Pirtobrutinib is the first FDA approved non-covalent BTK inhibitor (BTKi) for the treatment of CLL. The previously approved BTKi drugs (acalabrutinib, ibrutinib and zanubrutinib) bond covalently. Eventually, these drugs can stop inhibiting CLL, when DNA changes in the BTK enzyme prevent the BTKi from locking onto the enzyme in the B Cell Receptor (BCR) signalling pathway that keeps the CLL cells alive. The promise of non-covalent bonding BTKis, is that they usually work when CLL becomes resistant to a covalent BTKi. Early pirtobrutinib clinical trial results weren't all that encouraging, as trial participants had had previous treatments and we get our longest remissions from our first treatment.
From MedPage Today's ASH 2024 coverage (registration needed) of the international BRUIN CLL-321 Phase III randomized trial with 238 patients, with my emphasis; medpagetoday.com/meetingcov...
Pirtobrutinib (Jaypirca) delayed disease progression versus other available options in patients with chronic lymphocytic leukemia (CLL) who had previously received a covalent Bruton's tyrosine kinase (BTK) inhibitor, a phase III study showed.
Median progression-free survival (PFS) reached 14 months with pirtobrutinib, an oral non-covalent BTK inhibitor, as compared with 8.7 months with investigator's choice of idelalisib (Zydelig) plus rituximab (Rituxan) or bendamustine (Bendeka, Treanda) plus rituximab (HR 0.54, 95% CI 0.39-0.75, P=0.0002), reported Jeff Sharman, MD, of Willamette Valley Cancer Institute and Research Center and U.S. Oncology Research in Eugene, Oregon.
Though the trial met its primary endpoint of PFS, no significant difference in overall survival (OS) was observed (HR 1.09, 95% CI 0.68-1.75), with the analysis "confounded by over three-quarters of subjects who crossed over to subsequent pirtobrutinib from investigator's choice", he said during a presentation at the American Society of Hematology annual meeting.
"In this high-risk population with relapsed and refractory disease and extensive prior therapy, pirtobrutinib demonstrated superior PFS and low rates of treatment discontinuation," Sharman said in his conclusion. "Patients were able to delay next therapy or death for a median of approximately 2 years, or 2.5 years among venetoclax [Venclexta]-naive subjects. Pirtobrutinib is an effective, well-tolerated agent among patients with difficult-to-treat disease and provides a clinically meaningful way to sustain BTK inhibition."
- The study population had poor-prognosis disease, with 54% harboring 17p deletions and/or TP53 mutations, and over 60% with complex karyotype. They had been heavily pretreated as well, with a third having received at least four prior lines of therapy, including a BCL2 inhibitor in about 50%
- Venetoclax-naive patients had a median time to next treatment or death of 29.5 months with pirtobrutinib versus 12.5 months with investigator's choice (HR 0.36, 95% CI 0.21-0.61), while median times among venetoclax-exposed patients were 20 and 8.7 months, respectively (HR 0.37, 95% CI 0.23-0.60).
So while Pirtobrutinib is a better bridging treatment than alternatives, more still needs to be done for those who have developed resistance to covalent BTKi and BCL-2 treatments (lisaftoclax, sonrotoclax, venetoclax, etc.)
For background on BTKi drugs approved and in clinical trials, as well as other recent developments in the treatment of CLL, see healthunlocked.com/cllsuppo...
Neil
