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).

Abstract

LBA7502 Background: Elderly patients (pts) with MCL are unsuitable for intensive chemotherapy or transplantation due to excessive toxicities. Single-agent ibrutinib (Ibr), a first-in-class, oral Bruton’s tyrosine kinase inhibitor (BTKi), has transformed the care of pts with relapsed or refractory MCL with durable activity. We conducted a phase III trial (SHINE; NCT01776840) to evaluate combining Ibr with a standard chemoimmunotherapy (BR) and R maintenance in older pts with untreated MCL. Methods: Pts aged ≥ 65 years, enrolled between May 2013 and November 2014 from 183 sites across all geographical regions, were stratified by simplified MIPI score (low vs intermediate vs high risk) and were randomized 1:1 to Ibr (560 mg orally daily) or placebo (Pbo), plus 6 cycles of B (90 mg/m2) and R (375 mg/m2). Pts who achieved an objective response received R maintenance, administered every 8 weeks for up to 12 additional doses in both arms. Ibr and Pbo were administered until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by the investigators. Results: A total of 523 pts were randomized to Ibr + BR (n = 261) or Pbo + BR (n = 262). Median age was 71 years (range, 65–87), 65.6% of pts had low/intermediate simplified MIPI, and 8.6% had blastoid/pleiomorphic histology. At the primary analysis, median follow up was 84.7 months. The primary endpoint was met as PFS was significantly improved in the Ibr arm vs the Pbo arm (hazard ratio, 0.75; one-sided P = 0.011). Median PFS was 80.6 months with Ibr in combination with BR and R maintenance, a 50% improvement over Pbo in combination with BR and R maintenance (median PFS of 52.9 months). The complete response rate was 65.5% in the Ibr arm and 57.6% in the Pbo arm ( P = 0.0567). There was no difference in overall survival between treatment arms ( P = 0.648). Time to next treatment was longer in the Ibr arm compared with the Pbo arm ( P < 0.001). Fifty-two (19.9%) and 106 (40.5%) pts received subsequent anti-lymphoma therapy in the Ibr and Pbo arms, respectively; 41/106 (38.7%) received a second-line BTKi in the Pbo arm. Rates of grade 3 or 4 treatment-emergent adverse events were 81.5% and 77.3% in the Ibr and Pbo arms, respectively. Of adverse events of clinical interest for BTKis, atrial fibrillation was reported in 13.9% and 6.5% of pts in the Ibr and Pbo arms, respectively. Rates of major hemorrhage, hypertension, arthralgia, and secondary primary malignancies were similar in both arms. Quality of life was also similar in both arms. Conclusions: This phase III study in untreated MCL demonstrated that Ibr combined with BR and R maintenance significantly improved PFS compared with standard chemoimmunotherapy, with a median PFS of 6.7 years. The safety profile was consistent with the known profiles of the individual drugs. Clinical trial information: NCT01776840.