Jeff Sharman, MD, discusses the implications of real-world ibrutinib findings in mantle cell lymphoma and underscored the need for the development of more effective treatments for this patient population.
Jeff P. Sharman, MD
Real-world survival outcomes for patients with relapsed/refractory mantle cell lymphoma treated with ibrutinib (Imbruvica), one of the most significant new agents in mantle cell lymphoma, were consistent with findings from clinical trials, according to a retrospective study presented at the 2018 ASH Annual Meeting. However, ibrutinib is not a cure for these patients and more research is still needed to improve outcomes.
"How we manage patients with ibrutinib and how we treat them after ibrutinib are remaining questions in the field," said Jeff Sharman, MD, lead author of the study.
Sharman and his colleagues looked at structured and unstructured data pertaining to adult patients with MCL who were ≥18 years of age and had been treated with ibrutinib between November 1, 2013, and October 31, 2016. These patients had not been enrolled in a clinical trial and had made at least 2 visits to a US Oncology Network (USON) clinic. Those with other primary cancers were excluded from the analysis.
Through the USON’s electronic health records system, a total of 159 patients with MCL were identified. Most of these patients were male, Caucasian, and had a diagnosis of stage IV disease. About 7.5% (n = 12) received ibrutinib as a first-line therapy, while 54.1% (n = 86) and 38.4% (n = 61) received the agent as second- and third-line treatment, respectively. Ibrutinib was initiated at a median dose of 560 mg (range, 140-700).
Over the course of their treatment, 16.4% (n = 26) of patients experienced a dose reduction, while dose holds occurred in 30.2% (n = 48) of patients; 66.7% (n = 32) of those holds were due to toxicities. Overall, the discontinuation rate was 83.6%, with 34.6% (n = 46) stopping treatment due to progressive disease, and 25.6% (n = 34) due to toxicities. The median duration of treatment was higher in those who received ibrutinib in the third-line versus other lines (14.9; 95% CI, 8.8-17.1). For the overall population, median progression-free survival (PFS) was 19.6 months (95% CI, 16.5-24.3), while median overall survival (OS) was 25.8 months (95% CI, 19.9-not reached).
In an interview withTargeted Oncology, Sharman, director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network, discussed the implications of these findings and underscored the need for the development of more effective treatments for this patient population.
TARGETED ONCOLOGY:What was the rationale for the study?
Sharman:This was a study that was conducted because ibrutinib had been available for several years now and it is clearly one of the most remarkable novel agents across hematologic malignancies. Obviously, it has demonstrated significant benefit across a variety of diseases, including chronic lymphocytic leukemia (CLL), MCL, and Waldenström macroglobulinemia, and it has an [FDA] approval in marginal zone lymphoma as well. A lot of the data that came out for mantle cell early on was primarily, and understandably, the data that emerged from prospective interventional clinical studies.
What we’ve seen in several circumstances is that clinical trial populations really represent a small subset of patients with disease who are selected based upon their ability to make it to academic medical centers and have the fitness to enroll in a study, and there’s a strong selection bias that renders clinical trial patients not necessarily representative of what we encounter in day-to-day practice. Therefore, this was an effort to evaluate those patients in day-to-day practice, in a clearly clinical oncology setting, and see how they fared with ibrutinib. It’s a retrospective [analysis] which is, of course, different from a prospective trial, and it has its limitations, but we wanted to see how [real-world outcomes] compared with those observed in clinical trials. I would say that the assumption in many cases is that these patients aren’t going to do as well as is seen in clinical trial because they tend to be older patients with more comorbidities and so forth.
We looked at nearly 2000 patients who had a diagnosis of MCL, pulled out a subset of patients who had received appropriate therapyfor instance, who had ibrutinib prescription—and disqualified a handful of others. We ended up with a population of about 160 patients. We looked at their outcomes based upon what line of therapy they received it in—was ibrutinib given in the first-line, second-line or third-line setting? Ibrutinib is approved for relapsed/refractory disease, so those patients who received it in the first-line were given it outside of the prescribing label—that was a small group of patients, but they tended to be considerably older and probably not fit for more intensive chemotherapy.
TARGETED ONCOLOGY:What were the methods used in this study?
