Primary results from the phase III SHINE trial demonstrated that first-line treatment with ibrutinib combined with bendamustine/rituximab and rituximab maintenance achieves a substantial prolongation of progression-free survival in elderly patients with mantle cell lymphoma, according to a presentation at the 2022 ASCO Annual Meeting by lead investigator Michael Wang, MD, Professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, Houston.1 These findings were also simultaneously published in The New England Journal of Medicine.
Michael Wang, MD
In fact, the triplet regimen extended progression-free survival in the first-line setting by a net of 2.3 years compared with placebo plus bendamustine/rituximab. At a median follow-up of 7 years, median progression-free survival was 80.6 months (6.7 years) with ibrutinib plus bendamustine/rituximab and rituximab maintenance compared with 52.9 months (4.4 years) with placebo plus bendamustine/rituximab and rituximab maintenance (P = .011). There was no difference in overall survival between treatment arms.
“The SHINE phase III randomized trial showed a median progression-free survival of 6.7 years for the ibrutinib-plus-bendamustine/rituximab arm. These results represent an important advance in the field of mantle cell lymphoma. Phase III trials are rare for this disease. In my personal opinion, this is a new global standard to treat older patients with newly diagnosed mantle cell lymphoma. The side effects of ibrutinib plus bendamustine/rituximab and rituximab maintenance were within expectations,” said Dr. Wang.
“These results provide evidence that an ibrutinib-based combination front-line treatment regimen provides a significant progression-free survival benefit and may be a new treatment opportunity for this patient population who previously had few options. The SHINE data set a new benchmark for first-line therapy in older patients with mantle cell lymphoma,” Dr. Wang stated.
Study Background
Mantle cell lymphoma is a rare, incurable subtype of B-cell non-Hodgkin lymphoma that comprises an estimated 6% to 7% of all non-Hodgkin lymphoma diagnoses. Standard treatment with immunochemotherapy followed by rituximab maintenance has been shown to improve the duration of remission, but relapse is common. Ibrutinib has shown single-agent activity in relapsed or refractory mantle cell lymphoma, and preliminary research suggests that ibrutinib can be safely combined with bendamustine/rituximab in relapsed or refractory mantle cell lymphoma. SHINE is the first study to evaluate a Bruton’s tyrosine kinase (BTK) inhibitor as front-line therapy for mantle cell lymphoma.
“Single-agent ibrutinib has transformed the care of patients with relapsed/refractory mantle cell lymphoma with durable activity. These data in patients with relapsed/refractory disease suggested that combining ibrutinib with bendamustine/rituximab might improve the outcome of patients in the newly diagnosed setting,” Dr. Wang noted.
Ibrutinib has received accelerated approval from the U.S. Food and Drug Administration to treat patients with mantle cell lymphoma who have previously received at least one line of therapy.
Study Methodology
The double-blind, phase III SHINE study evaluated ibrutinib in combination with bendamustine/rituximab vs placebo plus bendamustine/rituximab for the treatment of elderly patients with newly diagnosed mantle cell lymphoma, a population generally not considered suitable for intensive chemotherapy or transplantation due to excessive toxicities.
Between May 2013 and November 2014, 523 patients aged 65 or older were enrolled from 183 sites in 28 different countries. Patients were randomly assigned in a 1:1 ratio to six cycles of ibrutinib plus bendamustine/rituximab vs six cycles of placebo plus bendamustine/rituximab. Ibrutinib was given at 560 mg orally. Bendamustine was administered at 90 mg/m2 and rituximab, at 375 mg/m2. Patients in either arm who achieved a complete response or partial response were treated with rituximab maintenance every 8 weeks for up to 12 additional doses.
Key exclusion criteria included diagnosis or treatment for malignancy other than mantle cell lymphoma, requirement for treatment with warfarin or equivalent vitamin K antagonists, and treatment with strong CYP3A4/5 inhibitors. Median patient age was 71 years (range = 65–87 years); 65% of patients had low- or intermediate-risk disease, and 8.6% had blastoid/pleiomorphic histology. The majority of patients were White (77%), similar to the racial breakdown of newly diagnosed patients with mantle cell lymphoma in the general population.
The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, complete response rate, duration of response, safety, and overall survival.
