Once-daily ibrutinib (Imbruvica) combined with bendamustine (Bendeka) and rituximab (Rituxan; BR) significantly improved progression-free survival (PFS) compared with placebo plus BR in patients aged ≥65 years with newly diagnosed mantle-cell lymphoma (MCL), according to data from the phase 3 SHINE trial. These results were presented at the 2022 American Society of Clinical Oncology Annual Meeting and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2022 June 3. Epub ahead of print).
These findings could elevate ibrutinib to standard treatment for older patients with MCL who often cannot tolerate chemotherapy or transplant strategies, said Michael Wang, MD, Professor, Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, who was the lead investigator of the study.
The difference in PFS between patients whose regimen included ibrutinib and those treated with standard of care was a median of 2.3 years.
“The median PFS of 6.7 years [in the ibrutinib arm] is one of the highest ever published in the literature. This study should set a new benchmark for first-line therapy of older patients with MCL or those unsuitable for stem-cell transplantation,” said Dr Wang during a press conference.
Ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor, is currently approved as a single agent for the treatment of patients with MCL who have received at least 1 previous therapy. Bendamustine and rituximab are commonly given in combination for the treatment of older patients with MCL.
Study Details
In the SHINE trial, 523 patients aged ≥65 years with newly diagnosed MCL were randomized to ibrutinib 560 mg orally daily or placebo plus BR for a maximum of six 28-day cycles. Participants who achieved a complete response (CR) or partial response (PR) continued to receive maintenance therapy with rituximab every second cycle for a maximum of 12 additional doses. Ibrutinib or placebo were administered until progression or unacceptable toxicity. The median patient age was 71 years, with approximately 30% being aged ≥70 years. Two-thirds (65.6%) of patients had low/intermediate risk simplified Mantle Cell Lymphoma International Prognostic Index, 8.6% had blastoid/pleomorphic histology, and approximately 10% had TP53 mutation.
In the primary analysis, median follow-up was 84.7 months. Median PFS was 80.6 months in the ibrutinib arm versus 52.9 months in the placebo arm, corresponding to a 25% reduction in the risk for disease progression or death (hazard ratio, 0.75; P = .011). The benefit with ibrutinib was apparent within the first year “and this benefit remained durable throughout the 7 years of follow-up,” said Dr Wang.
The PFS advantage in the ibrutinib arm was consistent across subgroups. Among patients with blastoid/pleomorphic histology, the median PFS was 25.6 months in the ibrutinib arm versus 10.3 months in the placebo arm. Among those with TP53 mutation, median PFS was 28.8 months versus 11.0 months, respectively.
Fewer patients in the ibrutinib arm required a next treatment compared with those in the placebo arm (19.9% vs 40.5%). The median time to next treatment was not reached in the ibrutinib plus BR arm and was 92 months in the placebo plus BR arm. The overall response rate was similar between the 2 arms, each approaching 90%, but the CR rate was numerically higher in the ibrutinib arm at 65.5% versus 57.6% in the placebo arm (P = .057).
Overall survival (OS) data are not mature. The median OS was not reached in either arm.
The safety profile was consistent with the known effects of ibrutinib and BR. The most common grade 3/4 adverse events were neutropenia (47.1% in the ibrutinib arm vs 48.1% in the placebo arm), pneumonia (20.1% vs 14.2%, respectively) anemia (15.4% vs 8.8%, respectively), thrombocytopenia (12.7% vs 13.1% respectively), rash (12.0% vs 1.9%, respectively), and diarrhea (6.9% vs 3.8%, respectively).