Triplet Could Become a New Standard in Tough-to-Treat CLL

Fixed-duration therapy with pirtobrutinib (Jaypirca) plus venetoclax (Venclexta) and rituximab improved progression-free survival (PFS) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to interim data from the phase III BRUIN CLL-322 trial.

In the intent-to-treat population, median PFS was not estimable with the triplet therapy versus 39.7 months with venetoclax and rituximab, with independent review committee-assessed 24-month PFS rates of 86.9% and 71.8% (HR 0.547, 95% CI 0.400-0.748, P=0.0001), reported Matthew S. Davids, MD, of Dana-Farber Cancer Institute in Boston, at the European Hematology Association annual congress in Stockholm.

The investigator-assessed 24-month PFS rates were 88.2% versus 71.9%, respectively (HR 0.487, 95% CI 0.352-0.674, P<0.0001).

“These results establish PVR [pirtobrutinib plus venetoclax and rituximab] as a potential new standard-of-care option for patients with previously treated CLL,” Davids said during a late-breaking abstract session.

Over the past 10 to 15 years, chemoimmunotherapy has been largely replaced by Bruton’s tyrosine kinase (BTK) and BCL-2 inhibitors in the treatment of relapsed/refractory CLL, with a common treatment sequence that starts with a covalent BTK inhibitor until time of progression, followed by fixed-duration therapy with venetoclax and rituximab.

This strategy is based primarily on results from a post-chemoimmunotherapy population in the MURANO trial, which showed that venetoclax and rituximab significantly improved PFS among patients with relapsed or refractory CLL.

Davids observed that the control arm in the current study is “also very important here with [venetoclax and rituximab], because this is the first time we’ve seen data in a post-covalent BTK inhibitor population, and the PFS rate of 72% is notably lower than what was seen in a chemoimmunotherapy-treated population in MURANO, which was closer to 85%. I think that suggests that the patients in the population of this study were particularly high risk.”

In the phase I/II BRUIN trial, pirtobrutinib, a non-covalent BTK inhibitor, demonstrated promising efficacy in patients with CLL or small lymphocytic lymphoma (SLL) previously exposed to covalent BTK inhibition, providing support for the current randomized trial.

The BRUIN CLL-322 trial enrolled 639 patients in 22 countries with relapsed/refractory CLL/SLL who had received at least one prior line of therapy, including covalent BTK inhibition. Patients with non-covalent BTK inhibitor or BCL-2 inhibitor exposure were excluded.

Across the two study arms, median age was 67-68, 67-70% were men, and 94-95% had an Eastern Cooperative Oncology Group performance status of 0-1. The median number of prior lines of systemic therapy was two, and 80% had received prior covalent BTK inhibition. More than half of these patients had discontinued covalent BTK inhibitor therapy due to progressive disease.

Both arms received venetoclax for 25 cycles and rituximab for 6 cycles, while the triplet arm also received fixed-duration pirtobrutinib for 28 cycles, with a 3-cycle pirtobrutinib-rituximab lead-in before venetoclax was initiated.

Among patients previously treated with a covalent BTK inhibitor, the triplet regimen continued to best the doublet, with overall independent review committee-assessed 24-month PFS rates of 87.7% versus 70% (HR 0.509, 95% CI 0.351-0.738). For those with prior covalent BTK inhibitor exposure who discontinued the treatment due to progressive disease, these rates were 88.3% versus 64.3% (HR 0.444, 95% CI 0.293-0.673).

Time to next treatment also favored the triplet arm. At 24 months, 87.7% of patients in the triplet group remained free from next treatment or death versus 77.2% who received the doublet (HR 0.498, 95% CI 0.352-0.704).

There was no significant difference in overall response rate between the two groups (88.5% and 83.3%). Overall survival data were immature at the time of the analysis.

In an exploratory analysis, patients receiving the triplet therapy had higher end-of-treatment undetectable minimal residual disease rates.

Rates of any grade treatment-emergent adverse events (TEAEs) were similar between the triplet and doublet groups (99.7% vs 98.1%, respectively), as were rates of grade ≥3 TEAEs (78.8% vs 73%). The most common grade ≥3 TEAE was neutropenia, which occurred in 49.7% and 43.7% of the two groups, respectively.

Rates of bleeding were higher with the triplet (25.9% vs 14.1%), which Davids said is expected with BTK inhibitors. However, he pointed out the rate of grade ≥3 bleeding was similar (2.8% vs 2.6%), “suggesting pirtobrutinib did not add significant bleeding risk.”

He also observed that rates of any grade atrial fibrillation/flutter were similar between the groups (3.5% vs 2.6%), “which is consistent with other studies of pirtobrutinib in randomized settings.”

Rates of discontinuation due to treatment-related TEAEs were similar for the two groups (5.4% vs 5.1%).

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