Investigators Link Novel Biomarker to Therapy in DLBCL Trial

Owen O'Connor MD, PhD

Investigators are exploring the novel genetic biomarker Denovo Genomic Marker 1 (DGM1) as a potential predictor of benefit from the experimental agent enzastaurin in treatment-naïve patients with high-risk diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma subtype.¹

DGM1 is a polymorphism on chromosome 8.² Encouraged by evidence that DGM1 positivity is predictive for efficacy with enzastaurin, investigators are evaluating the agent in the phase III ENGINE trial (NCT03263026).³

The study is designed to enroll 235 patients with CD20-positive DLBCL and randomize them to standard-of-care (SOC) rituximab (Rituxan) with cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) combined with enzastaurin or R-CHOP alone for 6 cycles during the combination phase (Figure).

The study’s primary endpoint is overall survival (OS) in patients with DLBCL who test positive for DGM1, and the secondary endpoint is OS in those without the genetic polymorphism. ENGINE’s investigators hope to discover whether enzastaurin combined with R-CHOP is a more efficacious frontline option than R-CHOP alone, as well as whether DGM1’s presence correlates with response to enzastaurin in this setting.³

Enzastaurin inhibits protein kinase C (PKC) β, an enzyme that promotes angiogenesis and thereby retards tumor growth.³ The PKCβ inhibitor has been tested in DLBCL in 2 previous trials, among more than 60 trials overall. The phase III PRELUDE study (NCT00332202) compared the agent with placebo in high-risk DLBCL. No difference was found in 4-year disease-free survival (70% vs 71%) or OS (81% vs 82%) between the enzastaurin and placebo arms. The phase II S028 trial (NCT00451178) evaluated enzastaurin in combination with R-CHOP versus R-CHOP in the frontline setting for those with intermediate/high-risk disease.

“Both studies failed to demonstrate any significant benefit [associated with] the addition of enzastaurin,” said Owen O’Connor, MD, PhD, an ENGINE investigator and director of the Center for Lymphoid Malignancies in the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center in New York, New York.

Multiple trials have failed to improve on R-CHOP by combining it with other agents, he noted. “Efforts to improve the care of patients with DLBCL have for the most part focused on CHOP or R-CHOP—plus studies, [but] over the last 10 to 15 years, all of these studies have been negative; all have failed to show that adding 1 more drug to R-CHOP produces positive changes in outcome.”

O’Connor cited the ROBUST (NCT02285062) and PHOENIX (NCT01855750) studies as recent examples of unfruitful attempts to yield a new R-CHOP—plus regimen in DLBCL. ROBUST was notably the first trial to compare lenalidomide (Revlimid) with R-CHOP (R2-CHOP) to R-CHOP alone in treatment-naïve patients with CD20-positive activated B cell–like DLBCL. Earlier phase II studies had suggested that this experimental combination might offset the poor prognosis inherent in the ABC phenotype.⁴ PHOENIX tested the combination of ibrutinib (Imbruvica) and R-CHOP with R-CHOP in patients with untreated non-germinal center B-cell DLBCL, including patients with the ABC subtype.⁵

Figure. Enzastaurin with R-CHOP in DGM1-Positive DLBCL

Neither lenalidomide nor ibrutinib added to R-CHOP in either study extended survival: ROBUST did not meet its primary end point of progression-free survival, and PHOENIX missed its primary end point of event-free survival.4,5 However, positive trends with R2-CHOP were noted in subgroups with high-risk and advanced stage DLBCL.

Precision Medicine in DLBCL

Although PRELUDE and S028 were both negative, patient DNA samples from study participants have proved useful in ensuing genomic research; specifically, in the discovery of the DGM1 polymorphism. Retrospective genotyping of PRELUDE patient samples, performed via whole genome single nucleotide polymorphism arrays, found the biomarker may be potentially predictive of response to enzastaurin. The agent significantly improved OS in DGM1-positive patients versus the DGM1negative population (HR 0.27, P = .0002).²

These findings were replicated by a biomarker analysis of patient DNA from the S028 study, in which enzastaurin was associated with greater survival benefit in patients with high-risk DLBCL who were DGM1 positive versus those in whom the polymorphism was not present (HR, 0.28; P = .018).² These genomic data provide the rationale for ENGINE, which was initiated to validate these findings.

