Fixed Duration Venclexta Combos Delay Progression in CLL Similarly to Imbruvica

Among previously untreated patients with chronic lymphocytic leukemia (CLL), fixed-duration therapy with Venclexta (venetoclax) plus Gazyva (obinutuzumab) or Imbruvica (ibrutinib) were associated with noninferior progression-free survival (PFS) versus continuous single-agent Imbruvica, meaning both the combination regimen and the single-agent treatment similarly delayed patients’ disease progression.

Prospective results of the phase 3 CLL17 trial were presented in a press briefing during the 2025 ASH Annual Meeting.

Findings showed that the three-year PFS rates were 81.1% with fixed-duration Venclexta/Gazyva, 79.4% with fixed-duration Venclexta/Imbruvica and 81% with continuous Imbruvica.

Three-year overall survival rates across the three arms were 91.5%, 96.0% and 95.7%, respectively.

“Fixed-duration treatments with both [Venclexta]/[Gazyva] and [Venclexta]/[Imbruvica], when administered over one year, are equally effective to continuous indefinite therapy. We see more deep remissions with the combination therapies,” lead study author Dr. Othman Al-Sawaf, hematologist and medical oncologist in the Department of Hematology and Oncology of the University Hospital of Cologne in Cologne, Germany said in an oral presentation at the press briefing. “For us, the findings mean that, nowadays, most patients with previously untreated CLL should be considered for a fixed-duration treatment to enable these treatment-free intervals. Of course, longer follow-up will substantiate our findings further.”

Data also showed that the objective response rates (ORRs) in the Venclexta/Gazyva, Venclexta/Imbruvica and Imbruvica arms were 84.2%, 88.5% and 86%, respectively. In the Venclexta/Gazyva arm, this comprised a 32.7% partial response (PR) rate and a 51.5% complete response (CR) rate; in the Venclexta/Imbruvica arm, these rates were 42.3% and 46.2%. In the continuous Imbruvica arm, 77.7% of patients had PRs, and 8.3% of patients had CRs.

“Response to therapy was very high … but only the combination therapies were able to produce meaningful CRs, which we do not see with single-agent therapy,” Al-Sawaf said.

Fixed-duration targeted therapy is defined as time-limited treatment that is generally 12 to 15 months and combines Venclexta with Gazyva or a BTK inhibitor. The goal, Al-Sawaf said, is to achieve deep remissions and allow patients a treatment-free interval.

Continuous therapy involves long-term daily treatment with a BTK inhibitor, which is continued until disease progression or intolerance.

In the open-label, multicenter, phase 3 CLL17 trial, investigators evaluated continuous Imbruvica compared with Venclexta plus Gazyva and Imbruvica plus Venclexta in 909 patients with previously untreated CLL. In the continuous Imbruvica arm, the oral BTK inhibitor was given at 420 milligrams daily until disease progression or intolerance. In the Venclexta/Gazyva arm, Venclexta was given orally at 400 milligrams daily starting on day 22 of cycle 1 until day 28 in cycle 12, while Gazyva was given at 1,000 milligrams intravenously starting on days 1, 8 and 15 of cycle 1, and day 1 on cycles 2 through 6. In the Imbruvica/Venclexta arm, Imbruvica was given at 420 milligrams daily on day 1 of cycle 1 through cycle 15 in 28-day cycles, and Venclexta was given at 400 milligrams daily on day 1 of cycle 4 through cycle 15 in 28-day cycles.

Patients, who were enrolled from February 2021 to November 2022, were randomly assigned to each of the three arms. Those with 17p deletion (del17p) and TP53 mutations were permitted, as well as both fit and unfit patients.

The primary end point was PFS. The median observation time was 34.2 months. Specifically, investigators independently tested the PFS noninferiority of fixed-duration Venclexta/Gazyva versus continuous Imbruvica and fixed-duration Venclexta/Imbruvica versus continuous Imbruvica.

Baseline characteristics in the Venclexta/Gazyva (303 patients), Venclexta/Imbruvica (305 patients) and Imbruvica (301 patients) arms showed that 71.3%, 66.9% and 65.1% of patients were male; the median age was 66 years, 66 years and 65 years; and 51.2%, 51.8% and 48.5% were 65 years or older.

Additional response data showed that undetectable minimal residual disease rates below 10^-4 in the peripheral blood and bone marrow, respectively, were 73.3% and 62% with Venclexta/Gazyva, 47.2% and 40% with Venclexta/ Imbruvica and 0% each with Imbruvica.

Regarding safety, any-grade side effects occurring in at least 15% of patients in the Venclexta/Gazyva, Venclexta/Imbruvica and Imbruvica arms, respectively, were blood and lymphatic system disorders (59%; 42.9%; 28.5%), gastrointestinal disorders (59.7%; 74.3%; 63.4%), diarrhea (27.1%; 47.2%; 34.9%), fatigue (25.4%; 25.4%; 19.1%), infections and infestations (76.3%; 80.2%; 79.9%), metabolism and nutrition disorders (30.5%; 24.8%; 24.2%), musculoskeletal and connective tissue disorders (37.6%; 49.2%; 56.7%), nervous system disorders (34.9%; 37.0%; 34.6%), respiratory/thoracic/mediastinal disorders (27.8%; 32.7%; 37.6%), skin and subcutaneous tissue disorders (29.5%; 55.8%; 55.7%) and vascular disorders (20.3%; 33.7%; 41.6%).

Grade 3 (severe) to 5 (fatal) infections of interest in the Venclexta/Gazyva, Venclexta/Imbruvica and Imbruvica arms, respectively, included infections and infestations (34.9%; 25.1%; 24.8%), comprising COVID-19 (15.9%; 8.6%; 6.7%) and pneumonia (9.8%; 7.3%; 7.4%). Data also showed grade 3 to 5 cardiac disorders (4.4%; 7.3%; and 11.4%), including atrial fibrillation (0.7%; 3.6%; 4%).

The FDA approved Venclexta in combination with Gazyva as a fixed-duration regimen in May 2019 for the treatment of patients with previously untreated CLL or small lymphocytic leukemia.

References

1. "Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: Results from the randomized CLL17 trial" by Dr. Othman Al-Sawaf et al., Blood.
2. "FDA approves new fixed-duration treatment option for previously untreated chronic lymphocytic leukemia," news release, https://tinyurl.com/ywdmz7v4

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