Frontline Acalabrutinib/BR Regimen Improves PFS in MCL

Michael Wang, MD

Professor Department of Lymphoma and Myeloma

The University of Texas MD Anderson Cancer Center

Houston, TX

Treatment with acalabrutinib (Calquence) combined with bendamustine and rituximab (Rituxan; BR) in the frontline setting led to a 27% reduction in the risk of disease progression or death in older patients with mantle cell lymphoma (MCL), according to findings from the phase 3 ECHO trial (NCT02972840) presented at the European Hematology Association 2024 Hybrid Congress in Madrid, Spain.¹

Results showed that the independent review committee (IRC)–assessed median progression-free survival (PFS) with acalabrutinib plus BR was 66.4 months (95% CI, 55.1-not estimable [NE]) compared with 49.6 months (95% CI, 36.064.1) with BR and placebo (stratified HR, 0.73 95% CI, 0.57-0.94; P=.016) at a median follow-up of 45 months. The data were found to be statistically significant and showed a trend toward improved overall survival (OS).

A total of 19.1% (n=57) and 33.1% (n=99) of patients in the acalabrutinib/BR and placebo/ BR arms, respectively, had progressive disease. Of those patients taking BR alone, 69% received a Bruton tyrosine kinase (BTK) inhibitor as a subsequent treatment, lead study author Michael Wang, MD, noted in an oral presentation during the meeting.

“ECHO [data] provide first evidence of a positive trend in OS when adding a BTK inhibitor to frontline standard chemoimmunotherapy for treatment of older patients with MCL,” Wang, professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center in Houston, said. “ECHO data suggest that acalabrutinib provides substantial benefit when given as a frontline therapy in combination with BR. In my opinion, this is a new standard therapy.”

Although current frontline therapeutic regimens, with the most common being BR, have efficacy in patients with MCL, they are intensive and not suitable for older and unfit patients, as they are not well tolerated. Additionally, adding ibrutinib (Imbruvica) to BR in the frontline setting prolongs PFS but not OS because of the associated adverse events (AEs), as seen in the phase 3 SHINE trial (NCT01776840) findings,² Wang explained. Phase 1 data previously demonstrated that acalabrutinib combined with BR in older patients with MCL has efficacy and tolerability.³

In the multicenter, double-blind, placebo-controlled, phase 3 ECHO trial, 598 patients with treatment-naive MCL were randomly assigned 11 to receive bendamustine at 90 mg/m² on days 1 and 2 with rituximab at 375 mg/m² on day 1 every six 28-day cycles plus oral acalabrutinib at 100 mg twice daily until disease progression or toxicity or to receive BR for 6 cycles plus twice-daily placebo until disease progression or toxicity. If patients in either arm achieved a partial response (PR) or higher with BR, they then received maintenance rituximab every 2 cycles for 2 years. Those in the placebo arm could cross over to acalabrutinib or another BT inhibitor after disease progression.

To be eligible for enrollment, patients had to be 65 years or older and have an ECOG performance status of 0 to 2. Stratification factors included a simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) score (low vs intermediate vs high) and geographic region (North America vs Western Europe vs other).

The primary end point was IRC-assessed PFS, and key secondary end points were OS and IRC-assessed overall response rate (ORR). Safety was also evaluated.

Regarding baseline characteristics, the median age across the 2 arms was 71 years (range, 65-86) and 27% of patients were older than 75 years. Most were men (70.8%) and had an ECOG performance status of 1 (43.6%). A total of 37.7% of patients had tumor bulk of at least 5 cm, and 13.2% of patients had blastoid/pleomorphic histology. The breakdown of sMIPI score was low (33.5%), intermediate (42.3%), and high risk (24.3%) most patients had extranodal disease (90.5%). A total of 8.6% of patients had TP53-mutated disease, and 47.9% had a i-67 score greater than 30%.

