Zanubrutinib Plus Obinutuzumab and Venetoclax Induces High Undetectable MRD Rate in CLL/SLL

Jacob Soumerai, MD

Zanubrutinib (Brukinsa) plus obinutuzumab (Gazyva) and venetoclax (Venclexta; BOVen) demonstrated lasting responses characterized by sustained progression-free survival (PFS) and undetectable minimal residual disease (uMRD) in peripheral blood and bone marrow in previously untreated patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to long-term findings from the phase 2 BOVen trial (NCT03824483) presented at the 17th Annual International Conference on Malignant Lymphoma.

Of the 50 patients evaluable for best end of treatment response, 48 (96%) and 46 (92%) achieved uMRD in peripheral blood alone and both the peripheral blood and bone marrow, respectively. All 46 patients met the prespecified MRD end point and treatment discontinuation criterion and stopped treatment after a median of 10 months (interquartile range [IQR], 8-12).

“BOVen was well tolerated with no additional safety signals and durable PFS with long-term follow-up,” lead study author Jacob Soumerai, MD, of Massachusetts General Hospital Cancer Center in Boston, said in a presentation of the data.

Venetoclax plus obinutuzumab is associated with a high rate of uMRD. Zanubrutinib is a second-generation BTK inhibitor with fewer cardiac adverse effects (AEs) and improved PFS compared with ibrutinib (Imbruvica) in relapsed/refractory CLL.

Previously reported data demonstrated that BOVen was well tolerated and led to a high rate of uMRD in previously untreated patients with CLL, despite reports that the addition of BCL-2 inhibition to BTK inhibition can lead to grade 3 or greater neutropenia in up to 56% of patients.

Given the potential for high uMRD and increased toxicity, investigators evaluated longer-term follow-up with the triplet to determine the possibility of an MRD-driven approach.

To be eligible for enrollment, patients had to have previously untreated CLL/SLL in need of treatment per International Workshop on CLL guidelines; an ECOG performance status between 0 and 2; and absolute neutrophil and platelet counts above 1,000 and 75, unless due to CLL, respectively. The use of warfarin (Coumadin) and dual antiplatelets were not allowed.

Zanubrutinib was administered at 160 mg twice daily alongside 1,000 mg of obinutuzumab, which was given on days 1, 2, 8, and 15 of cycle 1 and day 1 of cycles 2 through 8. Venetoclax was introduced in cycle 3 and was ramped up to the 400 mg once daily target dose.

Treatment was administered for a minimum of 8 months and could be continued up to 24 months. MRD was assessed in peripheral blood via flow cytometry every 2 cycles. If MRD was undetectable in peripheral blood (<10-4), MRD was evaluated in bone marrow within 14 days. If both peripheral blood and bone marrow showed uMRD, then repeat peripheral blood assessment was done after an additional 2 cycles. If the second consecutive peripheral blood and bone marrow assessment showed uMRD, treatment was discontinued. ΔMRD400, a measure of MRD kinetics quantifying at least a 400-fold reduction in MRD from baseline to cycle 5, was also evaluated on day 1 of cycle 5 in peripheral blood.

A total of 52 patients were enrolled into the primary cohort (n = 39) and expansion cohort (n = 13) between March 2019 and October 2019, and July 2020 and April 2021, respectively.

Median follow-up was 40 months (range, 4.1-47.4+). Median age was 62 years (range, 23-77) and men and women were enrolled at a 3:1 ratio. Most patients had unmutated IGHV (71%); TP53 and/or 17p deletion was present in 17% of patients.

Additional results showed the breakdown of first demonstration of uMRD in peripheral blood at 2 months (2%), 4 months (26%), 6 months (53.1%), and 8 months (77.6%).

Median PFS was not reached (range, 4.1-45.1+). Median MRD-free survival in the 46 patients who achieved uMRD in bone marrow was 29.8 months (range, 3.6-35.1+). Notably, despite a shorter median time on therapy (8 vs 13 months, P < .001), median MRD-free survival was not reached in patients who achieved ΔMRD400 (n = 21) vs 18.1 months in those who did not (n = 13; HR, 4.02; 95% CI, 1.37-11.81; log-rank P =.003).

A total of 60% (n = 21) of patients achieved ΔMRD400, all of whom went on to display uMRD in bone marrow at 8 months, compared with only 21% (n = 3) of the 14 (40%) patients who did not achieve ΔMRD400. In the former population, median time to bone marrow uMRD was 6 months (IQR, 6-6), and median time on therapy was 8 months (IQR, 8-10), vs 11 months (IQR, 10-15.5) and 13 months (IQR, 12-17.5), respectively, in the latter. “ΔMRD400 at cycle 5 day 1 predicted early uMRD in the bone marrow and shorter duration of therapy,” Soumerai said. He added that ΔMRD400 did not track with traditional risk factors, with 80% and 60% of patients with TP53/del(17p) (n = 5) and unmutated IGHV (n = 25) achieving ΔMRD400, respectively.

Regarding safety, grade 3 or greater AEs included decreased neutrophil count (grade 3, 10%; grade 4, 13%), decreased platelet count (grade 3, 8%), lung infection (grade 3, 6%), infusion related reaction (grade 3, 2%; grade 4, 2%), maculopapular rash (grade 3, 4%), and skin infection (grade 3, 4%).

Other common AEs included fatigue, diarrhea, bruising, cough, nausea, anemia, constipation, arthralgias, nasal congestion, gastroesophageal reflux disease, insomnia, myalgia, abdominal pain, dyspnea, headache, dizziness, aspartate aminotransferase increase, sinusitis, ALK phosphatase increase, anxiety, sore throat, hypocalcemia, dry skin, postnasal drip, back pain, weight loss, edema in the limbs, non-cardiac chest pain, and hypertension.

“On the basis of these data and the ΔMRD400 kinetics data, we have initiated a phase 2 study of BOVen with ΔMRD400-directed treatment duration wherein patients who fail to achieve ΔMRD400 will receive 24 vs 10 months of therapy. We hypothesize that longer duration of therapy for patients who fail to achieve ΔMRD400 will further improve uMRD duration in these patients,” Soumerai concluded.

Reference

Soumerai JD, Dogan A, Seshan V, et al. Long-term Follow-up of Multicenter Phase II Trial of Zanubrutinib, Obinutuzumab, and Venetoclax (BOVEN) in Previously Untreated Patients With CLL/SLL. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 153.