Covalent Bruton Tyrosine Kinase inhibitors (BTKi) like ibrutinib, acalabrutinib and zanubrutinib have completely changed the treatment landscape for CLL.
However, a group of patients can develop resistance (most commonly as a result of a BTK C481S mutation) to these effective treatments and require further therapy with other agents. One of the therapies that might be considered in the event of BTKi resistance is the non-covalent BTKi called Pirtobrutinib (Loxo-305) which does not bind to C481.
It has always been expected that some patients may still develop resistance to the noncovalent drug. In anticipation of this happening, the trial team at Memorial Sloan Kettering (MSK) Cancer Center, led by Dr Anthony Mato, joined with Omar Abdel-Wahab, who leads MSK’s Center for Hematologic Malignancies, to study the mechanisms of Pirtobrutinib resistance.
A report of the team’s findings was published in the New England Journal of Medicine (NEJM) this week: Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors.
nejm.org/doi/full/10.1056/N...
The team followed 55 patients on Pirtobrutinib, regularly analysing their blood samples with single cell sequencing and other technologies to track the development of any mutations and to look for signs of resistance. 9 patients developed resistance and 7 of those 9 developed one or more new mutations in BTK.
‘We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell–receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors.’
In other words, the mutations re-established the replication signalling through the CLL B Cell Receptor, working around Pirtobrutinib’s signal blocking.
The report concludes: ‘Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors.’
It’s important to remember that these patients were heavily treated with previous lines of therapy, including chemotherapy which could have contributed to their genomic instability. As treatments like FCR are used less, it’s hoped that some genomic instability may become less prevalent.
MSK's news article about this research provides a good overview of the findings and concludes:
‘The new mutations provided important clues as to how patients who develop resistance to pirtobrutinib might be treated going forward. The findings could lead to combination therapy, with the addition of other existing targeted therapies to pirtobrutinib. They could also inform the development of brand-new drugs for people with CLL and other B cell cancers.’
mskcc.org/news/what-causes-...
The NEJM article has an excellent short video summary which you can view if you have an account.
nejm.org/do/10.1056/NEJMdo0...
This is an unlocked post: healthunlocked.com/cllsuppo... and was last reviewed and updated on the 25th February 2022
