Ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech) combined with bendamustine (Treanda®; Cephalon/Teva) + rituximab (Rituxan®; Genentech/Mabthera®; Roche) improved progression-free survival by 50% for older patients with newly diagnosed mantle cell lymphoma (MCL) compared to patients who received a placebo plus bendamustine-rituximab.[1]

This is the outcome from the SHINE-study which was supported by Janssen Pharmaceuticals and Pharmacyclics (an AbbVie Company). The results of the study were reported at the annual meeting of the American Society of Clinical Oncology (ASCO), held from June 3-7, 2022 in Chicago, Il. [1]

A rare disease
Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin’s lymphoma (NHL), a cancer that affects the lymphatic system. It develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone.

The disease affects men more than women, and more commonly in those older than 65 years of age. Approximately one out of 200,000 individuals per year worldwide are diagnosed with mantle cell lymphoma. About 4,000 people a year are diagnosed with the disease in the United States. [2]

Drug combinations
There are several drug combinations used to treat mantle cell lymphoma and some are more intensive than others. Because more intensive treatments tend to have more side effects, they are often reserved for younger patients or patients in good overall health. Older people with mantle cell lymphoma can seldom tolerate intensive chemotherapy or stem cell transplantation due to the high degrees of toxicities associated with those therapies, leading to unsatisfactory outcomes in this group of people. Hence, there is an urgent unmet need to develop additional treatment options for older people with mantle cell lymphoma.

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Study design
The double-blind phase III SHINE trial randomly assigned 523 patients, age 65 or older with mantle cell lymphoma, to either ibrutinib plus bendamustine-rituximab (261 patients) or placebo plus bendamustine-rituximab (262 patients). Both study groups had similar baseline characteristics. The median age of the patients in the study was 71 years. The median time that the patients were followed was seven years.

Participating patients were stratified by simplified MIPI score (low vs intermediate vs high risk) and were randomized 1:1 to ibrutinib (560 mg orally daily) or placebo, plus 6 cycles of bendamustine (90 mg/m2) and rituximab (375 mg/m2). The median age of patients was 71 years (range, 65–87), 65.6% of patients had low/intermediate simplified MIPI, and 8.6% had blastoid/pleiomorphic histology.

Study Findings
The study results showed that at the primary analysis, median follow up was 84.7 months. The primary endpoint was met as PFS was significantly improved in the ibrutinib group vs the placebo with bendamustine-rituximab group (hazard ratio, 0.75; one-sided P = 0.011).

Median PFS was 80.6 months with ibrutinib in combination with bendamustine-rituximab and rituximab maintenance, a 50% improvement over the group that received a placebo with bendamustine-rituximab and rituximab maintenance, which saw a median PFS of 52.9 months. The complete response rate was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.0567). There was no difference in OS between treatment groups at the time of the latest assessment of outcomes (P = 0.648).

Positive impact
“The SHINE study is the first international phase III trial to show a positive impact of ibrutinib combined with standard-of-care treatment in this disease. The progression-free survival is substantially longer than the common treatment options used today, which is an important clinical advancement,” said lead author Michael Wang, MD, who is a professor in the department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center in Houston.

The time to the next treatment was longer in the ibrutinib arm compared with the placebo arm. The number of patients who needed a next treatment was lower in the ibrutinib group compared with the placebo group: 52 (19.9%) and 106 (40.5%) patients received subsequent anti-lymphoma therapy in the ibrutinib and placebo groups, respectively; 41 out of the 106 patients (38.7%) in the placebo group received a subsequent Bruton tyrosine kinase inhibitor (mostly ibrutinib).

Adverse events
Grade 3 or 4 adverse events during treatment were 81.5% and 77.3% in the ibrutinib vs. placebo groups, respectively. The safety profile of the combined treatment was consistent with the known profiles of ibrutinib and bendamustine-rituximab with adverse events of clinical interest for BTKis, atrial fibrillation reported in 13.9% and 6.5% of patients in the ibrutinib and placebo group, respectively.

Health related Quality of Life (hrQoL) was also similar in both groups.

Next Steps
The patients in the study continue to be followed for longer-term OS.

This phase III study in untreated mantle cell lymphoma (MCL) demonstrated that ibrutinib in combination with bendamustine + rituximab maintenance significantly improved progression free survival PFS compared with standard chemo-immunotherapy and could, potentially change in clinical practice.

Small molecule drug
Ibrutinib is a small molecule drug that inhibits immune system B-cell proliferation and survival by irreversibly binding to the protein Bruton’s tyrosine kinase. It is currently approved as a single agent for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

Bendamustine and rituximab are commonly given in combination for the treatment of older patients with mantle cell lymphoma.

Clinical trials
A Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Given in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell Lymphoma – NCT01776840

Highlights of prescribing information
Ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech)[Prescribing Information]
Bendamustine (Treanda; Cephalon/Teva)[Prescribing Information]
Rituximab (Rituxan®; Genentech/Mabthera®; Roche)[Prescribing Information]

[1] Wang M, Jurczak W, Jerkeman M, Trotman J, Zinzani PL, Walewski JA, Zhu J, Spurgeon S, 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 (MCL). J Clin Oncol 40, 2022 (suppl 17; abstr LBA7502) | DOI 10.1200/JCO.2022.40.17_suppl.LBA7502
[2] Rare Disease Database. Online. Last accessed on June 4, 2022.

Featured image: ASCO Annual Meeting, Physicians, researchers, and health care professionals from over 100 countries are attending the 58th ASCO Annual Meeting. Photo courtesy: © 2022 ASCO/Zach Boyden-Holmes. Used with permission.

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