The non-covalent BTK space expands

Hutchmed is taking its shot in one of the toughest B-cell cancer settings, pushing HMPL-760, a rare non-covalent BTK inhibitor that until now has had a very low profile, into a pivotal phase 3 trial in diffuse large B-cell lymphoma.

The move makes Hutchmed the third company to steer a non-covalent BTK inhibitor into late-stage development. Unlike earlier covalent drugs, these agents are designed to overcome resistance driven by the C481 escape mutation, but so far, Lilly's Jaypirca is the only one to make it to the market.

Lilly got Jaypirca through its $8bn takeover of Loxo Oncology. Another non-covalent, nemtabrutinb, was originated by Arqule, a biotech bought for $2.7bn by Merck & Co, which, after some delays, is now testing it in several pivotal trials.

Hutchmed's phase 3

Hutchmed's HMPL-760 appears to have been internally generated, and where many developers initially focused on mantle cell lymphoma or chronic lymphocytic leukaemia, that company is heading straight for diffuse large B-cell lymphoma (DLBCL).

The new phase 3 study, 2025-760-00CH1, will be conducted only in China and will evaluate HMPL-760 in combination with Rituxan plus chemotherapy versus Rituxan and chemo in patients with relapsed or refractory DLBCL. Progression-free survival and overall survival will serve as co-primary endpoints.

The existence of HMPL-760 was first revealed around ASCO in 2021, but so far clinical data disclosed are limited, making it hard to gauge the reasons behind Hutchmed's move into phase 3. The company has reported monotherapy results in 26 patients with various lymphomas, including seven with DLBCL; among those seven, four responses were observed, one complete and three partial.

That's clearly positive, but represents an extremely small dataset. More substantive support is expected to come from an ongoing phase 2 trial testing the same regimen in the same setting. Those results have yet to be presented, but could surface at upcoming meetings like ASCO or EHA.

Competition

Competition in pivotal DLBCL trials among any members of the BTK inhibitor class remains relatively sparse. AstraZeneca is evaluating its covalent BTK inhibitor Calquence in the global phase 3 Escalade trial in first-line DLBCL.

Meanwhile, Newave Pharmaceutical is advancing rocbrutinib, a covalent-noncovalent BTK inhibitor, in its China-only Rock-2 trial in heavily pretreated patients.

As for non-covalents in any setting, there's little competition beyond Jaypirca and nemtabrutinb. Japan's Carna Biosciences has docirbrutinib in early trials for the more typical indication of CLL, while Sunesis's vecabrutinib was discontinued as that company went out of business.

Selected pivotal trials evaluating BTK inhibitors in DLBCL

Source: OncoogyPipeline.