Add-on acalabrutinib prolongs PFS in older patients with untreated MCL

In older patients with untreated mantle cell lymphoma (MCL), the addition of the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib to bendamustine and rituximab (ABR) conferred a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with a favourable trend for overall survival (OS), findings from the phase III ECHO trial have shown.

After a median follow-up of 45 months, the median PFS was significantly longer with ABR vs placebo-BR (PBR; 66.4 vs 49.6 months). ABR reduced the risk of disease progression or death by 27 percent (hazard ratio [HR], 0.73; p=0.016).

There was a positive OS trend in favour of ABR despite placebo recipients crossing over to acalabrutinib after experiencing disease progression (HR, 0.86; p=0.2743). [EHA 2024, abstract LB3439]

In the prespecified sensitivity analysis that censored COVID-19 deaths – which had a relevant impact on the outcome – the median PFS improved in both ABR and PBR arms (not estimable vs 61.6 months). The former reduced the risk of disease progression or death by 36 percent (HR, 0.64; p=0.0017). A favourable OS trend was also observed with ABR (HR, 0.75; p=0.0797).

Overall response rate was better in the ABR vs PBR arm (91 percent vs 88 percent), as was complete response rate (66.6 percent vs 53.5 percent).

The rates of grade ≥3 treatment-emergent adverse events (TEAEs) were comparable between the ABR and PBR arms (88.9 percent and 88.2 percent), as were those of grade ≥3 serious AEs (64.3 percent and 55.9 percent) and grade 5 TEAEs (12.1 percent vs 10.1 percent).

Over 40 percent (42.8 percent) of acalabrutinib recipients discontinued the drug due to TEAEs, as opposed to 31 percent in the PBR arm.

The only BTK inhibitor for 1L MCL Tx

“Intensive therapies such as stem cell transplant and hyper-CVAD* are associated with >10-year survival in younger MCL patients at frontline,” said Dr Michael Wang from the MD Anderson Cancer Center, Houston, Texas, US, at EHA 2024. “However, such therapies cannot be tolerated by older/unfit patients. BR is the most common first-line (1L) therapy in this patient population.”

There is evidence showing that adding a BTK inhibitor (ibrutinib) to BR for 1L treatment of MCL improves PFS, but not OS. [N Engl J Med 2022;386:2482-2494] A phase I study showed the favourable efficacy and safety of ABR in older MCL patients. [J Clin Oncol 2023;41:7546]

To further validate the potential of ABR in this patient setting, Wang and colleagues conducted ECHO, which comprised 598 adults ≥65 years (median age 71 years, 71 percent men) with untreated MCL. They were randomized 1:1 to receive oral acalabrutinib 100 mg or placebo BID on 28-day treatment cycles, plus bendamustine 90 mg/m² (days 1 and 2) and rituximab 375 mg/m² (day 1). Both arms received six cycles of BR followed by 2 years of rituximab maintenance. Crossover from placebo to acalabrutinib was allowed after progressive disease.

“ECHO provides first evidence of a positive OS trend when adding a BTK inhibitor to frontline standard chemoimmunotherapy for the treatment of older patients with MCL,” said Wang. “The survival trend favouring ABR was sustained despite most patients receiving a BTK inhibitor as salvage therapy after disease progression with BR.”

“The ECHO data suggest that acalabrutinib provides substantial benefit when given as frontline therapy in combination with BR,” Wang added.

“For people living with MCL, a typically aggressive form of non-Hodgkin lymphoma, the findings offer promise of a new, effective treatment option for adults ≥65 years, who represent the majority of MCL patients,” he noted. “The improved PFS seen in patients treated with [ABR] demonstrate its potential to change the standard of care as the only BTK inhibitor in the 1L setting.”