Dr Dreyling on the Evolving Role of BTK Inhibitors in MCL Management

"BTK inhibitors will remain the cornerstone of first-line treatment in MCL, but the combination partners will potentially switch from chemotherapy to nonchemotherapy partners."

Martin Dreyling, MD, full professor, Department of Medicine, University Hospital LMU Munich, discussed the evolving role of BTK inhibitors, such as acalabrutinib (Calquence), in the management of mantle cell lymphoma (MCL).

The current treatment landscape for MCL is increasingly challenging the role of chemotherapy overall. Dreyling noted that strategies involving ibrutinib (Imbruvica) plus rituximab (Rituxan) alone have been shown to be inferior to chemotherapy combined with rituximab.

However, the field is moving toward highly effective non-cytostatic combinations. A triplet combination, including an anti-CD20 antibody, a BTK inhibitor, and venetoclax (Venclexta), demonstrated impressive results in the phase 1/2 OAsIs trial (NCT02558816). Data from OAsIs showed a 5-year progression-free survival (PFS) rate of 80% and an overall survival (OS) rate of 90%, despite involving a small patient number. This data drives the ongoing effort to conduct several randomized trials comparing chemotherapy against non-cytostatic combinations, Dreyling stated.

For patients categorized as classical-risk, Dreyling suggested that they might be better off avoiding chemotherapy entirely. However, the reality for high-risk patients in the first-line setting is challenging; even combinations like ibrutinib plus venetoclax have yielded short durations of remission in phase 2 studies. For very high-risk patients, such as those with high Ki-67 scores and TP53 alterations, Dreyling expressed hope that the combination of immunotherapy plus targeted therapy could potentially overcome the prognostic relevance of these adverse factors, offering an advantage over the current standard approach of chemotherapy plus a BTK inhibitor.

Although BTK inhibitors are anticipated to remain the cornerstone of first-line MCL management, Dreyling concluded that future combination partners are likely to switch away from chemotherapy toward non-chemotherapy options. This shift builds upon the successful incorporation of BTK inhibitors into regimens like acalabrutinib plus bendamustine and rituximab (Rituxan; BR), as evidenced by the significant PFS benefit and OS trend seen in the phase 3 ECHO trial (NCT02972840).