Venetoclax regimen not superior to standard therapy alone for older patients with CLL
Key takeaways:
- Older, treatment-naive patients receiving standard therapy had a PFS rate of 87% compared with 85% among those receiving standard therapy plus venetoclax.
- COVID-19 may have significantly affected the results.
CHICAGO — The addition of venetoclax to ibrutinib and obinutuzumab did not extend PFS among older patients with treatment-naive chronic lymphocytic leukemia during the COVID-19 pandemic, according to data presented at ASCO Annual Meeting.
Long-term follow-up of the phase 3 study is underway to determine potential advantages of the three-drug combination in other settings, researchers wrote.
“In this trial, [ibrutinib, obinutuzumab and venetoclax] is not superior to [obinutuzumab and ibrutinib] for the initial treatment of older patients with CLL; however, COVID-19 may have significantly altered these results, with data suggesting a death imbalance for patients treated [with the triplet regimen],” Jennifer A. Woyach, MD, a hematologist-oncologist at The Ohio State University Comprehensive Cancer Center, said during a presentation. “Long-term follow-up will be critical to determine whether some patients benefit from [ibrutinib, obinutuzumab and venetoclax].”
Background and methodology
Ibrutinib (Imbruvica; Pharmacyclics, Janssen), a Bruton tyrosine kinase inhibitor, with or without the anti-CD20 antibody obinutuzumab (Gazyva, Genentech) remains a standard front-line treatment regimen for older adults with CLL.
Smaller studies have shown evidence that the addition of venetoclax (Venclexta; Genentech, AbbVie) to ibrutinib and obinutuzumab can induce complete responses with undetectable minimal residual disease, which may allow for therapy discontinuation and thus lower risk for adverse events.
Woyach and colleagues conducted the multicenter Alliance for Clinical Trials in Oncology A041702 study to evaluate whether the addition of venetoclax to ibrutinib and obinutuzumab (IVO) with response-guided discontinuation improved PFS compared with ibrutinib and obinutuzumab (IO) among older patients with treatment-naive CLL.
Researchers randomly assigned 465 patients aged 65 years or older (median age, 74 years; 67.5% men) to either standard IO (n = 232) or IVO (n = 233), with venetoclax introduced at cycle 3 and continued until cycle 14. Patients with any response in the doublet group continued ibrutinib.
After 14 cycles, patients in the venetoclax group underwent response evaluation including CT scans and bone marrow biopsy with central minimal residual disease assessment. Those with complete response with undetectable minimal residual disease discontinued ibrutinib, and the other patients continued ibrutinib until disease progression or intolerable toxicity.
Median follow-up was 14 months.
Results
Researchers reported PFS rates at 18 months of 87% for the IO group and 85% for the IVO group (HR for IVO vs. IO = 1.12; 95% CI, 0.7-1.79). OS rates also did not differ significantly between the groups but trended toward favoring IO (HR = 1.34; 95% CI, 0.8-2.25).
The IVO group had a higher rate of grade 3 or higher hematologic adverse events than the IO group (61% vs. 48%; P = .006), but the groups had similar rates of nonhematologic grade 3 or higher adverse (67% vs. 66%).
Researchers noted COVID-19 as the leading cause of death in both groups, responsible for 11 deaths in the IO group and 19 in the IVO group; they attributed 13 additional IO deaths and 11 additional IVO deaths to other causes.
Excluding COVID-19 related deaths, researchers reported an HR for PFS of 0.82 (95% CI, 0.44-1.53), reflecting a trend favoring IVO. PFS rates increased to 92% with IO and 94% with IVO. OS also appeared similar with censoring for COVID-19-related deaths.
Evaluation of response after 14 cycles showed the IVO group had higher rates of complete response (68.5% vs. 31.3%) and undetectable minimal residual disease (86.8% vs. 33.3%) than the IO group.
Neither deletion(17p) nor IGHV status appeared associated with a significant PFS advantage for either treatment regimen, Woyach said, although researchers noted a trend toward PFS benefit with the doublet among those with deletion(17p).
Collapse
Woyach JA, et al. Abstract 7500. Presented at: ASCO Annual Meeting 2023; June 2-6, 2023; Chicago.