Adding a Kinase to Pembrolizumab May Increase CLL Treatment Efficacy

Photo Credit: Nemes Laszlo

Adding BCR kinase inhibitor ibrutinib or idelalisib to monoclonal antibody pembrolizumab increases treatment efficacy in CLL with Richter transformation.

According to updated results of an interventional trial, adding a kinase inhibitor to the monoclonal antibody pembrolizumab increases treatment efficacy in patients whose chronic lymphocytic leukemia (CLL) has undergone Richter transformation (RT).

“This expanded analysis confirmed that pembrolizumab has modest single-agent activity in RT. Combination therapy with pembrolizumab and a BCR [B-cell receptor] kinase inhibitor is associated with increased efficacy (ORR [overall response rate], >60%), similar to other reports,” Yucai Wang, MD, PhD, and coauthors wrote in the abstract of their presentation at the 2024 ASCO Annual Meeting and in the Journal of Clinical Oncology.

The research team noted in its poster that effectively managing Richter transformation (RT)—the development of aggressive large-cell lymphoma in the setting of underlying CLL or small lymphocytic lymphoma (SLL)—is a major clinical challenge. The current industry-supported study updates data from a phase II clinical trial that show modest efficacy of pembrolizumab monotherapy in patients with RT, including findings from an expansion cohort and a combination therapy cohort.

The researchers enrolled 26 patients with RT (9 in the initial group and 17 in the expansion group) at two Mayo Clinic sites in Minnesota and Arizona. The participants’ median age was 68.5 years, and 38% (10) had the del(17p) or the TP53 mutation. They had received between 1 and 10 prior lines of therapy, with a median of 3 lines; 58% (15) of patients had previously received ibrutinib, and among those, 14 had progressive disease while on ibrutinib.

Adding Kinase Inhibitors to Improve Survival

Participants received pembrolizumab monotherapy (200 mg IV Q3W) for up to 12 months. Those with stable disease (SD) after 3 months of pembrolizumab or with progressive disease (PD) at any time during monotherapy were given the option to enter the combination therapy phase by adding a B-cell receptor (BCR) kinase inhibitor to pembrolizumab. Dr. Wang and his colleagues investigated participants’ ORR, progression-free survival, and overall survival.

• Of the 26 participants taking pembrolizumab monotherapy, 6 (ORR 23.1%) responded after a median of 2 cycles of monotherapy: 2 patients (7.7%) demonstrated complete response, 4 (15.4%) showed partial response, and 7 (26.9%) maintained stable disease.
• The median duration of response was 3.2 months, and the median progression-free survival was 2.6 months. Of the 16 patients who opted to add a BCR kinase inhibitor to pembrolizumab after stable or progressive disease, 15 received the signal inhibitor ibrutinib, and one received the signal inhibitor idelalisib.
• The ORR to combination therapy was 62.5%, with 25.0% (4) having complete response and 37.5% (6) having partial response. Of the 10 patients with confirmed complete or partial response to combination therapy, responses occurred after a median of 4 cycles of therapy. The median duration of response was 4.5 months.
• The median progression-free survival was 7.6 months. After a median follow-up of 50.4 months, the median overall survival for all 26 patients with RT was 11.6 months, and the 2-year overall survival rate was 27%.
• Treatment-related adverse events of any severity occurred in 92% (24) of participants, including thrombocytopenia in 58%, neutropenia or anemia in 54% each, leukopenia in 35%, lymphopenia, dyspnea, or nausea in 23% each, and diarrhea in 19%.
• Treatment-related grade 3 or above adverse events occurred in 81% (21) patients, including neutropenia in 38%, leukopenia in 31%, thrombocytopenia in 27%, anemia in 15%, and febrile neutropenia or lung infection in 12% each.

“These results support further investigation of immune checkpoint inhibitor-based combination therapy in RT,” the researchers concluded.