The addition of venetoclax (Venclexta) to ibrutinib (Imbruvica) rendered BTK C481X resistance mutations undetectable in 74.1% of patients (n = 27) with chronic lymphocytic leukemia (CLL) who harbored them at baseline, according to long-term follow-up data from a phase 2 trial (NCT03513562) presented at the
Mutation-negative status was reached at a median of 7.1 months (range, 2.0-25.3) after venetoclax was added. At a median follow-up of 45.9 months (range, 2.8-79.1), the median progression-free survival (PFS) from the addition of venetoclax was 40.7 months (95% CI, 33.4-51.8), and the median overall survival (OS) was 79.2 months (95% CI, 53.9-not reached [NR]). Half of patients (n = 14/28) discontinued treatment for observation after meeting response criteria at cycle 12 (n = 5), cycle 19 (n = 1), cycle 25 (n = 6), and cycle 31 (n = 2).
Combination BTK inhibitor and BCL2 inhibitor regimens for a time-limited duration should be further tested in covalent BTK inhibitor resistance,” lead study author Kerry Rogers, MD, of The Ohio State University, and colleagues wrote in a poster presentation of the data.
Resistance to covalent BTK inhibitors is mediated by mutations in BTK, the drug-binding target, or in the immediately downstream protein PLCG2, and these resistance mutations are typically detectable 9 to 12 months before clinical disease progression. Investigators hypothesized that adding venetoclax to ibrutinib once resistance mutations developed would eliminate those mutations, produce deep remissions, and allow patients to stop treatment.
The single-arm, phase 2 study enrolled adult patients at least 18 years of age with CLL who were taking ibrutinib and had a detectable resistance mutation (BTK C481, T474, or PLCG2 L845, D334, D1140, R665, S707) at a variant allele frequency of at least 4%, or below 4% with an increasing frequency on assessments at least 4 weeks apart, with or without clinical progressive disease (PD).1,2
Venetoclax was started with ibrutinib during cycle 1 using a standard 5-week ramp-up to a target dose of 400 mg per day. After cycles 12 and 24, patients with a complete remission (CR) or CR with incomplete marrow recovery and undetectable minimal residual disease (MRD) per International Workshop on CLL criteria discontinued treatment; those without an undetectable-MRD response after cycle 24 continued venetoclax alone.
Mutation status after 12 cycles of combination therapy served as the trial’s primary end point.
The 28 enrolled patients had a median age of 62.5 years (range, 41-82); 75.0% had unmutated IGHV, 50% had TP53 mutations, 64.3% had a complex karyotype, and 42.9% had del(17p). The median number of treatments before ibrutinib was 2 (range, 0-13), and the median duration of prior ibrutinib exposure was 67.7 months (range, 29.4-131.5). The median time on study treatment was 24.2 months (range, 2.6-70.8).
Among patients in whom BTK C481X mutations had cleared, the mutation became detectable again in 50% (n = 10/20) at a median of 27.3 months (range, 5.3-56.2) after it had become undetectable. The study enrolled patients with or without clinical PD; lymphocytosis (absolute lymphocyte count >5 k/µL), lymphadenopathy (sum of the products of diameters >20 cm2), or both served as a surrogate for clinical PD and was present in 53.6% of patients. The median PFS was 37 months (95% CI, 25.1-47.1) for patients with PD vs 51.8 months (95% CI, 28.5-NR) for those without, and the median OS was NR (95% CI, 36.8-NR) vs 79.2 months (95% CI, 53.9-NR), respectively.
Among the 14 patients who discontinued study treatment in response, 7 started a subsequent therapy, at a median of 22 months (range, 17.1-46.4) from the end of treatment. Across the full cohort, 12 of 28 patients started a new CLL therapy—a BTK inhibitor (n = 7), venetoclax (n = 2), CAR T-cell therapy (n = 2), and intrathecal methotrexate for CNS disease with continued venetoclax (n = 1)—and 4 were treated for Richter transformation. Eight patients remained under observation without therapy.
Treatment was generally tolerated, with only 1 discontinuation for adverse effects (AEs), which were diarrhea and neutropenia. The most common grade 3 or higher nonhematologic AEs were hypertension (25%) and diarrhea (14%). Hematologic AEs were frequent, including lymphopenia (82%; 50% grade ≥3), neutropenia (61%; 14% grade ≥3), and thrombocytopenia (71%; 11% grade ≥3). At the time of analysis, 1 patient remained on venetoclax, 4 were in follow-up, 17 were off study, and 6 had died.
