MANGROVE PFS Win Tests Frontline Chemo-Sparing Against Thin Safety Data

BeOne's Brukinsa Achieves Blockbuster Status and Clinical Success

China aims to achieve five domestically developed blockbuster drugs by 2030, with BeOne Medicines' BTK inhibitor Brukinsa already surpassing the $1 billion annual sales threshold. First approved in late 2019 for mantle cell lymphoma, Brukinsa generated $3.9 billion in sales last year and is projected to reach $6.5 billion globally by 2030. The drug is approved for a broad range of cancers, including chronic lymphocytic leukemia and Waldenström’s macroglobulinemia, and continues to expand its indications. Recent Phase 3 MANGROVE study data demonstrated that Brukinsa plus rituximab met its primary endpoint of progression-free survival in treatment-naive mantle cell lymphoma, reducing the risk of progression or death by 43% compared to rituximab plus chemotherapy, with a regulatory submission planned for this year.

• Financial Performance & Blockbuster Status: Brukinsa achieved $3.9 billion in global sales last year, marking a 49% year-on-year increase, and $1.2 billion in Q2 sales. Evaluate forecasts the drug to reach $6.5 billion in annual global sales by 2030, solidifying its position as a key blockbuster.
• Clinical Efficacy in Mantle Cell Lymphoma: The Phase 3 MANGROVE study demonstrated Brukinsa's efficacy in treatment-naive mantle cell lymphoma, where it met the primary endpoint of progression-free survival. The combination of Brukinsa and rituximab reduced the risk of progression or death by 43% compared to rituximab plus chemotherapy.
• Broad & Expanding Indications: Initially approved for mantle cell lymphoma, Brukinsa's indications have expanded to include chronic lymphocytic leukemia and Waldenström’s macroglobulinemia. BeOne Medicines is actively pursuing further expansions into marginal zone lymphoma and primary membranous nephropathy, with a regulatory submission for treatment-naive MCL slated for this year.

The Evolving Mantle Cell Lymphoma Treatment Paradigm

Frontline management of mantle cell lymphoma (MCL) continues to center on cytarabine-based immuno-chemotherapy followed by autologous stem cell transplantation (ASCT) for younger, fit patients, but recent trial data have questioned the universal need for intensification. A retrospective adjusted comparison of 97 patients treated with rituximab plus bendamustine (R-B) versus 232 patients randomized to the R-CHOP/R-DHAP arm of the MCL Younger trial showed no differences in progression-free survival (PFS) in unadjusted (HR, 0.87; 95% CI, 0.53-1.41; P = .56) or adjusted (HR, 0.79; 95% CI, 0.45-1.37; P = .40) comparisons, with overall response rate (ORR) to R-B of 90% (54% complete response [CR]) and ORR to R-CHOP/R-DHAP of 94% (54% CR). Sequential rituximab/bendamustine and rituximab/high-dose cytarabine (RB/RC) followed by ASCT achieved end-of-induction overall and complete response rates of 97% and 90%, respectively, with 3-year progression-free survival and overall survival of 83% and 92% after median follow-up of 33 months, while a large Flatiron Health cohort of 4,216 patients found no significant association between ASCT and real-world time to next treatment (hazard ratio [HR], 0.84; 95% CI, 0.68 to 1.03; P = .10) or overall survival (HR, 0.86; 95% CI, 0.63 to 1.18; P = .4) among ASCT-eligible patients. Maintenance strategies have gained support, as maintenance rituximab (MR) after bendamustine plus rituximab (BR) versus BR alone was associated with longer real-world time to next treatment (HR, 1.96; 95% CI, 1.61 to 2.38; P < .001) and overall survival (HR, 1.51; 95% CI, 1.19 to 1.92; P < .001), and ibrutinib maintenance (I-M) 560 mg daily after frontline chemoimmunotherapy ± autologous stem cell transplantation (auto-SCT) produced 3-year PFS and overall survival (OS) rates of 94% and 97% at median follow-up of 55.7 months.

