Escalating the ESCALADE trial: untreated diffuse large B-cell lymphoma

Presented by

Dr Laurie Sehn, University of British Columbia, Vancouver, Canada

Journal

Physician's Weekly

Conference

ASCO 2021

Trial

Phase 3, ESCALADE

The ESCALADE phase 3 trial is interrogating the clinical benefit of acalabrutinib in combination with standard chemotherapy for patients age 65 and younger with newly diagnosed with diffuse large B-cell lymphoma (DLBLC), the most common type of non-Hodgkin lymphoma. This ongoing trial was presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, which was held virtually 4-10 June, 2021 [1]. Medicom’s journalist spoke with principle investigator medical oncologist Dr Laurie Sehn (University of British Columbia, Vancouver, Canada).

ESCALADE (NCT04529772) is a phase 3, placebo-controlled, randomized, global, double-blind study which aims to address the unmet need of the 35-40% DLBCL patients who will progress to experience relapsed/refractory disease despite an initial complete response to standard of care R-CHOP therapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The subset of patients who do relapse have a poor prognosis, and the question remains how to best treat these patients upon relapse. The phase 3 PHOENIX study suggested that the addition of the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib to R-CHOP did not improve outcomes in the overall cohort, although patients aged <60 years did show some parameters of response with manageable safety profiles. In contrast, however, patients 60 years or older had a much more likely risk for serious adverse events, coupled with decreased event-free survival, progression free survival, and overall survival. The primary endpoint for PHOENIX was not met [2]. A subgroup analysis suggested better responses occurred in patients with non-germinal center B-cell-like DLBCL (non-GCB DLBCL) than in patients with immunohistochemistry-confirmed GCB DLBCL.

These initial data indicating benefit for younger patients with non-GCB DLBCL warranted further research. Second-generation BTKi acalabrutinib has enhanced kinase selectivity and potential for better efficacy and tolerability when compared with earlier BTKis, including ibrutinib. The safety of acalabrutinib in combination with R-CHOP was recently shown in a phase 1b/2 study [3]. The rationale behind ESCALADE is to determine if the addition of acalabrutinib to R-CHOP leads to improved progression-free survival in patients age ≤65 years with untreated non-GCB DLBCL, as compared with placebo in combination with R-CHOP.

Adults 65 years and younger with previously untreated DLBCL are being enrolled, with a target of 600 patients at about 250 sites globally (about 300 patients in each arm). Prior to randomization, all patients will receive a single R-CHOP cycle (cycle 1) as standard-of-care treatment to prevent delays in therapy initiation. Gene expression profile testing is performed immediately after enrollment, and analyzed during the first cycle of R-CHOP. Patients whose gene profiling indicates that they manifest non-GCB DLBCL disease, are randomized to receive either 100 mg acalabrutinib twice daily plus R-CHOP or placebo twice daily plus R-CHOP from cycles 2-6 followed by 2 additional cycles of rituximab + acalabrutinib or placebo (cycles 7 and 8). All patients receive primary prophylaxis with granulocyte colony-stimulating factors accompanying all R-CHOP cycles. The primary endpoint is progression-free survival. Key secondary endpoints include event-free survival, complete response rate, overall survival, pharmacokinetics, and safety. Key exclusion criteria are central nervous system involvement, primary mediastinal lymphoma, high-grade B-cell lymphoma, diagnosis or treatment of malignancy other than DLBCL, and history of indolent lymphoma.

Medicom spoke with Dr. Sehn about this ongoing study:

“This is an ongoing randomized phase 3 trial, so it is being done internationally in patients with untreated diffuse large B-cell lymphoma. It will be testing the addition of acalabrutinib to R-CHOP versus R-CHOP alone, which is the current standard of care for patients with non-GCB diffuse large B-cell lymphoma, as determined by gene expression profiling.”

Stratification by genome profiling

“Relatively few studies have based treatment allocation based on gene expression profiling. ESCALADE is a biomarker-driven study using gene expression profiling. It is targeting non-GCB diffuse large B cell lymphoma, which has a poor prognosis. This high-risk subtype of diffuse large B cell lymphoma where the current standard of care is R-CHOP. Biologically, we know that activation of the B-cell receptor pathway is important in their pathogenesis. So, acalabrutinib, being a BTK inhibitor, aims to inhibit a main driver of its biology. ”

“This trial is being done because there was a previous trial called the PHOENIX trial that looked at the addition of ibrutinib, another BTK inhibitor, to R-CHOP versus R-CHOP alone and that trial, if you look at the overall population, was negative, meaning that it did not improve the overall outcome of the intent-to-treat population. However, a subgroup analysis found that the younger patients actually had an improvement in progression-free survival and overall survival that was quite significant. Yet the older patients, unfortunately, did not do as well because they had trouble tolerating the combination. So basically, it was a more toxic combination for them and they were not able to get the rituximab + CHOP as per usual. ”

“What this trial is trying to validate is whether or not that finding from PHOENIX is true: that younger patients with non-GCB subtype DLBCL will have improved progression-free and potentially overall survival. The uniqueness here is that it is: (1) targeting a younger patient population 65 years and under, and (2) that ESCALADE is biomarker driven, using gene expression profiling to determine non-GCB status, whereas the original PHOENIX trial used immunohistochemistry. We know that every time you create selection criteria, running a trial becomes more of a challenge. So it will be trying to enroll a younger population with biomarker-defined disease, but importantly, there are elements that have built into the trial design that hopefully will limit those problems associated with biomarker assessments. As you know, the biggest concern is that the biomarkers lead to a delay in treatment and you can lose patients. ”

“The trial participants enrolled will need immediate treatment, which is why they and they will immediately have the biomarker assessment performed. They will then get R-CHOP for one cycle. Only those patients who are proven by biomarker assessment to have non-GCB disease will then be randomized. The trial design attempted to create a built-in mechanism to avoid omitting patients because of the delay in biomarker testing. The trial started enrolling in October of 2020 and is basically ramping up across the world. We are still actively enrolling patients, and ramping up to still include more sites.”

“In my mind, the best possible results of this trial would be clear evidence as to whether or not acalabrutinib improves progression-free survival and hopefully the cure rate in patients with the non-GCB subtype of DLBCL.”

Stratification by genome profiling

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