What Causes Resistance to Leukemia Drug Pirtobrutinib? MSK Researchers Investigate

Since the first targeted therapies for blood cancer were developed more than 20 years ago, doctors and scientists have observed that many patients who respond well to these drugs initially end up developing resistance to them over time. There is an assumption among scientists that drug resistance will eventually occur. It has become so established that the study of resistance is being incorporated even into early stages of drug development.

In a study published February 24, 2022, in the New England Journal of Medicine (NEJM), a collaborative team of investigators at Memorial Sloan Kettering Cancer Center report that they have found what enables cancer cells to become resistant to the experimental drug pirtobrutinib. This drug has not yet been approved by the U.S. Food and Drug Administration, but it was shown to be effective in treating people with several kinds of leukemia and lymphoma, according to a phase 1/2 study published in The Lancet in March 2021.

Studying Resistance to First Noncovalent BTK Inhibitor

Pirtobrutinib is in a class of drugs called Bruton’s tyrosine kinase (BTK) inhibitors. They work by binding to a protein called BTK and blocking activity that leads to the growth of cancerous B cells, a type of white blood cell. BTK inhibitors have been used since 2014 and are currently the most important class of drugs for treating chronic lymphocytic leukemia (CLL). CLL is a type of leukemia that affects more than 21,000 people in the United States every year, mostly older adults. But more than half of CLL patients eventually stop taking BTK inhibitors due to resistance or side effects.

The first BTK inhibitors that were developed, such as the drug ibrutinib (Imbruvica®), are called covalent drugs. This means that when they bind to the BTK protein, they stay there. However, these drugs eventually stop working for many patients due to a genetic change (or mutation) that develops in BTK and blocks the drug’s binding. Pirtobrutinib is the first noncovalent BTK inhibitor, which means that it binds in a reversible fashion.

This new class of drugs is often effective in cases where patients develop resistance to covalent BTK inhibitors. In the phase 1/2 trial, MSK researchers reported that 62% of patients with CLL and other similar blood cancers responded to pirtobrutinib, even after they had stopped benefiting from other BTK inhibitors. They also experienced fewer side effects than patients taking older BTK inhibitors.

The investigators assumed that patients would eventually develop resistance to these noncovalent BTK inhibitors as well, and they wanted to develop a better understanding of how it might happen. To do that, the team joined forces with physician-scientist Omar Abdel-Wahab, who leads MSK’s Center for Hematologic Malignancies.

“Figuring out resistance is important, because it guides us in developing next-generation therapies,” says Dr. Abdel-Wahab, who was co-senior author of the NEJM paper. He explained that the research was made possible by the collection of samples from patients participating in clinical trials. This allowed the scientists to study what was happening in real patients.

Taking a Closer Look at Patient Samples

In the new paper, the researchers reported findings from 55 CLL patients treated with pirtobrutinib at MSK. Multiple samples were collected from each patient, allowing investigators to study how their cancers changed throughout their course of treatment.

Nine patients eventually developed resistance to the drug. In Dr. Abdel-Wahab’s lab, scientists took a closer look at the samples to figure out what was happening. They used a number of cutting-edge tools to study the genetic changes, including MSK-IMPACT™ and single-cell RNA sequencing. They discovered several additional mutations that formed during treatment and enabled the cancer to start growing again.

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.

A Focus on Collaboration

Dr. Abdel-Wahab stresses that this kind of collaborative study between doctors working in the clinic and laboratory scientists could only happen at a place like MSK, which has strong programs in both clinical and laboratory research.

“The study of blood cancers like CLL is heavily based on having access to patient samples,” Dr. Abdel-Wahab says. “These samples are what enable us to do the kind of research that moves from the laboratory bench to the patient’s bedside and back.”

Another aspect of this trial that’s important to note is that many patients whose samples were used for this research were treated at MSK’s locations in the tristate area, Extra efforts were required to collect the samples and get them back to Dr. Abdel-Wahab’s lab in Manhattan. Some of the key findings came from patients treated at the regional sites. 

The clinical and lab teams plan to continue working together to develop new drugs and combination therapies for CLL and other B cell blood cancers.

A co-corresponding author of the NEJM paper was Justin Taylor, a former fellow in Dr. Abdel-Wahab’s lab who is now at the University of Miami. Postdoctoral research fellow Eric Wang and hematologic oncology fellows Xiaoli Mi and Meghan Thompson were the co-first authors of the paper.