Ibrutinib regimen extends PFS for older adults with mantle cell lymphoma
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CHICAGO — A novel first-line regimen significantly improved PFS compared with standard chemoimmunotherapy for older patients with mantle cell lymphoma, according to randomized phase 3 study results presented at ASCO Annual Meeting.
The experimental regimen — ibrutinib (Imbruvica; Pharmacyclics, Janssen) combined with bendamustine and rituximab (Genentech, Biogen), followed by rituximab maintenance — exhibited a safety profile consistent with prior reports of each drug, results of the double-blind SHINE study showed.
Data derived from Wang M, et al. Abstract LBA7502. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
“The magnitude of benefit surprised me. We observed a 50% pure improvement in PFS in the treatment arm,” researcher Michael L. Wang, MD, professor in the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center, told Healio.
“This is great news for older patients with newly diagnosed mantle cell lymphoma,” Wang added. “In my opinion, this should set a new global standard.”
Background
Older individuals with mantle cell lymphoma are not candidates for intensive chemotherapy or hematopoietic stem cell transplantation because of risk for excessive toxicities, Wang said.
“They have much worse outcomes than younger patients, with current chemoimmunotherapies, with PFS in most cases ranging from 1.5 years to 3.5 years,” Wang said.
“There is an urgent need to improve treatment options for all patients with mantle cell lymphoma, but especially for the older population,” Wang added. “If we are not able to add more chemotherapy, we need to add something that does not increase too much toxicity but can improve efficacy.”
Ibrutinib — an oral Bruton tyrosine kinase inhibitor — is approved in the United States as monotherapy for patients with mantle cell lymphoma who received at least one prior therapy.
“It has revolutionized care for patients with relapsed disease, and data have shown it is especially good if used early,” Wang said.
Methodology
Wang and colleagues conducted the SHINE trial to assess the addition of ibrutinib to standard bendamustine and rituximab, followed by rituximab maintenance, for older adults with newly diagnosed mantle cell lymphoma.
The primary analysis included 523 adults (median age, 71 years; range, 65-87) from 183 sites in 28 countries enrolled between May 2013 and November 2014.
Two-thirds (65.6%) had low-risk or intermediate-risk simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, and 8.6% had blastoid/pleiomorphic histology.
Researchers randomly assigned 261 patients to 560 mg ibrutinib daily plus six cycles of bendamustine (90 mg/m2) and rituximab (375 mg/m2). The other 262 patients received placebo plus bendamustine-rituximab.
Patients received ibrutinib or placebo until disease progression or unacceptable toxicity.
Patients in both groups who achieved objective response to their assigned regimen received rituximab maintenance every 8 weeks for up to 12 additional doses.
PFS per investigator assessment served as the primary endpoint.
Efficacy results
Median follow-up was 84.7 months.
Patients assigned ibrutinib achieved significantly longer median PFS (6.7 years vs. 4.4 years; HR = 0.75; one-sided P = .011).
“It is great to see a 2.3-year pure benefit with ibrutinib in the first line,” Wang said.
A higher percentage of patients assigned ibrutinib achieved complete response (65.5% vs. 57.6%), and results showed the ibrutinib regimen significantly prolonged time to next treatment in the ibrutinib group (P < .001).
Fifty-two patients (19.9%) assigned ibrutinib and 106 patients (40.5%) assigned placebo received subsequent anti-lymphoma therapy. More than one-third (38.7%) of those in the placebo group received a Bruton tyrosine kinase inhibitor.
Researchers reported no difference in OS between the experimental and control groups (HR = 1.07; 95% CI, 0.81-1.4). OS rates at 7 years were 55% with ibrutinib and 56.8% with placebo.
However, the trial was not designed to show an OS benefit, Wang said.
“If we had designed the study with OS as the primary endpoint, that would have required 1,000 to 2,000 patients and it would have taken 15 to 20 years to complete,” Wang told Healio. “It would not be feasible.
“It also is important to emphasize OS is not only related to a patient’s lymphoma and toxicities,” he added. “In this trial, median age at enrollment was 71 years, and one-third of patients were over 75 years old at study entry 7 years ago. Now those patients are 80-some years old. They don’t die only of lymphoma or toxicity. They also die of COVID-19, pneumonia, cardiac problems or other factors not related to the study.”
Safety results
A comparable percentage of patients in the ibrutinib and placebo groups experienced grade 3 or grade 4 treatment-emergent adverse events (81.5% vs. 77.3%).