Sharman:US Oncology has a uniform electronic medical record throughout a large number of practices, so we were able to query that database by diagnosis code; that helped us identify the patients with MCL. Then, we reviewed both structured and unstructured data. Structured data is those datasets that have numbers filled in, or populated, [from] lab results and so forth. We can query structured data, for instance, [to find out] whether or not a patient receives a prescription for ibrutinib. Unstructured data elements [include things like] physician notes and the narrative associated with it, and the things that don’t necessarily [translate to] codes or numbers. For example, how is the patient doing? Are we doing an interruption? Has the patient been hospitalized? Those are the sorts of history pieces that come out of unstructured data. We looked at the patients involved through both structured and unstructured data elements in order to get the data that then became the substance of the report.
TARGETED ONCOLOGY:What were the key takeaways from the report?
Sharman:When we looked at patients who were treated, the patients who were treated in the first-linethat was a small subset of 12 out of 160 patients—were indeed older patients; I think their median age was about 4 or 5 years older than the patients who were treated in the second- and third-line, respectively. The second- and third-line [patients] represent, therefore, the much more common [population with MCL]—these were a substantial fraction above age 65, which is typical of the diagnosis. [There were more] males than females, which is also common with this disease. We had patients who generally had advanced disease, which is pretty standard for MCL, with probably two-thirds having stage IV disease. Performance status was a mix of zeros and ones, so no real surprise there. We looked at the dosing and those patients who were treated in the first-line oftentimes started with a lower dose. The approved dose in MCL is 560 mg and that was the most common dose for patients in relapsed/refractory disease. However, you can see with the first-line setting patients, [physicians were] maybe a little more cautious about dosing, probably because of the patients themselves.
We did see that a lot of patients had dose interruptions [and] reductions were fairly common. Dose holds occurred in about one-third of patients and the main reason was the side effects of the medication. When we looked at the length of treatment, I think that the numbers were probably biased. Those patients who were receiving therapy in the third-line may have had more indolent MCL because if patients make it to third-line therapy, they’re better patients than patients who pack away after second-line of therapy. I think that some of the numbers were skewed in favor of the patients who received it later, but it was probably because they had more indolent disease.
If we look at the whole group, our numbers for the typical treatment duration and PFS were actually very similar to the prospective trial by Michael L. Wang, MD, et al that was published [in theNew England Journal of Medicine] and then led to the approval [of ibrutinib].2Our numbers are actually pretty consistent with the prospective study.
Since we picked a relatively early timepoint, most of our patients had stopped therapy83%, had stopped therapy—but that’s because we started pretty early in the time frame, so patients are going to experience either progression or stop [therapy]. The main reason people stopped was progression, but toxicities and “other” were [reasons 2 and 3], and if you take toxicities and “other” combined, there were more patients who discontinued for that than disease progression, which I think speaks to the fact that ibrutinib does have side effects and that there really remains an unmet medical need in MCL for improved therapies. While this is great, these patients are not cured by this therapy, so they will experience reasons to come off therapy—whether due to progression or side effects. MCL remains an unmet medical need in our minds.
TARGETED ONCOLOGY:What are the next steps for this research?
Sharman:We’ve done a similar study in CLL, another disease for which ibrutinib is approved [by the FDA], and we’re working to generate manuscripts for both of these. In fact, they are pretty close to being done, so those will be submitted for publication soon. I think next steps really [has to do with] working with our pharmaceutical colleagues to try to create either new drug treatment strategies or [figure out] how to improve patient outcomes. We will also be conducting a very large MCL prospective registry study where we are going to be working to actually capture these [data] in a prospective manner, and that should be opening within the next month or 2.
TARGETED ONCOLOGY:What are some other investigational treatment approaches for MCL that you’re excited about?
Sharman:We are excited to see additional novel agents [in the space]. For example, venetoclax (Venclexta) in combination with ibrutinib appears to be very exciting. Chimeric antigen receptor T-cell therapies holds a lot of opportunity and promise for patients with relapsed disease. There are other novel molecules coming forward as welllenalidomide is approved [by the FDA] for [the treatment of patients with] MCL, but we’re seeing data with lenalidomide in combination with rituximab (Rituxan) that has shown favorable outcomes in MCL. So, there’s a number of emerging strategies that I think hold promise for these patients.