Real-World Study Shows Limited Implementation of Recommended Biomarker Testing in CLL
In an interview with Targeted Oncology, Mato, a hematologic oncologists and the director of the CLL Program at Memorial Sloan Kettering Cancer Center, discussed biomarker testing in CLL, and the future of BTK inhibitors in the CLL paradigm.
Anthony R. Mato, MD
Data presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition offer key insights into the developing chronic lymphocytic leukemia (CLL) space, both in terms of clinical practice and evolving Bruton’s tyrosine kinase (BTK) inhibitors.
Biomarker-driven care has become a major focus point. For many patients with mutations in the tumor, an inhibitor or immunotherapy may be a better option for patients than standard chemotherapy. However, testing for these mutations is underperformed, according to data from the informCLL registry study (NCT02582879), eventhough they should be the standard of care for all patients, according to Anthony R. Mato, MD.
The study found that fluorescence in situ hybridization (FISH) testing was performed in only 28% of patients.Immunoglobulin heavy chain (IGHV) was performed in just 12% of patients. Of the patients who received prognostic biomarker testing, 24% had 17p deletion, 27% had TP53 mutation, and 71% had unmutated IGHV.1
In terms of BTK inhibitors, 2 studies were presented. One study centered round the next-generation, non-covalent BTK inhibitor pirtobrutinib (LOXO-305) and the other covered the triplet combination of a BTK inhibitor, mTOR inhibitor, and immunomodulatory drugs (IMids). Both studies yielded promising results. For the pirtobrutinib, of the 186 patients treated at 7 dose levels, a response was seen at the first dose level of 25 mg once daily. The overall response rate was 57% and the median duration of response was 6.7 months.2 The triple combination study has met its primary endpoint of an acceptable safety profile.
In an interview with Targeted Oncology, Mato, a hematologc oncologists and the director of the CLL Program at Memorial Sloan Kettering Cancer Center, discussed biomarker testing in CLL, and the future of BTK inhibitors in the CLL paradigm.
TARGETED ONCOLOGY: What served as the basis to conduct this analysis?
MATO: This is a prospective registry of nearly 1500 patients, so it provides a great opportunity to study what's going on in clinical practice. Clinical trials are incredibly well controlled. Everyone has the same testing; everyone has the same time points. That uniformity is a weakness in terms of giving a window into how people are extrapolating results and how people are practicing in general. During the ASH meeting, we learned about all sorts of new sophisticated prognostic techniques, but it's sometimes a good idea to take a step back and see are people actually following the standards of care as recommended by the professional societies like the National Comprehensive Cancer Network (NCCN) and the International Workshop on Chronic Lymphocytic Leukemia (iwCLL)? And in this case, we decided to ask the simple question, are people having FISH prior to their first therapy or subsequent therapy? Are they having IGHV testing? Are they having next-generation sequencing (NGS) for TP53 mutations?
I think if you were to perform a survey, every oncologist would universally say they do this for every patient. But the results were fairly eye opening, and that there was really a small proportion of patients who had this type of important prognostic testing performed. But I think the real surprise and something we haven't seen in prior data sets was that this led to decision-making that I don't think would be considered the standard of care in 2020. These are decision in which patients with poor-risk features like a deletion 17p or a TP53 mutation were still getting therapies like chemoimmunotherapy in an era of drugs like ibrutinib (Imbruvica), and other targeted agents that are widely available in the United States. So, [this research] gives us a window into practice, and then provides us a great educational opportunity to remind folks about what the standards of care are in terms of prognostic testing.
TARGETED ONCOLOGY: What methods were used to conduct the analysis, and what was the breakdown of how treatments were being administered?
MATO: This was a prospective registry with no intervention at all. So, no matter what was done, the registry did not influence care. Patients who were eligible for this, were receiving CLL-directed therapy, either in the frontline or the relapsed/refractory setting. They had to enroll within 45 days of that therapy. They were then followed for a minimum of 5 years.
The purpose of the registry was to be an incredibly detailed collection of data, and that really opened the window to perform this type of analysis. FISH testing was per standard-of-care at the institution, and so was NGS, and IGHV testing. What I will say, which I think is helpful in terms of quality control with this type of registry, is that there was active querying of sites. Chart reviews were conducted in approximately 10% to 15% of charts already, and the goal is to confirm these findings and 100% of charts across the registry. So far, though, what I can tell you is what people are entering into the registry, and what we're finding upon audit is that the results are very concordant. It is likely this is a true result. In terms of what we're observing withpractice patterns, about 10% to 12% of people are having IGHV testing and/or NGS, depending on which test you're talking about. FISH testing was performed in about a third of people. What I think is more important is that of those small minorities 20% to 30% are still having what I would consider to be the non-optimal decision in terms of use of chemoimmunotherapy over targeted agents.
TARGETED ONCOLOGY: Now that we have this information, what can be done to ensure that patients are put back on the right track for therapy?
MATO: Its a great educational tool. It's unbiased in that it's simply not brand specific or drug specific, even though there is a sponsor. It provides patient societies like the Leukemia & Lymphoma Society, the CLL Society, and the Lymphoma Research Foundation opportunities to educate patients directly, so they know that these are tests that they should be having. It's also useful for providers. It's also quite helpful in terms of how we follow these patients over time. One of the efforts that we did was to say, 'maybe things weren't so great in 2015 when this began, but our practice patterns are changing over time, and we're starting to look into that data now.’ It also then becomes the baseline for the next registry that occurs when this registry finishes, in terms of following patients prospectively and looking at practice patterns.
TARGETED ONCOLOGY: Would you say the this is feasible across tumor types?
MATO: Absolutely. All it takes is a motivated sponso,r the funding, and people who are caring for patients who really believe in these types of data. This is a good opportunity as a plug to really support the role of real-world evidence in CLL and other tumor types, because clinical trials can only answer so many questions.
As we have more and more agents available, those comparisons are not likely to happen until a registry like this does provide opportunity to answer questions that we will never see in the context of a retrospective clinical research and interventional research.
It opens the window for really interesting outcomes data. We were reporting on practice patterns, but certainly not stratifying outcomes. It would be interesting to see now as we have longer-term follow up, how patient outcomes are influenced by these decisions. I think that'll be the next logical step in how we look at these data.
TARGETED ONCOLOGY: You also presented data around the phase 1/2 BRUIN study during the ASH meeting. What are the main takeaways from that trial?
MATO: The BRUINS study is looking at LOXO-305. This is a first-in-human phase 1 study, but then leading into phase 2 trial of this molecule, which has now been studied in more than 300 patients. It's also the first BTK inhibitor that's being studied in patients with progression on a prior covalent BTK inhibitor, which is a large patient population. The take home message from this study is really simple. The molecule was incredibly active in a heavily pretreated patient population and was incredibly well tolerated to the point that we're seeing minimal toxicities. As a clinician, it was mind blowing to see how active this molecule has been in patients who really have no standard-of-care options. I have patients calling on cycle 19 or 20 already, and still have no evidence of progression of disease and no toxicities whatsoever. So, I think while it's not changing the standard of care at all, there's no comparator in this trial, I think it's the first look into a class of molecules that may represent a paradigm shift for the management of CLL.
