Long-Term Follow-up and Analysis of Dose Groups with Ibrutinib in Relapsed Follicular Lymphoma
Authors: Fowler Nathan , Boyd Thomas E , Sharman Jeff P. , Smith Sonali M. , Clow Fong , Chu Alvina D. , Advani Ranjana H 
Published: October 2019

Abstract
Introduction: As outcomes in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) remain suboptimal, new, effective treatment options with a favorable safety profile are needed. Ibrutinib is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase (BTK), a key component of B-cell signaling involved in B-cell survival, proliferation and function. In lymphomas, ibrutinib is FDA-approved for treatment of mantle cell lymphoma in pts with ≥1 prior therapy. A phase 1 dose-escalation study with ibrutinib showed single-agent activity in pts with R/R B-cell malignancies (overall response rate [ORR] 60%; complete remission [CR] in 16%) including FL (Advani JCO 2013). In this trial, the 560 mg/day fixed dose was well tolerated and led to full BTK occupancy. We evaluated the efficacy, safety, and tolerability of single-agent ibrutinib by low- vs. high-dose groups with longer follow-up in pts with relapsed FL.
Methods: Data were analyzed for pts with R/R FL (N=16) treated with oral ibrutinib in the phase I study (PCYC-04753), where pts received escalating doses of ibrutinib 1.25-12.5 mg/kg/day per cycle (1 cycle = 28 days + 7 days rest) or continuous doses of ibrutinib 8.3 mg/kg/day or 560 mg/day fixed dose (1 cycle = 35 days). Pts with stable disease or better, who received therapy for 6 months, continued ibrutinib at a fixed dose of 560 mg/day in the extension study (PCYC-1103) until progression or unacceptable toxicity. Pt data categories included low-dose (1.25 mg/kg/day, 2.5 mg/kg/day, or 5 mg/kg/day) or high-dose (8.3 mg/kg/day or 12.5 mg/kg/day) groups.
Results: Eight pts each were categorized into low-dose and high-dose groups. Baseline characteristics were similar, but median treatment duration was longer for the high-dose group (Table; 12 vs. 4 months). Increased ORR (63% vs. 25%) and CR rates (38% vs. 0%) were observed in the high-dose compared with low-dose group (Table). Median duration of response (DOR) was longer in the high-dose group (12 vs. 3 months), as was median progression-free survival (PFS; 24 vs. 9 months). Median overall survival (OS) was not reached (NR) in either group. Grade ≥3 adverse events (AEs) occurred in 3 pts in each group. Common grade ≥3 AEs reported in ≥3 pts in the combined groups included (low-dose, high-dose) diarrhea (n=2, 6), fatigue (n=3, 4), nausea (n=2, 4), cough (n=3, 2), myalgia (n=1, 3), headache (n=0, 3), muscle spasms (n=1, 2), pruritus (n=0, 3), and rash (n=0, 3). Serious AEs occurred in 3 pts in the low-dose and 1 pt in the high-dose group. AEs leading to treatment discontinuation occurred in 2 pts in each group. No fatal AEs occurred. Among 4 pts (high-dose group) receiving ibrutinib beyond 1 year (range, 18 to 61 months), no unexpected or increased AEs were observed; 1 pt experienced 2 grade 3 AEs (non-cardiac chest pain and vomiting), both within 60 days from start of treatment and lasting 1 day. No other grade ≥3 AEs occurred among these 4 pts.
Conclusions: Higher doses of single-agent ibrutinib were associated with increased response rates and prolonged PFS in pts with R/R FL. A higher dose was not associated with increased AEs or with cumulative toxicity during extended therapy. In the current analysis, pts with FL derived the most benefit from ibrutinib doses at 8.3 mg/kg/day or higher. A study testing single-agent ibrutinib at 560 mg/day in pts with R/R FL is ongoing (Bartlett Blood 2014) as is a phase 2 study evaluating ibrutinib 560 mg/day in chemoimmunotherapy refractory FL.
Table 1. Patient Characteristics and Efficacy Low dose(n=8) High dose(n=8) Median age, yrs (range) Age ≥ 70 yrs, n (%) 57 (48-70)1 (13) 62.5 (41-71)1 (13) Median no. of prior therapies (range) 3 (1-4) 2 (1-5) Ann Arbor stage III/IV disease, n (%) 6 (75) 6 (75) FLIPI score, % (low / intermediate / high)* 25 / 38 / 38 13 / 38 / 50 Median treatment duration, months (range) 3.8 (0.5-11.1) 12.4 (0.2-61.5) ORR, n (%) CR, n (%) 2 (25)0 (0) 5 (63)3 (38) Median DOR, months (range) n=2; 3.4 (1.8-4.9) n=5; 12.3 (4.8-51.3) Median PFS, months (95% CI) 9.2 (0.5, 13.4) 23.7 (2.2, NE) 10-month PFS, % 35.7 70 Median OS, months (95% CI) NR NR 10-month OS, % 100 100 *FLIPI scores from baseline data. NE, not estimable

Disclosures
Off Label Use: single-agent ibrutinib therapy in patients with relapsed FL. Boyd:Celgene: Research Funding, Speakers Bureau; Genentech: Research Funding; US Oncology: Research Funding; GSK: Research Funding. Sharman:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding; Janssen: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Calistoga: Honoraria. Smith:Pharmacyclics: Consultancy; Celgene: Consultancy. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Chu:Pharmacyclics LLC, an AbbVie Company: Employment.