outcomes, about 40% of patients relapse after initial therapy, and a lot of them will have poor outcomes.

Other unmet needs are for patients who relapse on better therapies, those who are not eligible for high-dose chemotherapy and transplant, and those who not eligible for chimeric antigen receptor (CAR) T-cell therapy or relapsed after CAR T-cell therapy.

Looking at the field as a whole, and the patient journey from diagnosis to different lines of treatment, there is potential for building a better upfront therapy.

TARGETED ONCOLOGY: Can you discuss the mechanism of action for enzastaurin? What makes this agent particularly helpful for treatment of DLBCL?

Nowakowski: Enzastaurin is a very interesting molecule. It's an inhibitor of PKCβ. It was developed initially in solid tumors and hematologic malignancies and believed to have broad activity.

Later, it was discovered that it was critical for B-cell receptor signaling in B-cell malignancies. Because of this, there was a lot of interest in studying enzastaurin alone and in combinations for treatment of B-cell malignancies, particularly DLBCL, where frequently there is signaling engaged from a B-cell receptor.

TARGETED ONCOLOGY: What early research was done with enzastaurin in the DLBCL landscape?

Nowakowski: There are a couple of studies that have been performed, but the one that was really interesting was a phase 3 study, which used enzastaurin as maintenance after induction chemotherapy. This study was negative. It showed that the addition of enzastaurin maintenance following induction chemotherapy did not improve outcomes. However, it’s important to note that enzastaurin was used as maintenance, not concomitantly.

The other study was a randomized phase 2 study that compared enzastaurin in addition to R-CHOP 21 versus R-CHOP alone. In this study, we also did not necessarily see an improvement with enzastaurin. More recently, however, the genetic tools became available to interrogate the data in the study, and there's a new biomarker called DGM1 and this is a polymorphism in the germline genome. This polymorphism is associated with improved outcomes in about 90% of the patients who had this polymorphism. A re-analysis of this phase 2 study provided new momentum for the development of enzastaurin in combination with R-CHOP for the frontline treatment of DLBCL.

TARGETED ONCOLOGY: How did the phase III ENGINE study come about? What is the rationale for this study?

Nowakowski: In terms of the background of the ENGINE study, we know that, unfortunately, approximately 40% of patients will relapse after initial induction chemotherapy. But, if you look at the high-risk patients, which are the population of interested in the ENGINE study, the risk is even higher and approaches 50% to 60% of patients. Most of those patients will succumb to the disease if they relapse after initial induction therapy, despite recent progress in the treatment of patients with relapsed/refractory DLBCL.

This clinical information is an unmet need that propelled the development of the ENGINE study. We know from the previously completed phase 2 that enzastaurin added to R-CHOP is associated with a significant survival advantage in patients who are positive for a genetic marker called the DGM1. In this patient population, the edition of the enzastaurin was associated with an improvement in overall survival. These data led to the unusual design of the ENGINE study.

The primary endpoint is overall survival of patients. Trials like this traditionally have an end point of progression-free survival or event-free survival.

In the study, patients with high-risk disease is randomized to R-CHOP or R-CHOP plus enzastaurin. Following the completion of therapy, patients who are at least in a partial response can continue with enzastaurin for up to 3 years.

TARGETED ONCOLOGY: What efficacy or safety signals have been observed so far in the ENGINE study?

Nowakowski: The preliminary experience did not show any additional worrisome safety signals. The study is ongoing, and we'll have to wait to see the results for efficacy to demonstrate the superiority of enzastaurin plus R-CHOP versus R-CHOP alone.

TARGETED ONCOLOGY: Is there anything unique of the ENGINE study that you would like to highlight?

Nowakowski: That is a very practical study. What we have struggled with in the past was these complicated studies using real biomarker frequently selected for patients with low-risk disease, because the high-risk patients couldn't be recruited into the study. The ENGINE study removed many of the barriers for accrual and although they are looking at the patients with DGM1-positive tumors, the trial is open to all the patients. This is important because it limits the time from diagnosis to when the treatment can be initiated. It also allows us to capture data from patients with rapidly progressive disease who require early initiation of therapy. For this reason, I’m quite optimistic that the study is capturing the real-life population and looking at the real-life ultimate end point of overall survival.

If this study is positive, we hope that it will change the practice for newly-diagnosed DLBCL. The ENGINE study could also propel similar designs for other studies in this space.

_Reference:

_{Luo W, Sun H, Zhu J, et al. Improved survival with enzastaurin treatment in diffuse large b-cell lymphoma (dlbcl) patients with the novel genetic biomarker. Blood. 2018. 132 (Supplement 1): 4207. doi: 10.1182/blood-2018-99-115807}