The first-ever clinical trial of a new kind of drug for blood cancer has shown promising results. The drug, called pirtobrutinib or LOXO-305, was tested in people with several kinds of leukemia and lymphoma, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL) as well as other types of non-Hodgkin lymphoma.
The drug appears to be effective in patients who have stopped responding to all other standard treatments. The study was published March 4, 2021, in The Lancet. The rate of mild or severe side effects was very low. The drug is very active even in the sickest patients and very well tolerated.
The study is a phase I/II trial, and the paper includes findings from the first 323 patients receiving pirtobrutinib. MSK treated the largest number of patients in the trial in which many other hospitals around the United States, Europe, and Australia participated.
Of the 323 people who were treated with pirtobrutinib, the median number of prior therapies was three, including chemotherapy, immunotherapy, and other targeted drugs. Of the 121 people with CLL or SLL who were on the drug long enough to have follow-up testing, 62% responded to pirtobrutinib. For CLL and SLL patients who were on the drug for ten months or longer, that number increased to 86%. For MCL, 52% of patients responded.
The responses were long-lasting in most patients. Of the 117 patients across the entire study who responded to pirtobrutinib, all but eight of them are still doing well and remain on pirtobrutinib. These rates are excellent compared to what would have expected from other available standard therapies.”
The most common side effects, including fatigue, diarrhea, and bruising, were not severe. The more severe but less common side effect was neutropenia (low white blood cell counts). Only five patients stopped taking the drug because of side effects.
An Old Target with a New Twist
Pirtobrutinib belongs to a family of drugs called Bruton’s tyrosine kinase (BTK) inhibitors. BTK is an enzyme that exists in most kinds of blood cells. In the subset of blood cancers called B cell malignancies — which includes CLL, SLL, and MCL — the BTK enzyme is overactive, causing immune cells called B cells to become defective and grow out of control.
Other drugs that block BTK, including ibrutinib (Imbruvica®) and acalabrutinib (Calquence®), have been approved by the US Food and Drug Administration for several years to treat these cancers. While these agents have helped to shift the standard of care in CLL and lymphoma, patients may ultimately discontinue them due to intolerance or acquired resistance. The cancer cells can eventually develop additional mutations and then the drug is no longer effective. Additionally, intolerance to these agents has been a major reason for discontinuation.
Although pirtobrutinib is also a BTK inhibitor, it works in a different way from these earlier drugs, which are called covalent inhibitors. When other BTK inhibitors bind to the enzyme, they permanently attach themselves to it. This is a problem because it puts pressure on the cancer cells to find new ways to grow, leading to drug resistance. Pirtobrutinib, on the other hand, is a noncovalent inhibitor, and it binds in a reversible fashion. This means that it’s able to bind to and block the function of BTK, but also to release itself from the enzyme. This is important because it allows CLL and lymphoma cells that have acquired resistance to the covalent BTK inhibitors to again respond.
Plans to Expand Trials
Based on the results from this study, several randomized, controlled phase III trials are being planned. They are expected to launch within the next few months, including at least two in which MSK investigators will play a leading role. The phase III trials will have a control arm in which patients will receive another targeted drug or chemotherapy. A control arm is important because it allows researchers to compare the efficacy of an experimental drug to the standard treatment.
More than half of the patients who participated in the trial at MSK received their treatments at MSK’s locations in New Jersey, Long Island, and Westchester.
In addition, the phase II portion of the trial is still ongoing and is open to new patients, including at MSK. This part of the study also has been expanded, and now some patients are being given pirtobrutinib in combination with other leukemia and lymphoma drugs.
Harnessing Partnerships; Making Trial Participation Easier
In addition to the significance of the findings from this study, it’s also important to note the ways in which this research demonstrates MSK’s contributions to developing the most cutting-edge treatments for blood cancers.
The success of the trial highlights several different kinds of partnerships. This includes partnerships between MSK and the pharmaceutical industry, a partnership between MSK’s Leukemia and Lymphoma Services, and partnerships between MSK doctors who see patients in Manhattan and those who practice at regional sites.
More than half of the patients who participated in the trial at MSK received their treatments at MSK’s locations in New Jersey, Long Island, and Westchester. Until recently, participation in early-stage trials has been unusual for patients treated outside Manhattan, but MSK has increased efforts to make these trials more widely available at regional locations.