Two new medicines for recurrent anemia

What this examination is about

This research focuses on chronic lymphatic leukemia and a similar condition with lymphomas. These are forms of blood disorder in which certain blood cells continue to grow without valid reason. In the past, many patients have benefited from medicines that block a specific protein in these cells, a so-called tyrosine kinase inhibitor. Unfortunately, this treatment sometimes stops working, or patients cannot tolerate the medicine.

This study compares two new medicines that both target the same protein, but in slightly different ways. One medicine is already approved for use, the other is still experimental. Both medicines are specifically designed for patients for whom previous tyrosine kinase inhibitors no longer worked or were not well tolerated.

How it is investigated

The study comprises approximately 306 participants distributed across approximately 100 hospital centers worldwide. Half of them receive the experimental medication, the other half receive the already approved treatment. This is not a blinded study: both doctors and patients know which medication is being given.

Only patients who have previously been treated with first-generation medications and for whom that did not work well can participate. Researchers look not only at how well the medications work, but also at how safe they are. They follow patients through multiple treatment cycles to map out effects on the disease, survival, and side effects. Blood is also examined and conversations are conducted about how patients feel and how their daily lives are progressing.

What came out

This is an ongoing study; final results are not yet available. The research will ultimately show which medication works better and which is better tolerated by patients.

What this does not say

This is one of the first major comparative studies between these two medicines, so everything still needs to be investigated. The study focuses only on patients who have previously been treated with this type of medicine; therefore, it says nothing about how these agents work as a first treatment.

It is also still unclear whether one substance is truly better than the other, because the results have not yet been published. Patients who participate do not have the choice of which treatment they want: this is determined by chance. There is no possibility to switch medications later if someone has reason to do so.

What this examination is about

Chronic lymphocytic leukemia (CLL) and the closely related small lymphocytic lymphoma (SLL) are slow-growing forms of blood cancer. In these diseases, abnormal white blood cells accumulate and do not function properly. An important group of medicines against CLL/SLL are the so-called BTK inhibitors. BTK stands for Bruton's tyrosine kinase, a protein that cancer cells need to survive and grow. By blocking this protein, the medicines can slow down the disease.

The first generation of these drugs, the covalent BTK inhibitors, bind permanently to the BTK protein. This often works well, but over time cancer can develop a mutation that prevents the drug from working. Patients whose disease returns because of this or who cannot tolerate the drug have limited follow-up options. Pirtobrutinib is a newer BTK inhibitor that binds more loosely to the protein and has already been approved for use after a covalent BTK inhibitor. Rocbrutinib is another new drug that works in a slightly different way: it blocks both the normal BTK protein and the mutated variant that causes resistance.

This study, ROCKET-CLL, compares these two newer medicines directly with each other in people whose disease has returned or no longer responds after previous treatment with a covalent BTK inhibitor. The aim is to determine which of the two medicines keeps the disease under control longer and how the side effects compare.

Who participated

Approximately 306 adults with CLL or SLL will be recruited, distributed across approximately one hundred research centers worldwide. Everyone participating has already had at least one covalent BTK inhibitor and subsequently requires treatment because the disease has returned or is no longer under control. Participants may also have had previous other treatments, including a so-called BCL2 inhibitor, another type of medication for CLL.

To be eligible to participate, someone must have a reasonable physical condition (measured on a scale ranging from fully active to severely bedbound) and must have sufficient liver, kidney, and bone marrow function. Prior to participation, certain genetic characteristics of the cancer cells are also examined, namely whether a piece of chromosome 17 is missing (del17p) or a mutation in the TP53 gene is present. Both characteristics are known to result in a more difficult-to-treat form of the disease.

People who were not allowed to participate included patients whose cancer had already spread to the central nervous system, people with Richter syndrome (an aggressive transformation of CLL into another type of lymphoma), people with prolymphocytic leukemia, and people who had previously received a non-covalent BTK inhibitor or a so-called BTK degrader. People with severe cardiac arrhythmias or a prolonged QTc interval (a specific cardiac abnormality on the ECG) also did not participate, as well as pregnant women and people with uncontrolled infections or other serious conditions. This means that the results of this study say nothing about these groups: people with brain metastases from their CLL, with Richter syndrome, or with existing heart problems fall outside the scope of this research.

