Ibrutinib for MCL Just as Effective in the NHS as in Trials

Liam Davenport

May 08, 2020

NHS patients with mantle cell lymphoma (MCL), a rare and aggressive form of non-Hodgkin lymphoma, can respond similarly to the Bruton's tyrosine kinase inhibitor ibrutinib (Imbruvica, Janssen-Cilag) as those treated in the clinical trials, despite being more frail, suggests a real-world analysis of UK data.

The research was published as an abstract from the British Society for Haematology (BSH) 60th Annual Scientific Meeting, which was cancelled due to the COVID-19 pandemic.

NHS Study

Dr Rory McCulloch, Department of Haematology, University Hospitals Plymouth NHS Trust, Plymouth, and colleagues, studied more than 180 MCL patients treated with ibrutinib on the NHS after they had relapsed on first-line therapy.

They found that, after 2 years, median progression-free survival (PFS) was over 18 months, and overall survival was nearly 2 years, figures similar to those seen in the ongoing ibrutinib clinical trials.

However, the previously observed high rate of treatment discontinuation, primarily due to progressive disease, was also reproduced, with median survival as short as 1.2 months in those who stopped the drug.

The team notes that, while ibrutinib "represents a significant breakthrough with clear benefit to outcome irrespective of patient age, the results also highlight that response in many cases was limited", with the outcome for those who progressed "often very poor".

As a result, they say that "improved treatment strategies in the post-ibrutinib setting remains a priority".

Dr McCulloch told Medscape News UK that the patients in their study were "significantly more frail" than those included in the pivotal trials.

"These are the patients that are traditionally missed off from any analysis that you do in trials," he said, "and these are also the ones that are going to get the greatest benefit if you can give them a drug that is going to be well tolerated, because they are the ones that are really struggling for options."

He also noted that MCL patients "have historically done very poorly", with one UK registry indicating that, prior to the introduction of ibrutinib, the median overall survival at diagnosis was around 2.4 years, and 0.8 years at the start of second-line treatment.

Dr McCulloch pointed out that the overall survival that is now being achieved with ibrutinib in the second-line setting is consequently "not that dissimilar" to what was seen at the start of first-line therapy 15 years ago.

"So its moved on massively, but it is still an aggressive disease and ibrutinib isnt curative. As the trials consistently show, about 30% of patients dont really get a response, so for that group youve still got a lot of work to do."

Useful Analysis

Approached for comment, Dr Sunil Iyengar, a consultant haematologist at The Royal Marsden, London, who was not involved in the study, said that it is a "useful" real-world analysis of whether the clinical trial data is "reproducible".

He underlined that, while the PFS was [slightly] lower than that seen in clinical trials, it is a "higher risk group", owing to their higher performance status scores, older age, and the presence of central nervous system (CNS) involvement.

"So clearly ibrutinib is very active in this population, but you’re not getting durable responses; patients are still relapsing," Dr Iyengar told Medscape News UK.

He added that "they’ve tried to tease out what a higher risk group might be", identifying performance status and time to PFS on prior therapy as likely candidates.

Dr Iyengar also acknowledged the concerns expressed by the researchers over the post-ibrutinib setting, saying that, while it has been known "all along" that there was an issue, previous studies had included patients who had received several lines of treatment.

"Here, just looking at ibrutinib use in the second-line, patients still do badly if they relapse," he said, "so there’s clearly a need for improved treatments post-ibrutinib."

'Encouraging'

Stephen Scowcroft, director of operations and external affairs at the charity Lymphoma Action, welcomed the study.

He told Medscape News UK that ibrutinib "has changed the outlook for people with relapsed or refractory mantle cell lymphoma and it is encouraging that long-term real-world' data is similar to that reported in pivotal clinical trials".

Echoing Dr Iyengar’s concerns, he added: "However, there remains a need for effective treatments for people who do not respond to ibrutinib or who relapse after ibrutinib therapy."

Ibrutinib was approved by the US Food and Drug Administration in late 2013 for patients with MCL who have undergone at least one other therapy, after results indicated that 68% of MCL patients had their cancer shrink or disappear, double that seen with other drugs.

