Ibrutinib-bendamustine-rituximab combo promising for older patients with mantle-cell lymphoma

A treatment combination comprising the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib plus bendamustine and rituximab, followed by rituximab maintenance therapy, improved progression-free survival (PFS) in older patients with untreated mantle-cell lymphoma, according to results of the SHINE* trial presented at ASCO 2022.

“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 PFS is substantially longer than the common treatment options used today, which is an important clinical advancement,” said lead author Professor Michael Wang from The University of Texas MD Anderson Cancer Center, Houston, Texas, US.

Participants were 523 patients aged ≥65 years (median age 71 years) with previously untreated stage II–IV mantle-cell lymphoma* and ECOG performance status 0–1. They were randomized 1:1 to receive oral ibrutinib (560 mg QD) or placebo until disease progression or unacceptable toxicity, in addition to bendamustine (90 mg/m² on days 1 and 2 of a 28-day cycle) plus rituximab (375 mg/m² on day 1) every 4 weeks for six cycles. Patients who achieved an objective response (complete or partial response) received daily ibrutinib or placebo plus ≤12 additional doses of rituximab (Q8W) as maintenance therapy, while those with stable disease received ibrutinib or placebo only.

Most patients had stage IV disease (89.3 and 86.3 percent of the ibrutinib and placebo groups, respectively), and patients were randomized a median 1.4 and 1.5 months, respectively, following diagnosis. Patients in the ibrutinib and placebo groups received treatment for a median 24.1 and 34.1 months, respectively. Fifty-four percent received prophylactic anti-infective agents.

Investigator-assessed PFS was significantly improved with ibrutinib compared with placebo after a median 84.7 months of follow up (median 80.6 vs 52.9 months; hazard ratio [HR], 0.75, 95 percent confidence interval [CI], 0.59–0.96; p=0.01), with PFS events recorded in 44.4 and 58.0 percent of patients in the ibrutinib and placebo groups, respectively, at data cut-off. [ASCO 2022, abstract LBA7502; N Engl J Med 2022;doi:10.1056/NEJMoa2201817]

This PFS benefit was consistent across multiple subgroups, though it did not appear to extend to patients with a simplified MIPI** score category indicating high risk or those with TP53 mutations.

The lack of benefit in certain prespecified subgroups calls for further investigation as the present study was not powered to compare PFS in these groups, said Wang and co-authors.

A numerically greater proportion of patients in the ibrutinib than placebo group achieved investigator-assessed complete response (65.5 percent vs 57.6 percent; p=0.06), with a comparable proportion achieving objective response (89.7 percent vs 88.5 percent).

Overall survival did not differ between groups (39.8 percent vs 40.8 percent; median not reached [NR] in both groups; HR, 1.07, 95 percent CI, 0.81–1.40). Death was due to disease progression in 11.5 and 20.6 percent of patients in the ibrutinib and placebo groups, respectively.

Second-line treatments were administered in 19.9 and 40.5 percent of patients in the ibrutinib and placebo groups, respectively (time to next treatment: NR vs 92 months; HR, 0.48), with 12 and 39 percent, respectively, receiving a second-line BTK inhibitor.

Consistent AE profile

Grade 3–4 adverse events (AEs) were recorded in 81.5 and 77.3 percent of ibrutinib and placebo recipients, respectively. The most common grade 3–4 AEs (≥10 percent of either group) in ibrutinib vs placebo recipients were neutropenia (47.1 percent vs 48.1 percent), pneumonia (20.1 percent vs 14.2 percent), lymphopenia (16.2 percent vs 11.9 percent), anaemia (15.4 percent vs 8.8 percent), thrombocytopenia (12.7 percent vs 13.1 percent), rash (12.0 percent vs 1.9 percent), and leukopenia (10.0 percent vs 11.2 percent).

In ibrutinib recipients, grade 3–4 events associated with BTK inhibitor use such as atrial fibrillation, hypertension, diarrhoea, any bleeding, and arthralgia occurred in 3.9, 8.5, 6.9, 3.5, and 1.2 percent, respectively. One ibrutinib and placebo recipient each experienced pneumocystis pneumonia, while four and one, respectively, experienced aspergillus infection. Second primary cancers occurred in 20.8 and 18.8 percent, respectively, with acute myeloid leukaemia/myelodysplastic syndrome occurring in two and three patients, respectively.

At data-cut-off, 84.3 and 76.7 percent of ibrutinib and placebo recipients, respectively, had discontinued all trial medications. Patient-reported outcomes did not significantly differ between groups.

During the treatment period, AEs led to death in 10.7 and 6.1 percent of patients in the ibrutinib vs placebo group.

“The AEs were consistent with the known profiles of single-agent ibrutinib, bendamustine, and rituximab,” the authors said.

They noted that certain infections were more common with ibrutinib than placebo during the maintenance phase and were occasionally fatal, warranting monitoring and early detection and management of infections.

A promising choice for older patients

“Most patients with mantle-cell lymphoma are older and are unsuitable candidates for aggressive treatment or autologous stem-cell transplantation, a situation that results in unsatisfactory clinical outcomes,” said Wang and co-authors.

“Results from this trial bring new hope to newly diagnosed, older patients with this rare cancer who have had too few treatment options,” commented Dr Julie Gralow, ASCO Chief Medical Officer & Executive Vice President, who was not affiliated with the study.