How it has been addressed

Participants are divided into two groups by random assignment (randomization) in a ratio of 1 to 1. One group receives rocbrutinib daily as a tablet, the other group receives pirtobrutinib daily. Both medicines are given continuously in cycles of 28 days, until the disease progresses again, the side effects become too severe, or someone stops for another reason. Switching from one group to the other during the study is not permitted.

This is an open-label study, which means that both the participants and the treating physicians know which medication someone receives. There is therefore no blinding, as occurs in studies with a placebo. This can influence outcomes that are partly subjective, such as how someone assesses their quality of life. To limit this risk, the primary endpoint — whether the disease has started growing again — is assessed by an independent committee that reviews the scans without knowing which treatment someone received.

The decision was made to compare with pirtobrutinib rather than with a placebo or no treatment. This is because pirtobrutinib is already an established treatment option for this patient group, so it would not be ethical to give someone a placebo when an effective alternative already exists.

In the randomization, several characteristics that could influence the outcome are taken into account: whether someone has the aforementioned del17p mutation or TP53 mutation, why the previous BTK inhibitor was stopped, whether someone has already received a BCL2 inhibitor, and which region of the world someone comes from. By distributing these factors equally between the two groups, random differences in patient characteristics are prevented from skewing the results.

The primary outcome is progression-free survival: the time from randomization until the disease shows measurable growth again, or until death. Additionally, researchers look at, among other things, overall survival, the percentage of people who respond to the treatment, how long that response lasts, how long it takes before another treatment is needed, and adverse events. The follow-up continues for approximately four years after the start of treatment.

What came out

This study is currently still in the "recruitment" phase: participants are still being recruited and no results are yet available. Therefore, no figures can yet be given about how many people benefited from rocbrutinib or pirtobrutinib, how often the disease recurred, or how side effects differed between the two groups. Everything described above outlines the design and what will be measured, not what the outcomes are.

How strong this evidence is

When this study is completed, it is a phase 3 trial: the highest type of study in the common evidence hierarchy for a new drug, because randomization is used between groups and a large number of people participate (306 in total). This makes the final outcomes in principle reliable for the group of patients who meet the criteria. It is important to note that the study is funded by Newave Pharmaceutical Inc, the company that develops rocbrutinib. This in itself does not invalidate the design, but it is relevant to know who has a financial interest in a favorable outcome for rocbrutinib.

Because the study is still ongoing, there is no confirmation yet from any other independent research. There is therefore no evidence available at this time, only a research protocol.

What this does not say

This study says nothing about which of the two medicines works better, simply because there are no results yet. Even when results become available later, they will say nothing about people who did not meet the inclusion criteria: people with metastases to the central nervous system, with Richter transformation, with prolymphocytic leukemia, or with severe heart problems. Moreover, the open-label nature of the study means that outcomes that are partly based on perception, such as experienced quality of life, can be more susceptible to bias than outcomes that are objectively determined by scans. The study compares two active medicines with each other and therefore says nothing about how these agents relate to no treatment, to other types of medicines such as BCL2 inhibitors, or to stem cell transplantation.

What is still unknown

Because the study is still ongoing, it is not yet known how often the disease recurs with rocbrutinib versus pirtobrutinib, how the survival rates compare, and which side effects occur more frequently with which drug. It is also unclear how the two drugs score on patient-reported quality of life. Furthermore, the study also examines biomarkers: characteristics in blood or tumor tissue that may predict who benefits from which medication, but that is still completely open. Finally, it is unknown how long participants will ultimately be followed up after the planned four years, and whether the findings of this study will also apply to groups that were excluded here, such as people with additional heart conditions or with a more aggressive form of the disease.