“DGM1 is a polymorphism on chromosome 8 that codes for a transcription factor and has been implicated in the biology of DLBCL, but the relationship of that transcription factor is not clear,” O’Connor said. Investigators hope that ENGINE will further elucidate DGM1’s role in DLBCL.

ENGINE’s biomarker-driven design distinguishes it from PRELUDE and S028, as well as from other clinical trials in DLBCL, O’Connor said.

“What is different about ENGINE is [that] the founders have massive expertise in genetic profiling and bioinformatics and have spent a lot of time trying to identify potential biomarkers predictive of benefit,” he said. “Our platform is not simply going to be doing these big, randomized phase III trials and hoping that the addition of some new drug to R-CHOP is going to be positive.”

Although insight from the genomic screening of PRELUDE and S028 patient data has given investigators compelling reasons to hypothesize that enzastaurin will be efficacious in the DGM1-positive patient subgroup, the decision to jointly administer the agent with standard R-CHOP has less supportive clinical evidence.

“There are really no hardcore data that have systematically established synergy between enzastaurin and R-CHOP; [ENGINE is] mostly predicated on a far more rudimentary assumption, which is [that] if enzastaurin is active in large cell lymphoma and affects biology known to be important in large cell lymphoma, then adding it to an SOC regimen in large cell lymphoma should produce some benefit,” O’Connor said.

Enzastaurin’s mechanism of action and the extent of the agent’s synergy with R-CHOP are key foci of ENGINE investigators, who will conduct a response assessment and unblind each subject’s treatment assignment once the combination phase concludes.³ Those who have a complete or partial response with the combination therapy will be offered subsequent single-agent enzastaurin for up to 2 years.

Enzastaurin was originally developed by Eli Lilly. Denovo Biopharma, which acquired worldwide rights to the agent, said the drug did not demonstrate sufficient efficacy in the clinical trials in which it was originally tested, but that the company used its biomarker platform to identify DGM1 as a promising marker. ENGINE is currently active at 51 sites across the United States and China.⁶

References

1. NCCN Clinical Practice Guidelines In Oncology. B-Cell Lymphomas, version 5.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Published September, 2019. Accessed September 20, 2019.
2. Luo W, Sun H, Zhu J, Smith SD, Han I, Shazer R. Improved survival with enzastaurin treatment in diffuse large B-cell lymphoma patients with the novel genetic biomarker, DGM1. Blood. s2018;132 (suppl 1):4207. doi: 10.1182/blood-2018-99-115807.
3. Smith S, Zhu J, O’Connor OA, et al. ENGINE: phase III randomized study of enzastaurin/R-CHOP versus placebo/R-CHOP in frontline high-risk diffuse large B-cell lymphoma patients with novel genetic biomarker DGM1. J Clin Oncol. 2019;37(suppl 15; abstr TPS7569). doi: 10.1200/JCO.2019.37.15_suppl.TPS7569.
4. Vitolo U. ROBUST: first report of phase III randomized study of lenalidomide/RCHOP (R-CHOP) vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Presented at: 2019 International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 005.
5. Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37(15):1285-1295. doi: 10.1200/JCO.18.02403.
6. Denovo Biopharma receives FDA’s permission to proceed a phase 3 clinical trial wifirstth DB102 (Enzastaurin) in the first line treatment of high risk DLBCL. Denovo Biopharma. Published October 24, 2017. prnewswire.com/news-releases/denovo-biopharma-receives-fdas-permission-to-proceed-a-phase-3-clinicaltrial-with-db102-enzastaurin-in-the-first-line-treatment-of-highrisk-dlbcl-300541791.html. Accessed October 15, 2019.