Bruton tyrosine kinase (BTK) inhibitors have reshaped both relapsed/refractory and frontline paradigms, with differentiation by selectivity, tolerability, and activity after covalent BTK inhibitor failure. Zanubrutinib 160 mg twice daily in 86 patients with relapsed/refractory (R/R) MCL demonstrated ORR of 83.7%, with 77.9% achieving complete response (CR), median progression-free survival (PFS) of 33.0 months (95% confidence interval [CI], 19.4-NE), and 36-month PFS and overall survival (OS) rates of 47.6% (95% CI, 36.2-58.1) and 74.8% (95% CI, 63.7-83.0), with no cases of atrial fibrillation/flutter reported. Pirtobrutinib, a highly selective, reversible BTK inhibitor dosed at 200 mg daily, showed ORR of 52% (95% CI 38-66) in 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors in BRUIN (NCT03740529), and in the FDA accelerated approval dataset of 120 patients with relapsed or refractory MCL who had received a prior BTK inhibitor, ORR was 50% (95% confidence interval [CI]: 41, 59) and complete response rate was 13% (95% CI: 7, 20), with estimated median duration of response of 8.3 months. A propensity score-matched TriNetX cohort found newly recorded atrial fibrillation/flutter lower with acalabrutinib than ibrutinib, 4.5% versus 12.0%, RR 0.371, HR 0.387, and with zanubrutinib than ibrutinib, 5.0% versus 12.3%, RR 0.408, HR 0.421. Chemotherapy-free combinations have shown durable activity, including venetoclax-ibrutinib in the phase 2 AIM trial (NCT02471391) with estimated 7-year progression-free survival (PFS) of 30% (95% confidence interval [CI], 14-49; median, 28 months; 95% CI, 13-82) and overall survival (OS) of 43% (95% CI, 23-62; median, 32 months; 95% CI, 15 to not evaluable) for R/R MCL, ibrutinib 560 mg and venetoclax 400 mg in Japanese patients with R/R MCL with complete response (CR) rate and ORR both 83%, and lenalidomide, rituximab, and venetoclax 400 mg daily in untreated MCL with overall and complete response rates of 96% and 86%, respectively, and 86% achieving minimal residual disease undetectability via next-generation sequencing.

Cellular immunotherapy and T-cell engagers have emerged for high-risk and multiply relapsed disease, including after BTK inhibitor failure. Brexucabtagene autoleucel, an autologous CD19-directed CAR T-cell therapy approved in July 2020 for relapsed/refractory mantle cell lymphoma based on ZUMA-2, achieved overall response rate (ORR) of 100%, with complete response rate (CRR) of 80%, in five patients in Singapore with cytokine release syndrome (CRS) in 80% and grade 1 ICANS in 20%, and in 233 patients aged ≥70 years reported to the EBMT registry, complete remission in 78% and partial remission in 13% at day +100, with cumulative incidence at 30 days of any-grade cytokine release syndrome (CRS) of 80% (grade ≥3, 9%) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) of 57% (grade ≥3, 22%), and at 1 year overall survival (OS) of 74%, progression-free survival (PFS) of 62%, relapse/progression incidence (R-PI) of 25%, and non-relapse mortality (NRM) of 13%. Glofitamab, a bispecific antibody targeting CD20×CD3, showed responses in 7/9 evaluable heavily pretreated r/r MCL patients including complete response in 4/9 after median of five cycles, with cytokine-release syndrome in 7/10 (mostly Grade 1-2), including grade 3 events in 2/10, and ICANS in 2/10 patients, including one Grade 4 event, and all three patients receiving glofitamab as bridging therapy proceeded to CAR-T infusion. Glofitamab with obinutuzumab/rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (G/R-CHOP) in 31 patients with relapsed/refractory B-cell non-Hodgkin lymphoma produced complete metabolic response rate of 83.9% with median progression-free survival not reached after 44.2 months follow-up, while cytokine release syndrome occurred in 16 (51.6%) patients (grade 1/2, n = 12 [38.7%]; grade 3/4, n = 4 [12.9%]).

Brukinsa's Efficacy and Regulatory Journey in Mantle Cell Lymphoma

Reported outcomes in mantle cell lymphoma span BTK inhibitors, CAR T-cell therapy, and other targeted agents, with durable responses observed in both relapsed/refractory and frontline settings. Comparative analyses further differentiate efficacy between covalent BTK inhibitors and newer cellular and non-covalent approaches after prior BTK exposure.