Atrial fibrillation occurred among 13.9% of patients assigned ibrutinib and 6.5% of those assigned placebo. Wang said those rates were “in line” with his expectations.
Researchers reported higher rates of rash and pneumonia in the ibrutinib group.
Rates of major hemorrhage, hypertension, arthralgia and secondary primary malignancies appeared similar between groups, as did quality-of-life outcomes, Wang said.
Thirty patients (11.5%) in the ibrutinib group and 54 (20.6%) in the placebo group died due to disease progression.
Twenty-eight patients (10.7%) in the ibrutinib group and 16 (6.1%) in the placebo group died due to an adverse event during treatment. These events included infection or infestation excluding COVID-19 (ibrutinib, n = 9; placebo, n = 5), COVID-19-related events (3 vs. 0), unknown cause (3 vs. 0), cardiac disorder (3 vs. 5), sudden death (2 vs. 0) and multiple organ dysfunction syndrome (2 vs. 0). In the ibrutinib group, researchers reported one death due to each of the following causes: respiratory disorder, general physical health deterioration, traumatic intracranial hemorrhage, tumor lysis syndrome, cancer and ischemic stroke.
Next steps
“I think safety could be further improved,” Wang told Healio.
One key question is how long ibrutinib should be administered, he said, noting a 2-year median treatment duration for ibrutinib and a 3-year median duration for placebo.
“Even so, these results are significant and — in my opinion — this should change the standard of therapy,” Wang said.
Perspective
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Bijal Shah, MD, MS
Conducting a confirmatory phase 3 study in mantle cell lymphoma is about as hard as it gets. We can dissect the data all we want, but we have to start by acknowledging this is an amazing accomplishment.
That said, I would have liked to have seen a more significant OS benefit for a couple reasons. First, I’m trying to understand whether it makes sense to combine ibrutinib with bendamustine and rituximab. Second, does it make sense to begin the maintenance phase right after the bendamustine-rituximab portion is complete.
Bendamustine has proven to be an effective tool for mantle cell lymphoma. However, that doesn’t mean patients have pristine immune systems after six cycles of bendamustine.
We have tried giving maintenance with lenalidomide (Revlimid, Bristol Myers Squibb) in different lymphoid malignancies, and there’s a reason why — even with published data showing it can help — you don’t see it given very often. It’s hard to do. It’s not so much the drug, per se, but more so about who that patient is after they get done with their initial course of chemotherapy.
Getting back to the really important question of OS: If there is no survival benefit, why wouldn’t I give bendamustine-rituximab and, when they progress, give them ibrutinib? Alternatively, why not just start with ibrutinib and see where they land? If they progress, I can give them bendamustine or maybe consider CAR T-cell therapy. Why would I want to take on the toxicity that comes with this combinatorial therapeutic approach?
I think our colleagues in the CLL world are remarkably ahead of us in this particular space. They have the data set with bendamustine, rituximab and ibrutinib, as well, yet they don’t use it. If they have a newly diagnosed patient with CLL, they’ll treat that patient with ibrutinib. They understand there’s not much added benefit from the chemotherapy.
There is always a fear in mantle cell lymphoma that the disease is so aggressive, if you don’t include some chemotherapy, you will somehow imperil your ability to see the benefit with ibrutinib or any other novel agent. I hope some of the data sets that have been developed by Michael Wang, MD, Preetesh Jain, MD, and others at MD Anderson can finally put a rest to some of that. If you have a patient with highly aggressive mantle cell lymphoma, that’s not someone you want to put on a novel agent by itself, or a novel agent with rituximab. Quite frankly, you don’t want to put them on a bendamustine combination, either, because those patients are not likely to derive much benefit from that approach.
If we focus on the more common mantle cell lymphomas that we see — those that are low or intermediate risk — these patients will do fine with ibrutinib or ibrutinib-rituximab, and we can skip all of the toxicity that will come with the chemotherapy piece.
If you’re talking about “mantle cell 2022,” that’s not where we’re headed. It’s where we already are — not from a trial perspective, but with real-world data sets. We’re currently seeing Bruton tyrosine kinase inhibitors incorporated into the front-line setting and, importantly, this appears to come with reduced toxicity, as we reported at this meeting. These are important and needed data, but I think the impact will be to reinforce earlier exposure to the Bruton tyrosine kinase inhibitors rather than the combination with bendamustine.
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Wang M, et al. Abstract LBA7502. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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