IBRUTINIB-RITUXIMAB VERSUS PLACEBO-RITUXIMAB IN PATIENTS WITH PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA (FL): PRIMARY ANALYSIS OF THE PHASE 3 PERSPECTIVE STUDY

Introduction: Single-agent rituximab (R) is indicated as first-line treatment for patients (pts) with FL who are ineligible for chemoimmunotherapy (CIT). In a phase 2 trial, ibrutinib (Ibr) plus R showed promising activity in pts with FL. Here, we report primary analysis results from the multinational, randomized, double-blind, phase 3 PERSPECTIVE study (NCT02947347) comparing Ibr-R versus placebo (Pbo) plus R in pts with previously untreated FL not eligible for CIT due to age and/or comorbidities.

Methods: Eligible pts were ≥ 70 y, or 60–69 y with ≥ 1 comorbidity, and met ≥ 1 Groupe d'Etude des Lymphomes Folliculaires criterion for treatment. Pts were randomly assigned 3:1 to receive oral Ibr (560 mg) or Pbo once daily until progressive disease. All pts received R 375 mg/m² weekly for 4 wk then every 8 wk for up to 12 cycles. Randomization was stratified by age (60–69 years vs. ≥ 70 years), FLIPI-1 score (low vs. intermediate/high), and ECOG PS (0–1 vs. 2). The primary endpoint was progression-free survival (PFS) by investigator (INV) assessment per Cheson 2014 criteria using FDA censoring rules. PFS sensitivity analyses included PFS by independent review committee (IRC) assessment and use of global censoring rules. Secondary endpoints included overall response rate (ORR) by INV, overall survival (OS), infusion-related reaction (IRR) rates, and safety.

Results: In total, 445 pts were assigned to receive Ibr-R (n = 334) or Pbo-R (n = 111). At baseline, median age was 74 y versus 75 y, 66% versus 67% had FLIPI-1 score ≥ 3, and 75% versus 76% had ECOG PS 0–1, respectively. At data cutoff, all pts had completed R treatment; Ibr or Pbo treatment was ongoing in 20% and 22% of pts, respectively. With a median time on study of 53.8 mo, PFS was significantly improved with Ibr-R versus Pbo-R (hazard ratio [HR], 0.71 [95% CI 0.53–0.96]; p = 0.02; median 42.0 vs. 32.8 mo) per INV with FDA censoring rules and with consistency in sensitivity analyses (Figure). ORR was 81% versus 68% with Ibr-R versus Pbo-R (rate ratio 1.19 [95% CI 1.04–1.36]; p = 0.004) and 4-y OS rates were 67% versus 71% (HR 1.12 [95% CI 0.77–1.63]; p = 0.55). IRRs occurred in 21% versus 27% of pts with Ibr-R versus Pbo-R. Median overall treatment duration was 22.1 mo with both Ibr-R and Pbo-R. Grade ≥ 3 AEs occurred in 78% versus 57% of pts; the most frequent grade ≥ 3 AEs were neutropenia (16% versus 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%); atrial fibrillation occurred in 5% versus 2%. Primary causes of death included AEs (14% vs. 7%) and FL (7% vs. 9%). 327 pts (73%) received study treatment during the pandemic; COVID-19-related death occurred in 9% of pts in the Ibr-R arm and 7% in the Pbo-R arm.

Conclusions: In pts with previously untreated FL for whom R monotherapy is appropriate, addition of Ibr led to significantly and robustly improved PFS with supportively consistent increased ORR, but without improvement in OS. IRR rates were also improved, but AE rates were higher with Ibr-R.

Research funding declaration: This study was funded by Pharmacyclics LLC, an AbbVie Company

Keywords: combination therapies; indolent non-Hodgkin lymphoma

Potential sources of conflict of interest:

D. Belada

Consultant or advisory role: Roche, Takeda, Janssen-Cilag, Gilead Sciences, and Novartis

Educational grants: Roche, Takeda, and Gilead Sciences

Other remuneration: Roche, Janssen-Cilag, Genma, and Morphosys

F. P. Gardner

Honoraria: Regeneron

A. C de Oliveira

Consultant or advisory role: AbbVie, Alexion, AstraZeneca, Beigene, Johnson & Johnson, Roche and Takeda

J. Sancho

Consultant or advisory role: AbbVie, BeiGene, BMS, Gilead/Kite, Incyte, Janssen, Lilly, Miltenyi Biomedicine, Novartis, and Roche

Honoraria: AbbVie, BeiGene, BMS, Gilead/Kite, Incyte, Janssen, Lilly, Novartis, and Roche

E. Lomaia

Other remuneration: Lectures: Novartis, Pfizer, and R-Farm

B. Anz

Other remuneration: Sarah Cannon Research Institute

S. Opat

Consultant or advisory role: Roche, Janssen, AbbVie, Takeda, Merck, Gilead, AstraZeneca, Antengene, and CSL

Honoraria: Roche, Janssen, AbbVie, Takeda, Merck, Gilead, AstraZeneca, Antengene, and CSL

Other remuneration: Roche, Janssen, AbbVie, Beigene, Takeda, Merck, Gilead, AstraZeneca, Antengene, CSL, and Pharmacyclics LLC, an AbbVie Company

J. Pailden

Employment or leadership position: AbbVie

Stock ownership: AbbVie

H. M. Peltier

Employment or leadership position: AbbVie and Merck

Stock ownership: AbbVie and Merck

Other remuneration: AbbVie and UC Berkeley

E. Marturano

Employment or leadership position: AbbVie and Novartis

Stock ownership: AbbVie

J. P. Dean

Employment or leadership position: AbbVie

Stock ownership: AbbVie

I. W. Flinn

Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Century Therapeutics, Genentech, Genmab, Gilead Sciences, Great Point Partners, Hutchison MediPharma, Iksuda Therapeutics, InnoCare Pharma, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics LLC, an AbbVie Company, Roche, Seattle Genetics, Servier Pharmaceuticals, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, Vincerx Pharma, and Yingli Pharmaceuticals

Other remuneration: AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Curis, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Loxo, Merck, MorphoSys, Novartis, Pfizer, Pharmacyclics LLC, an AbbVie Company, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development Corp., Unum Therapeutics, and Verastem