Pirtobrutinib scores a phase III win in BTKi-pretreated CLL/SLL

The first phase III trial of pirtobrutinib in haematologic malignancies to readout has demonstrated superiority over investigator's choice in delaying progression in pretreated chronic lymphocytic leukaemia or small lymphocytic lymphoma (CLL/SLL), with results from the BRUIN CLL-321 study first presented at ASH 2024.

Among patients with CLL/SLL previously treated with ≥1 covalent Bruton's tyrosine kinase inhibitor (cBTKi), the median progression-free survival (PFS) assessed by an independent review committee (IRC) was 14 months for those randomized to pirtobrutinib vs 8.7 months for those randomized to either idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) by investigator's choice (hazard ratio [HR], 0.54, 95 percent confidence interval [CI], 0.39–0.75; nominal p=0.0002). [ASH 2024, abstract 886]

“Pirtobrutinib reduced the risk of progression or death by 46 percent,” said Dr Jeff Sharman from the Willamette Valley Cancer Institute and Research Center, Eugene, Oregon, US. “The shape of the Kaplan-Meier curves, stepwise for the pirtobrutinib arm and continuous for the control arm, suggests that many events in the former were asymptomatic progressions identified by protocol-mandated routine CT scans, whereas many progression events in the latter were clinically symptomatic and occurred between regularly scheduled scans.”

Pirtobrutinib also extended the time to next treatment (TTNT) vs IdelaR/BR in this heavily pretreated population (median three lines of prior systemic therapy), with a median of 2 years before patients treated with the third-generation noncovalent BTKi required the next line of treatment or died (median 24 vs 10.9 months; HR, 0.37, 95 percent CI, 0.25–0.52; nominal p<0.0001).

Sharman noted that the TTNT findings “capture the overall efficacy of the treatment, as patients with IRC-determined asymptomatic radiographic progressions who were benefiting were not required to discontinue the randomized treatment.”

Post-cBTKi setting

BRUIN CLL-321 is the first randomized phase III study conducted exclusively in a CLL/SLL population pretreated with a cBTKi (n=238). The trial design most closely resembles the ASCEND trial, which assessed a second-generation cBTKi vs IdelaR/BR in relapsed/refractory CLL. However, ASCEND excluded patients previously treated with BTKis, while BRUIN CLL-321 mandated that all enrolled patients had been treated with ≥1 of them. [J Clin Oncol 2020;38:2849-2861]

The current final prespecified analysis had a data cut-off at a median follow-up of 17.2 months and represents the final overall survival (OS) analysis.

Due to a high rate of post-progression crossover (75.8 percent), the OS results were confounded, showing no differences between arms. The 18-month OS rate was 73.4 percent with pirtobrutinib vs 70.8 percent with IdelaR/BR (HR, 1.09, 95 percent CI, 0.68–1.75; p=0.7202). In two separate analyses adjusting for crossover, the HR for OS trended in favour of pirtobrutinib.

Sustaining BTK inhibition

Regarding safety, fewer patients discontinued pirtobrutinib due to drug-related adverse events vs IdelaR/BR (5.2 percent vs 21.1 percent).

Event-free survival, which takes into account death, disease progression, initiation of subsequent anticancer therapy, and unacceptable toxicity leading to treatment discontinuation, was prolonged in those treated with pirtobrutinib (median 14.1 vs 7.6 months; HR, 0.39, 95 percent CI, 0.28–0.53; nominal p<0.0001).

“In this high-risk population with relapsed/refractory disease and extensive prior therapies, pirtobrutinib demonstrated superior PFS and a low rate of treatment discontinuation,” concluded Sharman. “Pirtobrutinib is an effective, well tolerated agent among patients with difficult-to-treat disease and provides a clinically meaningful way to sustain BTK inhibition.”