Chronic Lymphocytic Leukemia patients with high-risk genetics respond well with minimal toxicity to ONO/GS-4059 therapy – 3-year follow-up results of a phase I extension study

In a letter to the editor of Blood, published on 4^th April 2017, Harriet S. Walter from the Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK, et al. report updated, 3-year follow-up results of a phase I extension study of ONO/GS-4059 in patients with R/R CLL.¹

The safety and tolerability of ONO/GS-4059, a selective BTK inhibitor, in patients with R/R B-cell malignancies was assessed in the POE001 phase I trial (NCT01659255). In total, 90 patients were enrolled and those who continued to respond or who achieved stable disease were eligible to enroll in the long-term ONO/GS-US-1787 extension study (NCT02457559).

Key Highlights:

• All 28 pts in the CLL cohort of the extension study were evaluable for efficacy and safety
• At the time of updated analysis, 11 pts (39.3%) had discontinued ONO/GS-4059
• Reasons for discontinuation included death (n=3), PD (n=4), AEs (n=3), and sponsor decision due to extended drug interruption (n=1)
• Subjects remaining on study were receiving doses ranging from 40mg–600mg once daily or 300mg twice-daily; no MTD was determined in patients with CLL
• Median duration on study at censoring = 32.5 months
• Estimated median PFS = 38.5 months; median OS = 44.9 months
• In the initial phase I trial, responses (CR or PR) were reported in 96% (24/25) evaluable pts and 23 pts (82%) demonstrated lymphocytosis with a mean fold increase above baseline of 4.5²
• At day 8, serum levels of CCL3, CCL4, TNF-α, IL10, IL6, and IL8 had significantly decreased
• Immunoglobulin levels did not change significantly with long-term ONO/GS-4059 therapy
• DNA was extracted from peripheral blood from 27/28 patients before initiation of trial therapy
• At study entry, 21/25 pts had unmutated IGHV, 7 of these pts have discontinued treatment
• Of pts with TP53 mutation, 7/10 remain on therapy; of the 3 that discontinued therapy, 1 progressed, 1 withdrew due to an AE, and 1 died from septicemia
• Of pts with ATM mutation, 1/3 has progressed on study (930 days)
• Of pts with SF3B1 mutations, 5/8 have discontinued treatment (1 due to progression)
• Of pts with NOTCH1 mutations, 3/7 have come off study (1 due to progression)
• No mutations appeared to predict shorter PFS with ONO/GS-4059
• Previously unreported mutations in CLL included a mutation in MEK1 (E203K) in 1 patient with early progression and a POT1 mutation (E67K)
• The majority of TEAEs were grade 1–2
• The most reported all grade AEs = bruising (35.7%) and neutropenia (35.7% each), and anemia (32.1%)
• Only 1 grade 3 bleeding event (3.6%; hematoma) reported during the study
• ≥Grade 3 infections reported in 12 pts (42.9%); grade 1–3 weight gain reported in 14 pts (50%)
• No cases of Richter’s transformation reported

The authors concluded that patients with high-risk CLL genetics responded well to ONO/GS-4059 therapy with minimal toxicity. They went on to say that the tolerability of ONO/GS-4059 is beneficial especially “in the context of combination therapies and in ibrutinib intolerant patients.”

Abstract:

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