Key Findings
The study met its primary endpoint, with a significant prolongation of progression-free survival in patients who were randomly assigned to the ibrutinib-containing arm (P = .011). The complete response rate was 65.5% with ibrutinib plus bendamustine/rituximab and 57.6% with placebo plus bendamustine/rituximab (P = .0567). Median overall survival had not been reached in either arm at the time of follow-up.
After 7 years of follow-up, the time to next treatment was significantly longer in the experimental arm compared with placebo: not reached in the ibrutinib arm vs 92 months in the placebo arm, representing a 52% improvement favoring ibrutinib (P < .001).
Subsequent antilymphoma treatment was administered to 19.9% and 40.5% of patients, respectively. A second BTK inhibitor was given to 38.7% of the patients who received placebo.
Adverse Events
No new safety signals emerged for any of the agents used in the trial. Numerically higher rates of grade 3 and 4 treatment-emergent adverse events were reported with ibrutinib vs placebo: 81.5% and 77.3%, respectively. The most common grade 3 and 4 adverse events were rash, pneumonia, and atrial fibrillation, and the rates of all three were much higher in the ibrutinib arm. The rate of any-grade atrial fibrillation, an adverse event of concern with BTK inhibitors, was higher in the ibrutinib arm: 13.9% and 6.5%, respectively.
The rate of any bleeding was higher in the ibrutinib arm: 42% vs 21%, respectively. “There was no difference in major bleeding between the two arms,” Dr. Wang stated. The rates of other adverse events, including major hemorrhage, hypertension, arthralgia, and secondary primary malignancies, were similar in both arms.
“There were more deaths due to progressive disease in the placebo arm and more deaths due to toxicity in the ibrutinib arm,” Dr. Wang said. The rate of deaths due to progressive disease and treatment-related adverse events combined was 22% in the ibrutinib arm and 26% in the placebo arm.
“An exploratory analysis of cause-specific survival including only death due to progressive disease or treatment-related adverse events trended in favor of the ibrutinib arm, with a hazard ratio of 0.88,” he continued.
When asked whether this triplet regimen should be used in all newly diagnosed older patients with mantle cell lymphoma, Dr. Wang had some specific recommendations. “This treatment is suitable for older patients who need therapy for mantle cell lymphoma. This combination would not be advised in patients with baseline atrial fibrillation, heavy bleeding, or a history of chronic obstructive pulmonary disease with pneumonia.”
A separate secondary analysis of quality of life will be performed and reported separately.
DISCLOSURE: The study was funded by Janssen Pharmaceuticals NV & Pharmacyclics LLC, an AbbVie Company. Dr. Wang has received honoraria from Acerta, AstraZeneca, BeiGene, Breast Gynecological International Cancer Society, Chinese American Hematologist and Oncologist Network, Chinese Anti-Cancer Association, Chinese Medical Association, Clinical Care Options, Dava Oncology, Epizyme, Hebei Cancer Prevention Federation, Imedex, Janssen Research & Development, Kite, Miltenyi Biomedical, Moffitt Cancer Center, Mumbai Hematology Group, Newbridge Pharmaceuticals, OM Pharmaceutical Industries, Pharmacyclics/Janssen, Physicians’ Education Resource, Scripps Health, and The First Affiliated Hospital of Zhejiang University; has served as a consultant or advisor to AstraZeneca, Bayer, BeiGene, Bioinvent, CStone Pharmaceuticals, DTRM, Epizyme, Genentech, Guidepoint Global, InnoCare, Janssen Research & Development, Juno Therapeutics, Kite, Loxo, Miltenyi Biomedicine, Oncternal Therapeutics, Pharmacyclics/Janssen, Pulse Biosciences, and VelosBio; has received research funding from Acerta Pharma, AstraZeneca, BeiGene, Bioinvent, Celgene, InnoCare, Janssen Research & Development, Juno Therapeutics, Kite, Lilly, Loxo, Molecular Templates, Oncternal Therapeutics, Pharmacyclics, and VelosBio; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Celgene, Dava Oncology, Janssen Research & Development, and OM Pharmaceutical Industries.
REFERENCE
1. Wang M, Jurczak W, Jerkeman M, et al: Primary results from the double-blind, placebo-controlled, phase III SHINE study of ibrutinib in combination with bendamustine-rituximab (BR) and R maintenance as a first-line treatment for older patients with mantle cell lymphoma. 2022 ASCO Annual Meeting. Abstract LBA7502. Presented June 3, 2022.
