Novel triplet combination of orelabrutinib, lenalidomide, and rituximab as frontline therapy for mantle cell lymphoma: Final results of POLARIS multicenter phase II study.

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Background: Despite the established efficacy of chemoimmunotherapy in untreated mantle cell lymphoma (MCL), its clinical utility remains limited by suboptimal long-term outcomes and chemotherapy-associated toxicities. These challenges have driven the exploration of chemotherapy-free approaches, as pioneered by lenalidomide plus rituximab (LR). Given the potential association of enhanced response and survival with earlier incorporation of BTK inhibitors, this POLARIS study attempts to improve upon the LR regimen in these patients, by assessing the triplet incorporating orelabrutinib (called ‘OLR’), a potent and highly selective BTK inhibitor approved for lymphoma. Methods: In this multicenter, open-label phase II study, untreated MCL pts received six 28-day cycles of induction therapy with orelabrutinib (150 mg once daily) plus LR, followed by OLR maintenance for up to 18 cycles. The primary endpoint was complete response rate (CRR) at the end of the 6-cycle induction therapy (EOIT). Results: As of February 20, 2025, 29 patients (male, 89.7%; median age, 62 years) were enrolled, most with Ki67 index ≥ 30% (55.2%), and Ann Arbor stage III-IV disease (82.8%), bulky mass (58.6%). One (3.4%) and 5 (17.2%) cases had high MIPI-C and TP53 mutations, respectively. All 29 patients completed 6-cycle OLR induction, among whom 22 completed maintenance. By data cutoff, 3 (10.3%) remain in the study. Of 29 patients evaluated for efficacy, CRR and overall response rate (ORR) at EOIT were respectively 69% (95% CI, 49.2-84.7%) and 96.6% (95% CI, 82.2-99.9%). During the study, 26 (89.7%) had CR and 3 (10.3%) had a partial response as the best outcomes, for the best ORR of 100.0%. Among responders, the median time to response and duration of response were 3.0 months and not reached (NR), respectively. With 4 progressive or fatal events during a median follow-up of 29.6 months, median progression-free survival (PFS) and overall survival had not yet been reached. ctDNA positivity rate after 6 cycles was 32.1% (9/28). The most frequent mutation in tumor tissues at baseline was CCND1 . TP53 mutations were significantly correlated to PFS. Grade 3-4 treatment-related adverse events were seen in 24 (82.8%) of 29 patients and mainly included neutrophil count decreased (65.5%). Conclusions: The OLR regimen provided an encouraging clinical and molecular response and favorable safety in untreated MCL, potentially representing a highly active and less toxic chemotherapy-free option. More data will be reported from this study. Clinical trial information: NCT05076097 .