Ibrutinib and Venetoclax Under Investigation as First-Line Combo in MCL

The combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) will be tested as frontline therapy in previously untreated patients with mantle cell lymphoma (MCL) as part of the 3-part phase 3 SYMPATICO trial.

“SYMPATICO is a global multicenter study, with study sites in the United States, Canada, Australia, South Korea, and Europe,” said Michael L. Wang, MD, lead author and professor at the University of Texas MD Anderson Cancer Center, in a virtual presentation during the 2020 SOHO Annual Meeting.

The open-label arm of the trial, which is actively enrolling at 46 sites across 17 countries, will evaluate the combination in previously untreated patients with MCL who are 65 years or older (n = 50) and those under the age of 65 who harbor a TP53 mutation (n = 25). Both populations are transplant ineligible, high risk, and have limited treatment options and an unmet need for chemotherapy-free regimens.

Ibrutinib is a once-daily BTK inhibitor that is currently approved for patients with MCL who have received at least 1 prior line of therapy. Venetoclax is a BCL-2 inhibitor, and though not yet approved in MCL, has shown complete response (CR) rates of 21%.

In preclinical models, the combination of ibrutinib and venetoclax showed synergistic antitumor activity through dual inhibition of the BTK and BCL-2 pathways. In the phase 2 AIM study, 71% of patients (n = 24) with MCL who received the combination experienced a CR as their best response. Notably, the CR rate was 50% in patients with TP53 aberrations, a population that is known to be chemotherapy resistant. Moreover, the median progression-free survival (PFS) was 29 months.

In this arm, patients will receive 560 mg of ibrutinib once daily plus a 5-week ramp-up of venetoclax, starting at 20 mg and ending at 400 mg. After 2 years, patients will discontinue venetoclax and continue ibrutinib until progressive disease or unacceptable toxicity.

To be eligible for this arm, patients have to be at least 65 years or between the ages of 18 and 64 and harbor a TP53 mutation; have previously untreated MCL; have pathologically confirmed MCL with either cyclin D1 overexpression in association with other relevant markers (i.e. CD19, CD20, PAX5, or CD5), or evidence of t(11;14); at least 1 measurable disease site 2 cm or greater; an ECOG performance status of 0-2; and formalin fixed paraffin embeddedtumor tissue submitted to the central laboratory.

Exclusion criteria include blastoid variant MCL; history or current evidence of CNS lymphoma; prior treatment with a BTK or BCL-2 inhibitor; history of HIV or active hepatitis B or C virus; and known bleeding disorders.

The primary end point in this arm is the CR rate in patients with previously untreated MCL. Secondary end points include objective response rate (ORR), minimal residual disease-negative rate, PFS, overall survival (OS), time to next treatment, safety, and pharmacokinetics.

In the open-label safety run-in arm of the trial, investigators are evaluating the combination in patients with relapsed or refractory MCL and assessing tumor lysis syndrome (TLS) events and dose-limiting toxicities (DLTs).

In the double-blind randomized arm, investigators are evaluating the combination versus ibrutinib plus placebo in patients with relapsed or refractory MCL. Both the safety run-in and randomized arms have been fully enrolled.

Preliminary efficacy results from the safety run-in indicated an investigator-assessed ORR of 76% in all patients, which is in line with the ORR of ibrutinib alone in the relapsed/refractory setting. Additionally, the combination led to a CR rate of 48%, which is more than double that seen with ibrutinib or venetoclax alone in the relapsed/refractory setting.

Patients at high risk for TLS had an ORR of 73% and a CR rate of 40%. Patients at low risk for TLS had an ORR of 83% and a CR rate of 67%. The median PFS was not reached after a median follow-up of 10 months.

Regarding safety, no clinical TLS events occurred. Though, 1 patient at high risk for TLS had laboratory TLS. In total, 3 patients (14%; n = 21) had DLTs, including grade 4 neutropenia, grade 4 infection, and grade 3 atrial fibrillation and grade 3 hypotension. All 3 patients were at high risk for TLS.

The authors concluded that the rates of TLS events and DLTs were low and that the study should proceed with the concurrent administration of the combination, without an ibrutinib lead in.

_Reference

_{Wang M, Jurczak W, Eckert K, et al. First-line ibrutinib plus venetoclax in mantle cell lymphoma for older patients or those with a TP53 mutation: ongoing open-label arm of the PCYC-1143 phase 3 SYMPATICO study. Presented at: SOHO 2020 Annual Meeting; September 9-12, 2020; Virtual. Abstract 1143.}