Acalabrutinib plus chemoimmunotherapy reduces the risk of disease progression or death in elderly patients with untreated mantle cell lymphoma

In the randomised, double-blind, placebo-controlled, phase III ECHO trial, the efficacy and safety of first-line treatment with acalabrutinib plus bendamustine and rituximab were compared to placebo plus bendamustine and rituximab in elderly patients with untreated mantle cell lymphoma. With a median follow-up of 45 months, the addition of acalabrutinib to bendamustine-rituximab led to a statistically significant improvement in progression-free survival and a positive trend in overall survival.

Intensive first-line therapies for mantle cell lymphoma (MCL) can provide durable responses and prolonged progression-free survival (PFS) but are unsuitable for older/unfit patients due to poor tolerability. In this patient population, bendamustine plus rituximab (BR) is the most common first-line therapy. The addition of the Bruton’s Tyrosine Kinase inhibitor (BTKi) ibrutinib to BR for first-line treatment of MCL in the SHINE study demonstrated a prolonged PFS, although without improvements in overall survival (OS) due to excess toxicity. A phase I study of acalabrutinib plus BR (ABR) in older patients with MCL has demonstrated favourable efficacy and safety. The phase III ECHO trial now evaluates the ABR regimen in elderly patients with previously untreated MCL.

Study design

In the randomised, double-blind, placebo-controlled, phase III ECHO trial, patients aged ≥65 year with previously untreated MCL and ECOG PS ≤2 were randomly assigned (1:1) to receive ABR or placebo plus BR (PBR). Enrolment occurred between April 2017 and March 2023 from 195 sites globally. BR was administered for six cycles followed by rituximab maintenance for two year in patients achieving a partial or complete response (PR or CR). Acalabrutinib (100 mg twice daily) or placebo was administered until disease progression or unacceptable toxicity. Crossover to acalabrutinib was allowed at disease progression. The primary endpoint was progression-free survival (PFS) per independent review committee.

Results

A total of 598 patients were included in this analysis (299 patients in both arms). The median age was 71 years, 76% had a low or moderate Mantle Cell Lymphoma International Prognostic Index (MIPI) score and 13% had blastoid or pleiomorphic histology. Patient characteristics were balanced between study arms. After a median follow-up of 45 months, overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% with ABR and PBR, respectively. Median PFS was 66.4 months in the ABR group and 49.6 months in the PBR group, translating into a 27% reduction in the risk of disease progression or death (HR[95%CI]: 0.73[0.57-0.94], p= 0.016). The secondary endpoint of OS showed a positive trend in favour of ABR (HR[95%CI]: 0.86[0.65-1.13], p= 0.2743), despite the fact that 51 patients in the placebo group were switched to treatment with acalabrutinib after disease progression. Furthermore, a pre-specified analysis censoring for COVID-19-related deaths was conducted to assess the impact of the pandemic. Both PFS (median not reached with ABR vs. 61.6 months with PBR; HR[95%CI]: 0.64[0.48-0.84], p= 0.0017) and OS (HR[95%CI]: 0.75[0.53-1.04], p= 0.0797) were further improved.

The number of treatment-emergent adverse events (TEAEs) of grade 3 or higher was similar in both study groups (88.9% and 88.2% of patients in the ABR and PBR groups, respectively). Grade ≥3 AEs of special interest were atrial fibrillation (3.7% vs. 1.7%), hypertension (5.4% vs. 8.4%), major bleeding (2.0% vs. 3.4%), infections (41.1% vs. 34.0%) and second primary malignancies (5.4% vs. 6.7%). TEAEs leading to acalabrutinib/placebo discontinuation were observed in 42.8% and 31.0% of patients, respectively. Median treatment exposure was longer in the acalabrutinib-arm, as compared to the placebo-arm (29 vs. 25 months). AEs of any grade related to COVID-19 were reported in 40.7% versus 29.61% of patients in the ABR and PBR groups, respectively.

Conclusion

The addition of acalabrutinib to BR in older patients with MCL reduced the risk of disease progression or death by 27%, with a 36% risk reduction when censoring COVID-19 deaths. The safety profile of acalabrutinib + BR is consistent with that of the individual drugs. ECHO provides the first evidence of a positive trend in OS when adding a BTKi to frontline standard chemoimmunotherapy for treatment of older patients with MCL.  The survival trend favouring acalabrutinib + BR was sustained despite most patients receiving a BTKi as salvage therapy after disease progression with BR.

Reference

Wang M, et al. Acalabrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma: results from the phase 3, double-blind, placebo-controlled ECHO trial. Presented at EHA 2024; Abstract LB3439.