Further efficacy findings showed that the ORR with acalabrutinib/BR was 91%, which comprised a 66.6% complete response (CR) rate and a 24.4% PR rate, compared with 88% in the BR/placebo arm, which comprised a 53.5% CR rate and a 34.4% PR rate. hen evaluating OS and including crossover, the median OS was NE with both acalabrutinib/BR (95% CI, 72.1-NE) and BR/ placebo (95% CI, 73.8-NE), demonstrating a 14% reduction in the risk of death (HR, 0.86 95% CI, 0.65-1.13 P=.2743), but this was not found to be statistically significant, Wang said, adding that the subsequent crossover to another BTK inhibitor did not affect OS.

“Many ask, Should we give concurrent therapy in the first line with BR plus acalabrutinib, or should we give BR sequential therapy with acalabrutinib in the second line?’ But these curves indicate concurrent therapy with BR/acalabrutinib in the front-line as better than subsequencing acalabrutinib,” Wang said.

A prespecified sensitivity analysis was also conducted to determine the PFS and OS when censored for COVID-19 deaths. The median PFS in this analysis was NE (95% CI, 66.4-NE) with acalabrutinib/BR vs 61.6 months (95% CI, 49.6-68.9) with placebo/BR (HR, 0.64 95% CI, 0.48-0.84; P=.0017). Median OS was NE in both the acalabrutinib/BR (95% CI, NE-NE) and placebo/BR (95% CI, 73.8-NE) arms, leading to a 25% reduction in the risk of death (HR, 0.75 95% CI, 0.53-1.04; P=.0797).

Regarding safety, any treatment-emergent AEs (TEAEs) occurred in most patients taking acalabrutinib/BR (99.7%) and placebo/BR alone (99%) grade 3 or higher AEs occurred in 88.9% and 88.2% of patients, respectively. TEAEs that led to death occurred in 12.1% and 10.1% of patients taking acalabrutinib/ BR and placebo/BR alone, respectively. All-grade and grade 3 or higher serious AEs occurred in 69% and 64.3% of patients taking acalabrutinib and 62% and 55.9% of patients taking placebo/BR.

All-grade and grade 3 or higher AEs of interest on acalabrutinib/BR and placebo/ BR, respectively, included atrial fibrillation (6.1% and 3.7% vs 4.4% and 1.7%), hypertension (12.1% and 5.4% vs 15.8% and 8.4%), and major bleeding (2.4% and 2.0% vs 5.4% and 3.4%). The median treatment exposure was 29 months (range, 0.1-80.1) in the acalabrutinib arm and 25 months (range, 0.03-76.4) in the BR arm.

Total deaths were 32.4% (n=97) with acalabrutinib/BR vs 35.5% (n=106) with placebo/ BR. In the acalabrutinib arm, these were due to disease progression (10%), within 30 days after the last dose due to AEs (9%), more than 30 days after the last dose due to an AE (6.4%), due to other reason (4.7%), or due to unknown reason (2.3%). In the placebo/BR arm, including crossover, these cause rates were 14.4%, 9%, 4.7%, 5.4%, and 2%, respectively.

Total deaths were 32.4% (n=97) with acalabrutinib/BR vs 35.5% (n=106) with placebo/ BR. In the acalabrutinib arm, these were due to disease progression (10%), within 30 days after the last dose due to AEs (9%), more than 30 days after the last dose due to an AE (6.4%), due to other reason (4.7%), or due to unknown reason (2.3%). In the placebo/BR arm, including crossover, these cause rates were 14.4%, 9%, 4.7%, 5.4%, and 2%, respectively.

REFERENCES:

1. Wang ML, Mayer J, Belada D, et al. Acalabrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma: results from the phase 3, double-blind, placebo-controlled ECHO trial. Abstract presented at: European Hematology Association 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain. Abstract LBA3439.

2. Wang ML, Jurczak W, Jerkeman M, et al; SHINE Investiga Dr_Microbe - stock.adobe.com tors. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med. 2022;386(26):24822494. doi:10.1056/NEJMoa2201817

3. Phillips TJ, Wang ML, Robak T, et al. Safety and efficacy of ABR in pts with TN or R/R MCL: ph Ib trial. J Clin Oncol. 2023;41(suppl 16):7546. doi:10.1200/JCO.2023.41.16_suppl.7546