Frontline Acalabrutinib Combo Reduces Risk for Disease Progression, Death in Mantle Cell Lymphoma

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Treatment with acalabrutinib and bendamustine/rituximab in the frontline setting improved progression-free survival in older patients with MCL.

Frontline Acalabrutinib Combo Reduces Risk for Disease Progression, Death in Mantle Cell Lymphoma

Frontline Acalabrutinib Combo Reduces Risk for Disease Progression, Death in Mantle Cell Lymphoma

Older patients with mantle cell lymphoma (MCL) treated with acalabrutinib (Calquence) plus bendamustine and rituximab (Rituxan; BR) in the frontline setting experienced a 27% reduction in the risk of disease progression or death, according to findings from the phase 3 ECHO trial (NCT02972840) that were presented at the 2024 EHA Congress.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, 36.0-64.1) with BR and placebo (stratified HR, 0.73; 95% CI, 0.57-0.94; P = .0160) 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 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 on BR alone, 69% received a BTK inhibitor as a subsequent treatment, noted lead study author Michael Wang, MD, in an oral presentation during the meeting.

“ECHO provides 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, a 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 personal opinion, this is a new standard therapy.”

While current frontline therapeutic regimens, the most common being BR, do 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 effects (AEs) as seen in the phase 3 SHINE trial (NCT01776840),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-naïve MCL were randomized 1:1 to received 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 BR for 6 cycles plus twice-daily placebo until disease progression or toxicity. If patients in both arms achieved a partial response (PR) or higher to BR, they then received maintenance rituximab every 2 cycles for 2 years. Those on the placebo arm could cross over to acalabrutinib or another BTK inhibitor after disease progression.

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

The primary end point was IRC-assessed PFS, while key secondary end points were OS and IRC-ORR. Safety was also evaluated.

Regarding baseline characteristics, the median age across the 2 arms was 71 years (range, 65-86) and 27.0% of patients were older than 75 years. Most were male (70.8%) and had an ECOG performance status of 1 (43.6%). A total 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 8.6% of patients had TP53-mutated disease and 47.9% had a Ki-67 score greater than 30%.

Further efficacy findings showed that the overall response rate (ORR) with acalabrutinib/BR was 91.0%, which comprised a 66.6% complete response (CR) rate and a 24.4% PR rate, compared with 88.0% in the BR/placebo arm of a 53.5% CR rate and a 34.4% PR rate.

When 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 would often ask, ‘Michael, 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 frontline as better than subsequencing acalabrutinib,” he emphasized.

A prespecified sensitivity analysis was also conducted to determine the PFS and OS when censored for COVID-19 deaths. Here, the median PFS 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 arms (95% CI, 73.8-NE), 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 on acalabrutinib/BR (99.7%) and placebo/BR alone (99.0%); 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 on acalabrutinib/BR and placebo/BR alone, respectively. All-grade and grade 3 or higher serious AEs occurred in 69.0% and 64.3% of acalabrutinib-treated patients and 62.0% and 55.9% of patients on placebo/BR. Sixty-eight percent of TEAEs were related to acalabrutinib vs 55.6% that were related to placebo, and TEAEs leading to acalabrutinib and placebo discontinuation occurred in 42.8% and 31.0% of patients, respectively.

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% vs 8.4%), major bleeding (2.4% and 2.0% vs 5.4% and 3.4%), infections (78.1% and 41.1% vs 71.0% and 34.0%), and second primary malignancies excluding non-melanoma skin cancer (9.8% and 5.4% vs 10.8% and 6.7%). 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.

Deaths were also evaluated on ECHO. Total deaths were 32.4% (n = 97) with acalabrutinib/BR vs 35.5% (n = 106) with placebo/BR. On the acalabrutinib arm, these were due to disease progression (10.0%), were within 30 days after the last dose due to AEs (9.0%), more than 30 days after their last dose due to an AE (6.4%), other (4.7%), or unknown (2.3%). On the placebo/BR arm, including crossover, these cause rates were 14.4%, 9.0%, 4.7%, 5.4%, and 2.0%, respectively.

Investigators also looked at COVID-19–related AEs, which occurred in 40.7% and 29.6% of patients on acalabrutinib/BR and placebo/BR, respectively; these were grade 3 and higher in 20.2% and 16.8% of patients, respectively. COVID-19–related deaths occurred in 9.4% (n = 28) and 6.7% (n = 20) of patients, respectively. Any-grade and grade 3 or higher serious COVID-related AEs occurred in 20.2% and 19.5% of acalabrutinib-treated patients compared with 17.5% and 16.2% of those on placebo/BR. There were 10.4% of COVID-19–related AEs that led to acalabrutinib discontinuation vs 6.4% that led to placebo discontinuation.

Disclosures: Wang cited consulting roles with AbbVie, Acerta Pharma, ADC Therapeutics America, Amphista Therapeutics Limited, AstraZeneca, BeiGene, Be BioPharma, BioInvent, Bristol Myers Squibb, Deciphera, Genentech, InnoCare, Janssen, Kite Pharma, Eli Lilly, Merck, Miltenyi Biomedicine, Oncternal, Parexel, Pepromene Bio, and Pharmacyclics; research with Acerta Pharama, AstraZeneca, BeiGene, BioInvent, Celgene, Genmab, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Eli Lilly, Loxo Oncology, Molecular Templates, Oncternal, Phamacyclics, and Vincerx; and honoraria from AbbVie, Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Bristol Myers Squibb, Cahon, Catamount Medical Education, Dava Oncology, Genmab, Janssen, Kite Pharma, MJH Life Sciences, Merck, MSC National Research Institute of Oncology, NIH, Nurix, Pharmacyclics, Physician’s Education Resource (PER), Research to Practice, Scripps, Studio ER Congressi, South African Clinical Hematological Society, and WebMD.

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. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract LB3439.
  2. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med. 2022;386(26):2482-2494.
  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
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