Phase 3 PERSPECTIVE study: Ibrutinib with rituximab for initial treatment of patients with follicular lymphoma.

We report primary analysis results from the Phase 3 PERSPECTIVE study comparing ibrutinib + rituximab versus placebo + rituximab in patients with previously untreated follicular lymphoma requiring treatment per Groupe d'Etude des Lymphomes Folliculaires criteria who were ineligible for chemoimmunotherapy due to age and/or comorbidities. The primary endpoint was investigator-assessed progression-free survival (PFS). Patients were randomly assigned 3:1 to receive ibrutinib (560 mg) or placebo once daily until progression, together with rituximab 375 mg/m2 weekly for 4 weeks, then every 8 weeks for 12 cycles. Overall, 445 patients were assigned to receive ibrutinib + rituximab (n = 334) or placebo + rituximab (n = 111). With a median follow-up of 53.7 months, PFS was significantly improved with ibrutinib + rituximab versus placebo + rituximab (hazard ratio, 0.713 [95% CI, 0.532-0.955]; P = 0.0231; median 42.0 vs. 32.8 months), as was overall response rate (81% vs. 68%; rate ratio, 1.190 [95% CI, 1.039-1.364]; P = 0.004). Complete response rates also favored ibrutinib + rituximab (31% vs. 26%). Overall survival (OS) was immature and not significantly different between arms (hazard ratio 1.121 [95% CI, 0.771-1.631]; P = 0.5485). Grade ≥3 adverse events occurred in 78% versus 57% of patients with ibrutinib + rituximab versus placebo + rituximab, most commonly neutropenia (16% vs. 7%), pneumonia (9% vs. 5%), hypertension (8% vs. 5%), COVID-19 (6% vs. 2%), COVID-19 pneumonia (6% vs. 3%), and diarrhea (6% vs. 2%). In patients with previously untreated follicular lymphoma, adding ibrutinib to rituximab significantly improved PFS and response rates but did not improve OS. This trial was registered at www.clinicaltrials.gov, NCT02947347.