Fixed-duration pirtobrutinib plus venetoclax, rituximab promising in CLL
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Key takeaways:
- Fixed-duration pirtobrutinib plus venetoclax with or without rituximab was well-tolerated in relapsed or refractory CLL.
- These findings warrant further investigation in this population.
Fixed-duration pirtobrutinib plus venetoclax with or without rituximab was well tolerated and showed promising efficacy in patients with relapsed or refractory chronic lymphocytic leukemia, according to data presented at ASH Annual Meeting.
Lindsey E. Roeker, MD, of Memorial Sloan Kettering Cancer Center, and colleagues examined the safety and efficacy of fixed-duration pirtobrutinib (Jaypirca, Eli Lilly & Co. — a noncovalent Bruton tyrosine kinase inhibitor — combined with venetoclax (Venclexta; Genentech, AbbVie) with and without rituximab (Rituxan; Genentech, Biogen) in patients with relapsed or refractory CLL. The primary endpoint was safety (as assessed by treatment-emergent adverse events), and other endpoints included overall response rate, PFS and minimal residual disease (MRD).
Patients from the BRUIN phase 1b study who received prior therapy with a covalent BTK inhibitor were enrolled, but not those who received prior venetoclax. They were first enrolled into the pirtobrutinib plus venetoclax cohort and then into the pirtobrutinib plus venetoclax plus rituximab cohort.
According to the abstract, pirtobrutinib (200 mg) was given once daily starting on cycle 1 day 1, with venetoclax beginning on cycle 2 day 1 with the standard 5-week dose ramp to 400 mg once daily target dose. Patients received pirtobrutinib plus venetoclax for up to 24 cycles; each cycle was 28 days. In the pirtobrutinib plus venetoclax plus rituximab cohort, patients received rituximab at 375 mg/m2 on cycle 1 day 1 then increased to 500 mg/m2 on day 1 of cycles 2-6.
Most patients had received prior chemotherapy, CD20 monoclonal antibody and treatment with covalent BTK inhibitor and had IGHV unmutated CLL, according to the abstract.
The results showed an ORR of 93.3% (95% CI, 68.1-99.8) among the 15 patients who received pirtobrutinib plus venetoclax and an ORR of 100% (95% CI, 69.2-100) among the 10 patients who received pirtobrutinib, venetoclax and rituximab. In addition, seven patients in the pirtobrutinib plus venetoclax cohort and three in the pirtobrutinib, venetoclax and rituximab had complete responses.
The researchers reported that PFS at 18 months was 92.9% (95% CI, 59.1-99) among the pirtobrutinib plus venetoclax patients and 80% (95% CI, 40.9-94.6) among the pirtobrutinib plus venetoclax plus rituximab patients, and median duration of PFS follow-up was 22.1 months for both groups.
For the 24 evaluable patients, the overall undetectable MRD rate at cycle 13 was 70.8%, and 87.5% of patients achieved undetectable MRD at some time during the trial, according to the results. Further, all but one patient had sustained undetectable MRD during later assessments.
Overall, 14 patients in the pirtobrutinib plus venetoclax cohort and eight in the pirtobrutinib plus venetoclax plus rituximab cohort discontinued treatment. Of these, 14 patients completed all 24 cycles of therapy and eight discontinued early because of progressive disease, adverse events, protocol noncompliance, death unrelated to treatment or other reasons, according to the abstract. One patient receiving pirtobrutinib plus venetoclax and two receiving pirtobrutinib plus venetoclax plus rituximab continue to receive treatment. Both cohorts had similar median relative dose intensity.
The most common treatment-emergent adverse events included nausea, fatigue and diarrhea, and the most common grade 3 or higher treatment-emergent adverse event was neutropenia/neutrophil count decreased.
The results also showed that grade 3 or higher clinical tumor lysis syndrome occurred during venetoclax dose escalation among two patients receiving pirtobrutinib plus venetoclax, including a grade 3 case that resolved spontaneously after 24 hours and a grade 4 case that resolved after short-term intravenous fluids.
Treatment-related adverse events led to dose reductions in one patient receiving pirtobrutinib plus venetoclax and two receiving pirtobrutinib plus venetoclax plus rituximab, as well as treatment discontinuation in two patients receiving pirtobrutinib plus venetoclax plus rituximab.
“Pirtobrutinib combined with venetoclax with or without rituximab has promising efficacy in heavily pretreated patients with relapsed or refractory CLL, including a majority who were previously treated with covalent BTK inhibitors,” Roeker said during the presentation.
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