Acalabrutinib extends PFS in treatment-naive chronic lymphocytic leukemia
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ORLANDO — Acalabrutinib alone and in combination with obinutuzumab improved PFS compared with obinutuzumab and chlorambucil among patients with treatment-naive chronic lymphocytic leukemia, according to results of the randomized phase 3 ELEVATE-TN study presented at ASH Annual Meeting and Exposition.
“Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment of CLL,” Jeff P. Sharman, MD, director of research at Willamette Valley Cancer Institute and medical director of hematology research for the US Oncology Network, said in a press release. “This study led to the FDA approval of acalabrutinib [Calquence, AstraZeneca] in previously untreated CLL and presents compelling evidence of both safety and efficacy of the drug. With a second approved BTK inhibitor in CLL, there are now more available options for patients in need of therapy.”
Acalabrutinib previously demonstrated efficacy among patients with treatment-naive CLL as a single agent or in combination with obinutuzumab (Gazyva, Genentech).
“Acalabrutinib is a more select BTK inhibitor, with less off-target kinase inhibition in vitro compared with ibrutinib [Imbruvica; Janssen, Pharmacyclics] and a favorable safety profile, prompting this evaluation as a frontline therapy with or without obinutuzumab,” Sharman said during his presentation.
In the multicenter, open label trial, Sharman and colleagues randomly assigned 535 patients with treatment-naive CLL (median age, 70 years; range, 41-91) to one of three treatment arms:
- 100 mg acalabrutinib twice daily (n = 179);
- acalabrutinib in combination with 1,000 mg IV obinutuzumab on days 1 to 2 (split 100 mg and 900 mg), 8 and 15 of the first cycle and day 1 of five other 28-day cycles (n = 179); or
- obinutuzumab in combination with 0.5 mg/kg chlorambucil on days 1 and 15 of six 28-day cycles (n = 177).
Most participants (69%) had high-risk CLL international prognostic index scores, and 12% had very high-risk scores.
PFS with acalabrutinib plus obinutuzumab vs. obinutuzumab plus chlorambucil served as the study’s primary endpoint. Secondary endpoints included PFS with acalabrutinib monotherapy vs. obinutuzumab plus chlorambucil, overall response rate, OS and safety. Researchers assessed minimal residual disease in peripheral blood or bone marrow among patients with complete response or complete response with incomplete marrow recovery.
Median follow-up was 28 months.
Results showed acalabrutinib plus obinutuzumab significantly extended PFS compared with obinutuzumab plus chlorambucil (median, not reached vs. 22.6 months; HR = 0.1; 95% CI, 0.06-0.18), reducing the risk for progression or death by 90%.
Acalabrutinib monotherapy also prolonged PFS (median, not reached) compared with obinutuzumab plus chlorambucil (HR = 0.2; 95% CI, 0.13-0.31).
Estimated 30-month PFS rates were 90% with acalabrutinib plus obinutuzumab, 82% with acalabrutinib monotherapy, and 34% with obinutuzumab plus chlorambucil.
PFS improvement with the acalabrutinib regimens vs. obinutuzumab and chlorambucil was consistent across subgroups, including among those with 17p deletion.
Median OS was not reached in any of the groups. Researchers reported HRs for OS of 0.47 (95% CI, 0.21-1.06) for acalabrutinib plus obinutuzumab vs. obinutuzumab and chlorambucil and 0.6 (95% CI, 0.28-1.27) for acalabrutinib vs. obinutuzumab and chlorambucil.
Estimated 30-month OS rates were 95% with acalabrutinib plus obinutuzumab, 94% with acalabrutinib monotherapy, and 90% with obinutuzumab and chlorambucil.
Five patients in the acalabrutinib combination group, 11 patients in the acalabrutinib monotherapy group and 55 patients in the obinutuzumab-chlorambucil group received subsequent therapy. One-quarter of patients in the obinutuzumab-chlorambucil group (n = 45) crossed over to acalabrutinib monotherapy.
Researchers reported a higher ORR with acalabrutinib plus obinutuzumab (94%; 95% CI, 89.3-96.5) vs. obinutuzumab plus chlorambucil (79%; 95% CI, 71.9-83.9), as well as a higher complete response rate (13% vs. 5%). The ORR with acalabrutinib monotherapy was 85%, with one complete response.
Median treatment duration was 27.7 months for the acalabrutinib groups and 5.6 months for the obinutuzumab-chlorambucil group.
Patients in the acalabrutinib groups experienced similar adverse events, with a lower rate of infusion-related reactions in the acalabrutinib combination group vs. the obinutuzumab-chlorambucil group (13% vs. 40%). Adverse events of interest in the acalabrutinib combination, acalabrutinib monotherapy and obinutuzumab-chlorambucil groups included atrial fibrillation (3% vs. 4% vs. 1%), bleeding (any grade, 43% vs. 39% vs. 12%; grade 3 or higher, 2% vs. 2% vs. 0%) and hypertension (grade 3 or higher, 3% vs. 2% vs. 3%).
Adverse events led to treatment discontinuation by 20 patients in the acalabrutinib-obinutuzumab group, 16 patients in the acalabrutinib monotherapy group and 25 patients in the obinutuzumab-chlorambucil group.
After 2 years of follow-up, 79.3% of patients in the acalabrutinib groups remained on single-agent acalabrutinib.
“With regards to BTK options, I would encourage treating physicians to get familiar be comfortable with all of them,” Sharman said. “Picking between them can be tailored more toward the patient. ... There are going to be conversations with patients who they may have their own preferences, and we have to look at that and take into account their goals for treatment.”– by John DeRosier
Reference:
Sharman JP, et al. Abstract 31; Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Sharman reports advisory/consultant roles with and honoraria and research funding from AbbVie, Acerta, AstraZeneca, Genentech, Janssen, Juno Therapeutics, Pfizer and TG Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.