KEY TAKEAWAYS
- The ECHO phase 3 trial aimed to assess the combination of acala with BR in elderly patients with untreated MCL in ECHO.
- The primary endpoint was PFS.
- The addition of acala to BR in ECHO trial for elderly patients with MCL significantly improved PFS and showed positive OS trends.
Aggressive initial treatments for mantle cell lymphoma (MCL) offer lasting responses and extended progression-free survival (PFS), but pose challenges for elderly or medically unfit individuals due to their poor tolerability. Combining the Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy (CIT; bendamustine + rituximab [BR]) as a first-line treatment for MCL (SHINE) has shown promise in prolonging PFS.
However, this approach has been associated with compromised overall survival (OS) because of increased toxicity.
Michael Wang and the team conducted a study that aimed to assess the efficacy of combining acalabrutinib with BR in elderly patients with previously untreated MCL in the randomized, double-blind, placebo-controlled Phase 3 ECHO trial.
Patients aged 65 years or older with previously untreated MCL and an ECOG performance status of 2 or less were randomly assigned in a 1:1 ratio to receive either ABR or placebo in combination with BR (PBR).
Enrollment took place between April 2017 and March 2023 across 195 global sites. BR treatment consisted of 6 cycles, followed by rituximab maintenance for 2 years in patients achieving a partial or complete response. Acala (100 mg twice daily) or placebo was administered until disease progression or unacceptable toxicity, with the option to switch to acala upon disease progression. The primary endpoint was PFS as assessed by an independent review committee.
About 598 patients were included in the analysis, evenly distributed with 299 patients in each arm. The median age was 71 years, and 76% had low/intermediate simplified MIPI while 13% had blastoid/pleiomorphic histology. Patient characteristics were well balanced between the two treatment arms. After a median follow-up of 45 months, 31.8% and 25.8% of patients continued treatment in the ABR and PBR arms, respectively.
Overall response rates (ORR) were 91.0% and 88.0% with ABR and PBR, respectively, with corresponding complete response rates of 66.6% and 53.5%. Median PFS was 66.4 months with ABR compared to 49.6 months with PBR (HR 0.73; 95% CI 0.57, 0.94; P=0.0160). OS data showed a positive trend favoring the ABR arm (HR 0.86; 95% CI 0.65, 1.13; P=0.27), despite 51 patients crossing over to acala after disease progression with PBR. COVID-19 deaths significantly influenced study outcomes.
After censoring for COVID-19 deaths, median PFS improved in both arms: not reached with ABR vs 61.6 months with PBR (HR 0.65; 95% CI 0.49, 0.86; P=0.0027). A similar trend was observed in OS (HR 0.78; 95% CI 0.56, 1.07; P=0.12).
Regarding safety, grade ≥3 adverse events (AEs) and serious AEs were comparable between both arms. Among grade ≥3 AEs of clinical interest, atrial fibrillation, hypertension, neutropenia, infections, and pneumonia were reported in both arms. COVID-19-related events and deaths were also reported, with discontinuation of acala due to AEs occurring in a higher proportion of patients compared to the placebo arm, primarily due to COVID-19.
The study concluded that adding acalabrutinib to BR in the ECHO trial for elderly patients with untreated MCL resulted in a statistically significant enhancement in PFS over a 45-month median follow-up period. Additionally, a favorable trend in OS was observed, particularly evident in patients unaffected by COVID-19.
The trial was sponsored by the Acerta Pharma BV.
Clinical Trial: https://clinicaltrials.gov/study/NCT02972840
Wang M, Mayer J, Belada D, Song Y, et al. (2024). “CALABRUTINIB PLUS BENDAMUSTINE AND RITUXIMAB IN UNTREATEDMANTLE CELL LYMPHOMA: RESULTS FROM THE PHASE 3, DOUBLE-BLIND,PLACEBO-CONTROLLED ECHO TRIAL.” Presented at EHA 2024. (LB3439)
