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CHICAGO -- A combination of chemoimmunotherapy plus ibrutinib (Imbruvica) significantly reduced the risk of disease progression or death in older patients with untreated mantle cell lymphoma, a randomized study found.

All patients in the so-called received standard bendamustine (Bendeka, Treanda) plus rituximab, but median progression-free survival (PFS) reached 80.6 months in the ibrutinib arm versus 52.9 months in the study's placebo arm (HR 0.75, 95% CI 0.59-0.96, P=0.01), reported Michael Wang, MD, of MD Anderson Cancer Center in Houston.

However, no difference in overall survival (OS) was observed between the two groups (HR 1.07, 95% CI 0.81-1.40), with 7-year OS rates 0f 55% in the ibrutinib group and 56.8% in the placebo group, according to findings presented at the American Society of Clinical Oncology (ASCO) annual meeting.

"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," said Wang in a statement. "The progression-free survival is substantially longer than the common treatment options used today, which is an important clinical advancement."

"Older people are generally underrepresented in clinical trials," commented Julie Gralow, MD, ASCO's chief medical officer, in a statement. "Some lymphoma treatments, including intensive chemotherapy, targeted agents, or transplantation may have excessive toxicities in older patients, making them unsuitable choices for treatment."

"Patients with mantle cell lymphoma are often older and their inclusion in clinical trials can provide us with a better understanding of the balance between benefit and toxicity of treatments in their age group," Gralow continued. "Results from this trial bring new hope to newly diagnosed, older patients with this rare cancer who have had too few treatment options."

Results of the study were published concurrently in the .

SHINE enrolled 523 patients 65 years and older from 183 sites across all geographical regions. Patients were stratified by disease status (low, intermediate, or high) and randomized 1:1 to six cycles of bendamustine (90 mg/m²) and rituximab (375 mg/m²) plus either oral ibrutinib (560 mg once daily) or placebo, with treatment given until disease progression or unacceptable toxic effects. Patients with an objective response received rituximab maintenance therapy every 8 weeks for up to 12 additional doses. The primary endpoint was PFS.

The PFS benefit with ibrutinib extended to most, but not all, prespecified subgroups. In particular, patients who had high-risk disease (HR 1.02, 95% CI 0.71-1.48) and TP53 mutations (HR 0.95, 95% CI 0.50-1.80) failed to benefit from the addition of the Bruton's tyrosine kinase (BTK) inhibitor.

While objective response rates were similar between groups (89.7% with ibrutinib and 88.5% with placebo), complete response rates were significantly higher with ibrutinib (65.5% vs 57.6%, respectively) and rates of undetectable minimal residual disease were numerically higher (62.1% vs 56.5%).

Half as many patients in the ibrutinib group needed a second-line treatment compared with the placebo group (19.9% vs 40.5%), and median time to next treatment was longer with ibrutinib (not reached vs 92.0 months in the placebo group; HR 0.48, 95% CI 0.34-0.66).

More deaths occurred due to toxicity in the ibrutinib group (10.7% vs 6.1%).

Grade 3/4 adverse events (AEs) during treatment occurred in 81.5% of patients in the ibrutinib group and 77.3% in the placebo group. The most common of these high-grade AEs were neutropenia (47.1% vs 48.1%, respectively), pneumonia (20.1% vs 14.2%), lymphopenia (16.2% vs 11.9%), anemia (15.4% vs 8.8%), thrombocytopenia (12.7% vs 13.1%), rash (12.0% vs 1.9%), and leukopenia (10.0% vs 11.2%).

As for AEs of particular interest for BTK inhibitors, atrial fibrillation was reported in 13.9% of patients in the ibrutinib group versus 6.5% in the placebo group; hypertension in 13.5% and 11.2%, respectively; diarrhea in 46.3% and 36.9%; major hemorrhage in 5.8% and 4.2%; and arthralgia in 17.4% and 16.9%.