Pembrolizumab Plus B-Cell Receptor Inhibitors Generates Responses in Richter Transformation of CLL/SLL

Yucai Wang, MD, PhD,

The addition of a B-cell receptor (BCR) inhibitor to pembrolizumab (Keytruda) led to responses in patients with Richter transformation of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to data from a phase 2 trial (NCT02332980) presented at the 2024 ASCO Annual Meeting.

Findings showed that patients treated during the combination phase of the study (n = 16) experienced an overall response rate (ORR) of 62.5%, including a complete response (CR) rate of 25.0% and a partial response (PR) rate of 37.5%. The respective rates of stable disease (SD) and progressive disease (PD) were 0% and 25.0%. Notably, 2 patients (12.5%) were not evaluable for response due to death before response assessment (n = 1) and loss of follow-up (n = 1). Within the combination cohort, patients received either pembrolizumab plus ibrutinib (Imbruvica; n = 14) or pembrolizumab plus idelalisib (Zydelig; n = 2).

In patients treated with pembrolizumab monotherapy (n = 26), the ORR was 23.1%, including a CR rate of 7.7% and a PR rate of 15.4%. The SD and PD rates were 26.9% and 46.2%, respectively, and 1 patient (3.8%) was not evaluable for response due to death before response assessment.

“Combination therapy with pembrolizumab and a BCR kinase inhibitor is associated with increased efficacy, similar to other reports,” lead study author Yucai Wang, MD, PhD, of Mayo Clinic in Rochester, Minnesota, and colleagues wrote in a poster presentation of the data.

Previously reported data from the phase 2 trial showed that patients with CLL/SLL or Richter transformation treated with pembrolizumab monotherapy achieved an ORR of 44%. In data presented at the 2024 ASCO Annual Meeting, investigators included updated results for patients in the initial cohort (n = 9) and an expansion cohort (n = 17).

The trial enrolled patients with a history of pathologically confirmed CLL or SLL and biopsy-confirmed Richter transformation. Patients were required to have measurable disease defined as at least 1.5 cm in 1 dimension. Notably, prior treatment for Richter transformation was not required for enrollment.

During the monotherapy portion of the study, patients received single-agent pembrolizumab at 200 mg once every 3 weeks for up to 12 months. Those who had SD following 3 months of pembrolizumab monotherapy or experienced PD at any point during the monotherapy portion of the study were permitted to receive combination therapy, which consisted of pembrolizumab at 200 mg plus ibrutinib or idelalisib for up to 12 months.

ORR served as the trial’s primary end point, and progression-free survival (PFS) and overall survival (OS) were key secondary end points.

Among all enrolled patients, the median age was 68.5 years (range, 46-83), and 35% of patients were at least 70 years of age. Seventy percent of patients were male, and 92% were Caucasian. Patients had an ECOG performance status of 0 (31%), 1 (58%), or 2 (11%). Rai stage included 0 (15%), 1 to 2 (27%), 3 to 4 (54%), or missing (4%).

Per fluorescence in situ hybridization, 23% of patients had CLL without genomic abnormalities, and data were missing for 8% of patients. Genomic abnormalities detected at baseline included 17p deletion (31%), 11q deletion (8%), trisomy 12 (8%), and 13q deletion (23%). Sixty-nine percent of patients had unmutated IGHV, 23% had mutated IGHV, and data were missing for 8% of patients. Forty-two percent of patients had bulky nodal disease of at least 5 cm. The median lactate dehydrogenase level was 237 (range, 147-725).

Patients received a median of 3 prior lines of therapy for CLL/SLL or Richter transformation (range, 1-10). Fifty-eight percent of patients had prior exposure to ibrutinib, and 54% of patients experienced PD on ibrutinib.

Additional data showed that the median PFS in the combination cohort was 7.6 months (95% CI, 2.3-13.3). The median PFS was 2.6 months (95% CI, 1.6-3.6) in the monotherapy cohort.

The median OS among all patients was 11.6 months (95% CI, 7.5-20.1), and the 2-year OS rate was 27%.

Regarding safety, the most common adverse effects reported in more than 10% of all patients included decreased platelet count (any grade, 57.7%; grade ≥3, 26.9%), anemia (53.8%; 15.4%), decreased neutrophil count (53.8%; 38.5%), decreased white blood cell count (34.6%; 30.8%), dyspnea (23.1%; 0%), decreased lymphocyte count (23.1%; 7.7%), nausea (23.1%; 0%); diarrhea (19.2%; 0%), lung infection (19.2%; 11.5%), increased blood bilirubin (15.4%; 3.8%), fatigue (15.4%; 3.8%), maculopapular rash (15.4%; 3.8%), vomiting (15.4%; 0%), cough (11.5%; 0%), febrile neutropenia (11.5%; 11.5%), fever (11.5%; 3.8%), increased lymphocyte count (11.5%; 7.7%), and pneumonitis (11.5%; 3.8%).

“These results support further investigation or immune checkpoint inhibitor–based combination therapy in Richter transformation,” Wang and colleagues concluded.

Reference

Wang Y, LaPlant BR, Parikh SA, et al. Efficacy of pembrolizumab monotherapy and in combination with BCR inhibitors for Richter transformation of chronic lymphocytic leukemia (CLL). J Clin Oncol. 2024;42(suppl 16):7050. doi:10.1200/JCO.2024.42.16_suppl.7050