Noncovalent BTK Inhibitors, CAR T-Cell Therapy Generate Excitement in CLL

Alexey V. Danilov, MD, PhD

Sitting at the forefront of clinical development, pirtobrutinib (LOXO-305) and lisocabtagene maraleucel (Breyanzi) have generated significant enthusiasm in chronic lymphocytic leukemia (CLL), explained Alexey V. Danilov, MD, PhD.

“This is a very exciting area right now with multiple new targets in the works, both [in terms of] targeted agents and small molecules, as well as antibodies and cellular therapies,” said Danilov, associate director of the Toni Stephenson Lymphoma Center and professor in the Division of Lymphoma and Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, in a virtual presentation during the 2021 SOHO Annual Meeting.¹

Targeted Therapy

First, Danilov highlighted the novelty of noncovalent, reversible BTK inhibitors, which is an approach that is currently under study to circumvent resistance to currently approved, covalent, irreversible BTK inhibitors.

“The noncovalent, reversible BTK inhibitors have been introduced into clinical trials recently, and several of them have been studied. Pirtobrutinib is probably the most advanced,” said Danilov.

The agent is a highly potent and selective noncovalent BTK inhibitor that is being evaluated in the phase 1/2 BRUIN trial (NCT03740529). Updated findings from the trial, which were presented at the 2021 SOHO Annual Meeting, demonstrated an objective response rate (ORR) of 63% in patients with CLL and small lymphocytic lymphoma (SLL) and 62% in patients with BTK inhibitor–pretreated CLL/SLL.

Notably, the ORR was 86% in patients with previously treated CLL/SLL who had at least 10 months of follow-up since the start of treatment (n = 29).2

“Treatment with pirtobrutinib has been associated with a very high response rate, and patients who have been identified to have BTK C481S mutations also obtained response, including patients who progressed on prior BCL2 inhibitors,” said Danilov.

If approved, Danilov said that he expects the agent to be used after patients progress on ibrutinib (Imbruvica) or acalabrutinib (Calquence).

Cellular Therapy

Another treatment avenue under evaluation is cellular therapy, explained Danilov, citing the phase 1/2 TRANSCEND CLL 004 study (NCT03331198), which is evaluating lisocabtagene maraleucel, a CD19-directed, defined composition CAR T-cell therapy in patients with relapsed/refractory CLL/SLL.

Updated findings from the study, which were presented at the 2020 ASH Annual Meeting and Exposition, demonstrated an ORR of 82% at a median follow-up of 24 months and a median progression-free survival of 18 months.3 Approximately half of responders derived a complete response (CR) or CR with incomplete hematologic recovery (46%), and 36% of patients derived a partial response.

Notably, 68% of patients achieved a response within 30 days of receiving treatment, and 27% of patients had a deepening of response. Moreover, responses were durable. At 12 months, 50% of patients were in a response and only 2 of these responders experienced progressive disease after 1 year.

“CD19 CAR T cells have shown significant efficacy in patients with CLL, including patients with double-refractory disease,” said Danilov.

In addition to BTK- and CD19-directed approaches, also of interest in CLL are natural killer cells, alternative BH3 mimetics targeting MCL1 and BCL-XL, as well as indirect inhibitors and novel CD20-directed antibodies, concluded Danilov.

References

1. Danilov AV. New targetable pathways in CLL. Presented at: Society of Hematologic Oncology 2021 Annual Meeting; September 8-11, 2021; virtual. Session V.
2. Coombs C, Pagel JM, Shah NN, et al. Pirtobrutinib (LOXO-305), a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study. Presented at: Society of Hematologic Oncology 2021 Annual Meeting; September 8-11, 2021; virtual. Poster CLL-039.
3. Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; virtual. Abstract 544.