Fixed-duration pirtobrutinib plus venetoclax with or without rituximab in relapsed/refractory CLL: the phase 1b BRUIN trial

Abstract

Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial. Prior covalent BTKi therapy was allowed, but not prior treatment with venetoclax. Patients were assigned to receive PV (n = 15) or PVR (n = 10) for 25 cycles. Most patients (68%) had received prior covalent BTKi therapy. At the data cutoff date, the median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% confidence interval [CI], 68.1-99.8) for PV and 100% (95% CI, 69.2-100.0) for PVR, with 10 complete responses (PV: 7; PVR: 3). After 12 cycles of treatment, 85.7% (95% CI, 57.2-98.2) of PV and 90.0% (95% CI, 55.5-99.7) of PVR patients achieved undetectable minimal residual disease (<10-4) in peripheral blood. Progression-free survival at 18 months was 92.9% (95% CI, 59.1-99.0) for PV patients and 80.0% (95% CI, 40.9-94.6) for PVR patients. No dose-limiting toxicities were observed during the 5-week assessment period. The most common grade ≥3 adverse events (AEs) for all patients included neutropenia (52%) and anemia (16%). AEs led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529.

Graphical abstract

Figure 1.

Change in tumor size from baseline to the time of best overall response. Tumor size was calculated as the sum of product diameters of the target lesions. Asterisks (∗) indicate patients who achieved uMRD (<10^–4).

Figure 2.

PFS and OS rates. Kaplan-Meier curves for PFS (A-B) and OS (C-D) for patients treated with pirtobrutinib-based combination therapies. Tick marks indicate censored data.

Figure 3.

Depth of MRD response in peripheral blood. MRD was assessed by clonoSEQ assay (Adaptive Biotechnologies, Seattle, WA) at screening and starting with cycle 3 day 1. (A-B) Sankey plots showing changes in MRD status at a sensitivity of <1 CLL cell per 10 000 nucleated cells (<10^–4). (C-D) Line graphs showing MRD response for individual patients at a sensitivity of <1 CLL cell per 1 000 000 nucleated cells (<10^–6). MRD was assessed in 24 evaluable patients during 25 cycles of therapy. MRD data for 1 patient in the PV cohort are not shown because calibration did not identify a suitable dominant DNA sequence for MRD tracking. The study protocol required a lead-in cycle of pirtobrutinib monotherapy followed by 24 cycles of combination therapy with venetoclax, for a total of 25 cycles. C, cycle; D, day.

Figure 4.

Pirtobrutinib and venetoclax concentrations in patients treated with pirtobrutinib and venetoclax with or without rituximab. For pirtobrutinib concentrations, the open circles of cycle 1 day 8 represent pirtobrutinib alone, and closed symbols from cycle 2 and later represent pirtobrutinib with venetoclax.