Ibrutinib has revolutionized the treatment of CLL by blocking the B cell receptor that our cancer cells are dependent on for messages to survive, home to the nodes and marrow, and proliferate.
It does this by irreversibly or covalently binding to and occupying the BTK (Bruton’s Tyrosine Kinase) receptor, and by doing so, preventing the messages from the B cell receptors getting through to the cell’s nucleus.
Proliferation and homing to the nodes and marrow are thus blocked.
However, CLL is a smart cancer and the BTK binding site, C481 can mutate preventing ibrutinib from exchanging an electron and covalently binding. The ibrutinib becomes largely ineffective, the BCR pathway is turned on again and the cancer is once again off to the races. This is not the only cause of ibrutinib or acalabrutinib resistance, but it is the most common.
Fortunately, there are new reversible (non- covalent) molecules in development that block BTK that could once again turn off the BCR and muzzle our cancer that binding in a different way.
There are three reversible BTK inhibitors that are moving through trials now. None are yet approved.
- SNS 062 (vecabrutinib)
- ARQ 531
- LOXO 305
The hope for these molecules is that they may lead to new durable remissions for CLL patients who have failed irreversible BTK inhibitors such as the two approved drugs, acalabrutinib and ibrutinib. They also should work for patients who are not resistant to a reversible BTK inhibitor.
At ASH 2019, I spoke with Dr. Jennifer Brown of Dana Farber Cancer Institute at Harvard, MASS about the first in human phase 1 trial of LOXO 305.
- Only 8 CLL patients were studied but all 5 for whom we have data had partial responses.
- That included 1 with the C481 mutation and one resistant to venetoclax.
- 6 of the 8 CLL patients had high risk disease including unmutated IGHV (4), complex karyotype (4) and del17p (3).
- Median number of prior therapies was 3 (range 2-6).
- Adverse events were generally mild.
This is very early data with a difficult group to treat and admittedly a very small number of patients, but the results are most encouraging.
It just makes good sense to try to stretch the success of blocking the BCR receptor by blocking BTK in a new way so I am glad to see this research advancing, though I suspect there won’t be a strong role for all three potential reversible drugs.
Here is a link to my brief interview with Dr. Brown.
The future is looking brighter and brighter. This is an important developing option to better treat chronic lymphocytic leukemia.
We are all in this together.