Orelabrutinib Plus Lenalidomide and Rituximab Demonstrates Efficacy in Frontline MCL

Huilai Zhang, MD

The investigational BTK inhibitor orelabrutinib in combination with lenalidomide (Revlimid) and rituximab (Rituxan) displayed activity with a manageable safety profile in patients with untreated MCL, according to findings from the phase 2 POLARIS study (NCT05076097) presented during the 2024 EHA Congress.¹

At the February 15, 2024, data cutoff, response-evaluable patients who had completed 6 cycles of induction therapy achieved an objective response rate (ORR) of 85.8%, including a complete response (CR) rate of 67.9%. In the overall population (n = 29), 22 patients achieved a CR, 6 experienced a partial response (PR), and 1 experienced stable disease, for an ORR of 96.6%.

“These data confirm the potent antitumor activity and manageable safety of the orelabrutinib/lenalidomide/rituximabregimen in patients with untreated MCL,” Huilai Zhang, MD, of Tianjin Medical University Cancer Institute and Hospital, in China, and coauthors wrote in a poster presentation of the findings. “Data will continue to be updated.”

In June 2021, the FDA granted breakthrough therapy designation to orelabrutinib for the treatment of patients with relapsed/refractory MCL.²

The single-arm, multicenter, open-label POLARIS trial enrolled patients aged 18 to 70 years with treatment-naive MCL and an ECOG performance status of 2 or less in China. During the induction phase from cycles 1 to 6, all patients received daily orelabrutinib at a dose of 150 mg; daily lenalidomide at dose of 15 mg on days 1 to 21 of cycle 1, then at 20 mg on days 1 to 21 of cycles 2 through 6; and daily rituximab at a dose of 375 mg/m² on days 1, 8, 15, and 22, then at 375 mg/m² on day 1 of cycles 3 and 5. During the maintenance phase, spanning cycles 7 to 24, patients received orelabrutinib at 150 mg on days 1 through 28 of each cycle; lenalidomide at 15 mg on days 1 through 21 of each cycle; and rituximab at 375 mg/m² on day 1 of every 2 cycles.¹

The primary end point was CR rate at the end of cycle 6; secondary end points included safety, ORR, duration of response (DOR), time to response (TTR), progression-free survival (PFS), and overall survival (OS). Peripheral blood and bone marrow minimal residual disease (MRD) were assessed as exploratory end points, as was peripheral blood and tissue circulating tumor DNA (ctDNA).

At baseline, the median age was 61.0 years (IQR, 53.0-65.0). Most patients had low-risk disease by Mantle Cell Lymphoma International Prognostic Index score (72.4%), stage III or IV disease (82.2%), an ECOG performance status of 1 or less (96.6%), and KI67 levels of at least 30% (55.2%). Among patients with available laboratory characteristics, most had no peripheral blood MRD (65.5%), no bone marrow MRD (65.5%), a maximum lesion diameter of 5 cm or more (58.6%), no bone marrow involvement (57.1%), and no gastrointestinal involvement (81.5%).

Additional findings from the study showed that of the 25 patients with MRD analysis data, peripheral blood MRD and bone marrow MRD were negative at the data cutoff. At a median follow-up of 17.5 months, the median TTR was 2.9 months (range, 2.7-3.0); the median DOR and PFS were not reached. The estimated 12-month DOR and PFS rates were 96.3% and 92.2%, respectively.

Patients with peripheral blood and tissue samples at baseline (n = 23) most frequently had alterations in ATM (48%), KMT2D (39%), DNMT3A (17%), BIRC3 (13%), and TP53 (13%) in peripheral blood. The most frequently altered genes in tissue samples were ATM (48%), KMT2D (43%), CCND1 (17%), SMARCA4 (17%), ARID2 (13%), BCOR (13%), and TP53 (13%). Five patients with these data available experienced a PR, of which 4 had multiple gene mutations in peripheral blood, including in TP53 and CARD11.

“Overall, ctDNA detection may potentially predict the association between gene mutations and depth of remission,” study authors wrote.

In terms of safety, 96.6% of patients in the overall population experienced an any-grade adverse effect (AE). The most common any-grade AEs consisted of neutropenia (89.7%), leukopenia (75.9%), lymphopenia (51.7%), anemia (48.3%), and thrombocytopenia (41.4%). These events were reported at grade 3 or higher severity in 58.6%, 41.4%, 17.2%, 13.8%, and 6.9% of patients, respectively. No atrial fibrillation or bleeding occurred that was deemed to be associated with off-target BTK inhibition; at the data cutoff, 26 patients remained on study and no deaths were reported.

References

1. Zhang H, Su L, Liu L, et al. Orelabrutinib-lenalidomide-rituximab in patients with untreated mantle cell lymphoma (mcl): updated results of the multicenter, phase II POLARIS study.Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract P1141.
2. InnoCare announces breakthrough therapy designation of orelabrutinib by US FDA for treatment of R/R MCL. News release. InnoCare Pharma. June 28, 2021. Accessed August 5, 2024. https://prn.to/35VpN4Z