EDITOR’S NOTE, April 13, 2023: Since the publishing of this story, pharmaceutical companies Johnson & Johnson and AbbVie Company have withdrawn the U.S. indications for Imbruvica for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, according to a press release from J&J. The Food & Drug Administration had previously granted accelerated approval for Imbruvica in MCL based on overall response rates in the Phase 2 SHINE clinical trial. “Continued approval was contingent upon the demonstration of clinical benefit in the confirmatory Phase 3 SHINE study in previously untreated patients with MCL.” While the Phase 3 study “met its primary endpoint and demonstrated a significant progression-free survival advantage” in patients with previously untreated MCL,” it did not show an overall survival advantage. And the FDA advised that these results were insufficient for full approval.
Below is the original news story we published in June 2022 on the Phase 3 SHINE trial.
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What Is Mantle Cell Lymphoma?
Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma than can either grow slowly or quickly. Aggressive treatment is needed for fast-growing mantle cell lymphoma. The current approach to therapy is a combination of the monoclonal antibody drug, rituximab (Rituxan), and chemotherapy, bendamustine, followed by stem cell transplantation. The drug ibrutinib taken as a daily oral medication is currently approved for patients with relapsed/refractory mantle cell lymphoma and has shown to be effective.Studying Ibrutinib for MCL treatment
Ibrutinib in combination with the standard of care regimen can improve progression-free survival, or PFS, by 2.3 years among newly diagnosed patients with MCL, according to new data from the randomized, phase 3 SHINE trial.
PFS is the length of time from random assignment to disease progression or death. The latest SHINE findings were presented at the ASCO by Michael Wang, MD, Department of Lymphoma & Myeloma, University of Texas MD Anderson Cancer Center, Houston. The results were also published in the New England Journal of Medicine.
A total of 520 treatment-naive patients (aged ≥ 65 years) participated in SHINE trial. They were randomly assigned to receive ibrutinib or placebo plus bendamustine-rituximab (BR), and both groups then had maintenance treatment with rituximab. When looking at the PFS in years, the median PFS is 6.7 years with ibrutinib and 4.4 years with standard therapy, which is "a very meaningful benefit" with first-line treatment in this older population, Dr Wang said.
Ibrutinib prolonged the time to the next necessary treatment compared to the standard group as well. But the study failed to find any significant difference in OS, or overall survival. OS means the time from treatment to death and is the most appropriate measure for clinical trials.
In addition, higher rates of side effects were reported with ibrutinib vs placebo: 81.5% and 77.3%, respectively. The most common side effects were rash, pneumonia and atrial fibrillation (an irregular and often very rapid heart rhythm, or arrhythmia, that can lead to blood clots in the heart), and the rates of all three were much higher with ibrutinib compared to placebo. The rate of any bleeding was also higher in the ibrutinib arm: 42% vs 21%, respectively.
A Mixed Response to the Study Results
The study received mixed responses from several hematology experts.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University in London, UK, highlighted the fact that the triplet treatment option has no overall survival benefit and comes with more toxicity.
Dr. Bijal Shah, a medical oncologist in Moffitt Cancer Center's Malignant Hematology Department, says "it is still too soon to say if this regimen will lead to a new standard of care for older patients with mantle cell lymphoma.”
“I think a major challenge with the data presented relates to the need and benefit versus the toxicity of adding bendamustine,” Dr. Shah said. “Notably, overall survival was not improved, and it suggests that a safe alternative is to deliver ibrutinib-based therapy at the time of relapse. It is hoped with future BTKi trials, we will learn more about the importance, or lack thereof, of the bendamustine component."
Dr. Adam Asch, division chief of the hematology-oncology department at the University of Oklahoma, also shared his opinion on whether to consider this trial as a practice-changing study.
"SHINE trial represents some important data, it is, in my mind, the glass half full story,” Dr. Asch said in an interview with SurvivorNet. “There was an improvement in PFS but no improvement in OS, and more disappointingly there was no difference in disease-free survival for those patients who have TP53 mutations, which is the group of patients who are at most risk and need improved therapy the most.” He discussed that the lack of difference in OS with ibrutinib may be a less attractive choice for clinicians and the physicians may be more inclined to use newer generations of similar drugs on the progression of the disease.
Dr. Asch also said he did not see the research are “particularly practice-changing.”
“I think it is the discussion to have with patients but there were in fact some increased toxicities from ibrutinib and some trends towards worsening OS in the ibrutinib group,” Dr. Asch said. “I see this is mixed results in terms of benefit and again not particularly practice-changing."
Looking Ahead in the Fight Against Mantle Cell Leukemia
The 2022 ASCO annual meeting also included discussions on prognostic markers TP53 to facilitate risk stratifications. In other words, doctors are trying to figure out how to better identify high-risk mantle cell lymphoma patients through via the TP53 marker. A change or mutation in the TP53 gene means people with mantle cell lymphoma are at a higher risk of their cancer returning. Other discussions included ones one the utility of CART cell, bispecific antibodies and novel small molecules.
"From CART cell therapy to bispecific antibodies to novel biologically targeted therapies, there are many new therapies available that are rapidly changing treatment paradigms in MCL," said session chair Dr. Anita Kumar of Memorial Sloan Kettering Cancer Center.
The management of MCL still requires more research, and clinicians need updates on how to incorporate individual risk profiles into clinical decision-making and better tailor treatment strategies to improve clinical outcomes.
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