Closing Gaps: Targeting Unmet Needs in Mantle Cell Lymphoma

Recent literature in mantle cell lymphoma (MCL) concentrates on high-risk biology and treatment-experienced populations where relapse is frequent and survival remains limited despite Bruton tyrosine kinase (BTK) inhibitors. Focus has shifted toward chemotherapy-free targeted combinations, cellular immunotherapy, and risk-adapted strategies for elderly and transplant-ineligible patients.

• TP53-mutated MCL with poor prognosis on chemoimmunotherapy: TP53 mutation is described as a critical predictor of early disease progression and poor prognosis, and as the only genetic biomarker with established clinical prognostic value. Investigational approaches include zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated patients with a TP53 mutation with best overall response rate of 96% (24/25) and complete response rate of 88% (22/25), and with 2-year progression-free, disease-specific, and overall survival of 72%, 91%, and 76%, respectively; rituximab, bendamustine, and cytarabine followed by venetoclax (FIL_V-RBAC) in high-risk disease with 2-year progression-free survival of 60% (95% CI 48-74); and targeted therapy, allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and chimeric antigen receptor-T (CAR-T) cell therapy for relapsed/refractory TP53-mutated disease.

• Blastoid variant MCL (BV-MCL) and other high-risk features: Blastoid variant represents an aggressive subset with no established standard of care treatment approach, associated with increased risk of central nervous system (CNS) involvement and high mortality rates. Reported outcomes include complete response rate to frontline and salvage therapy of 66.7% and 25%, respectively, and 2-year overall survival (OS) of 62.5% (95% CI, 34.7%-81.1%); variables associated with higher OS included receipt of consolidative HSCT (p = 0.017), TP53-wild type (p = 0.031), and achieving complete response with induction therapy (p = 0.027). High-risk MCL defined by TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic morphology, or Ki67 ≥ 30% showed median progression-free survival of 13.7 months vs not reached (NR) for low risk (hazard ratio [HR], 2.19; P = .004) and median OS of 14.8 months vs NR (HR, 2.36; P = .005) on first-line ibrutinib with or without rituximab.

• Relapsed/refractory MCL after covalent BTK inhibitor (cBTKi) failure and resistance mutations: Efficacy of BTK inhibitors such as ibrutinib, acalabrutinib, and pirtobrutinib is challenged by resistance mutations (e.g., BTK C481S) and off-target toxicities, with resistance further sustained by stromal support and immunosuppressive cellular interactions. Strategies under investigation include next-generation reversible BTKis with activity in the setting of resistance, combination strategies incorporating BTKis with BCL-2 inhibitors, monoclonal antibodies, and cellular therapies, and comparison of brexucabtagene autoleucel (brexu-cel) vs pirtobrutinib for post-cBTKi disease where brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81-38.46]) and complete response (OR 10.11 [95% CI 4.26-24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25-0.75]).

• Post CAR-T failure with limited salvage options: Among 61 patients with failure after brexu-cel, median OS2 and PFS2 were 5.8 and 1.8 months, respectively, after median follow-up of 15 months post-failure; patients experiencing early failure (<3 months) had median OS2 of 1.8 months. Post-salvage response rate was 20% (9 CR, 1 PR) across lenalidomide ± rituximab, immunochemotherapy, BTK inhibitor ± venetoclax, and bispecific T-cell engager, with 1-year OS2 of 36% for lenalidomide ± rituximab and immunochemotherapy, 57% for bispecific T-cell engager and 0% for others type of salvage.

• Elderly, transplant-ineligible, and ibrutinib-intolerant patients: Elderly patients require individualized treatment based on comprehensive geriatric assessment due to poor tolerance, while transplant-ineligible patients have no standard first-line immunochemotherapy regimen. In 3664 elderly patients receiving 1L treatment, median OS from initiation of 1L was 53.5 months; 2L: 22.0 months; 3L: 11.8 months; 4L: 7.8 months, with 51.8% having all-cause hospitalization within 12 months of initiating 1L. For ibrutinib-intolerant patients, off-target adverse effects such as atrial fibrillation, hypertension, and bleeding may limit tolerance, with no well-established treatment regimen and approaches including supportive care or dose reductions, switching to an alternative covalent BTK inhibitor, or abandoning covalent BTK inhibitors for alternative forms of treatment.