The largest trial to date in mantle cell lymphoma shows that adding the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) to standard of care treatment improves progression-free survival (PFS) by 50%.

The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.

After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.

Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.

“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.

He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.

These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.

She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”

Some lymphoma experts not impressed

The study got pushback from several lymphoma experts commenting on Twitter.

Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.

“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.

“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.

“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.

Potential for first-line use

Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.

These new data could lead to approval for first-line use of the drug.

“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”

Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.

He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.

Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.

At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.

Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.

The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.

At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).

Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”

Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.

He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.

The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”

Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.

In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.

He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.

The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.

A version of this article first appeared on Medscape.com.

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