The European Medicines Agency followed suit the next year, and it became available to NHS patients via the Cancer Drugs Fund in January 2015.

However, it has also long been known that ibrutinib initially works in only around two-thirds of patients, with even responders eventually acquiring resistance.

Consequently, Dr McCulloch and colleagues sought to examine the clinical effectiveness of ibrutinib at first relapse, where it is now standard of care in the UK, in a non-clinical, real-world population.

They drew comparison with a pooled analysis of three ibrutinib trials involving 370 patients with relapsed/refractory MCL enrolled between 2011 and 2013, from which extended 3.5-year follow-up data was recently published.

This showed that median PFS was 12.5 months and overall survival 26.7 months. Patients receiving the drug in the second-line had better outcomes than those treated later, at a median PFS of 25.4 months, with overall survival not estimable.

However, the median duration of treatment exposure was 11.1 months, with treatment discontinuation rates due to disease progression, adverse events, and death at 59.2%, 10.3%, and 5.1%, respectively.

Study Details

For the current analysis, the team gathered data from 35 NHS Trusts on 185 patients who received the drug between January 2015 and June 2019.

The median age at the start of ibrutinib was 73 years, 68.6% were male, and 53.2% had progressed within 2 years on frontline therapy.

The majority (56.2%) were classified as high risk on the mantle cell lymphoma prognostic index, 23.8% had an Eastern Cooperative Oncology Group (ECOG) performance status of ≥2, and 3.8% had central nervous system (CNS) involvement.

Over a median follow-up of 24 months, the median PFS with ibrutinib was 18.9 months, and the median overall survival was 23.9 months.

Univariate analysis suggested that the strongest predictors of PFS were ECOG score ≥2, at a hazard ratio of 2.14 (p=0.001), and time to progression on frontline therapy <24 months, at a hazard ratio of 1.93 (p=0.001), while being aged 75 or over was not predictive.

The team reports that 118 (63.7%) patients discontinued ibrutinib, 69.1% of them due to progressive disease, 13.6% for consolidation haematopoietic stem cell transplantation, 6.8% due to drug toxicity, and 5.1% due to co-morbidities, while 12.7% died while on therapy.

The median overall survival among patients who stopped ibrutinib due to progressive disease was 1.2 months, rising to 9.3 months among those who received further systemic therapy.

Next Steps

Dr McCulloch said that the question of what to offer patients who have progressed on ibrutinib remains unanswered.

"At the moment in the UK, once you’ve gone through ibrutinib, there isn’t a very defined pathway [for] what you do next," he explained.

"There is a lot of concern from all the data that’s been accrued over the years that post-relapse, post-ibrutinib, is a very difficult-to-treat disease, but what we’re not sure of is if it’s any harder than post-second-line, whatever you give."

He continued: "I don’t think there is any data to suggest it is, really, but in the UK only about a third of patients who do relapse on ibrutinib are getting any more therapy, which seems quite low."

Dr McCulloch said that, potentially, "we could be treating more patients, but that is just because the algorithm isn’t well defined".

He added that "maybe some of those patients who aren’t getting treatment could get a benefit," as the patients in their study who received systemic therapy after ibrutinib "actually did reasonably well".

Second Study

In another study published in the BSH meeting abstracts, Dr David Tucker, department of haematology, Royal Cornwall Hospitals NHS Trust, Truro, and colleagues studied 65 patients treated with ibrutinib between November 2014 to December 2015 and identified from a named patient programme database.

After 5 years of follow-up, the median PFS was 12.0 months, and the median overall survival was 18.5 months, while 80% of patients had discontinued treatment, primarily due to progressive disease.

No funding declared.

Dr Tucker declares honoraria to attend educational events from Amgen and Takeda; advisory board member for Novartis. Dr McCulloch declares a potential conflict with: Janssen. Other potential conflicts of interest declared by other authors.

BSH 2020: Abstracts BSH2020-OR-025 & BSH2020-PO-092

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