Zanubrutinib Triplet Shows Early Promise in Treatment-Naive TP53-Mutant MCL

Anita Kumar, MD

The combination comprised of zanubrutinib (Brukinsa), obinutuzumab (Gazyva), and venetoclax (Venclexta), also referred to as BOVen, elicited high response rates and 2-year progression-free survival (PFS) rates that compared favorably with historical outcomes achieved with chemoimmunotherapy in high-risk patients with previously untreated mantle cell lymphoma (MCL) harboring TP53 mutations, according to data from a phase 2 trial (NCT03824483) presented at the 2023 ASH Annual Meeting.¹

“This is the first dedicated study with reported outcomes specifically for TP53-mutant mantle cell lymphoma, demonstrating that clinical trials are feasible in this high-risk cohort,” Anita Kumar, MD, lymphoma service, Department of Medicine, Memorial Sloan Kettering Cancer Center, said during a presentation of the data. “We found the BOVen treatment to be well tolerated, administered in the outpatient context, and associated with high response rates.”

After a median follow-up of 23.3 months, the study met its primary end point of PFS. The 2-year PFS rate was 72% (95% CI, 56%-92%), and median PFS was not reached as 11 patients were progression-free at 2 years.

“Of note, the 2-year PFS in the pooled NORDIC analysis2 [of 20 patients] was 20%, and the 2-year PFS in the SHINE study3 … in which patients received bendamustine and rituximab [Rituxan] in conjunction with ibrutinib [Imbruvica] was approximately 55%. Therefore, BOVen emerges as a promising treatment option for TP53-mutant mantle cell lymphoma,” Kumar said.

Additional Efficacy, Safety

Further, 2-year overall survival was 75% (95% CI, 58%-93%), and the median was also not reached.1 Two-year disease-free survival (DFS) was 88% (95% CI, 76%-100%), and the median was not reached. Kumar acknowledged that the DFS was superior to PFS likely as a result of the COVID-19 deaths that were reported as the trial was conducted during the pandemic.

Further, she added that while the trial’s analyses were limited by the small number of patients, there was no significant association with baseline factors in DFS, including morphology, Ki-67, age, and TP53 mutation or deletion.

After 2 cycles of zanubrutinib and obinutuzumab, 68% of patients induced a complete metabolic response and 8% had a partial metabolic response. This response rate was sustained, with an overall response rate of 96%: an 88% complete metabolic response rate and an 8% partial metabolic response rate.

There were 5 patients who experience disease progression and 4 deaths (2 COVID-related, 1 unknown, and 1 respiratory failure). Kumar noted that the 4 deaths occurred in patients who were in ongoing response at the time of their death.

At the cycle 24 minimal residual disease (MRD) assessment, 11 patients had completed all 24 cycles—all of which had a complete response (CR) to the BOVen triplet. There was 1 patient who did not have MRD results, and as a result, are continuing treatment with zanubrutinib and venetoclax. Eight of the remaining 10 patients with MRD results stopped the BOVen triplet therapy, including 6 with MRD at a sensitivity level of 10-6 and 2 with MRD at a sensitivity level of 10-5.

“One of these patients subsequently had detectable MRD at 2 time points and restarted zanubrutinib and venetoclax. Another patient clinically relapsed before their 3-month follow-up and also restarted zanubrutinib and venetoclax. Two patients had detectable MRD status and continued on zanubrutinib and venetoclax and 1 of these patients subsequently clinically relapsed,” Kumar added.

She noted that the BOVen regimen appeared to be well tolerated and safe, with the most common adverse events (AEs) being diarrhea (60%), which was mostly grade 1 (48%) and manageable; COVID-19 infection (48%); neutropenia (32%), of which grade 3 events (16%) were resolved with growth-factor support; and infusion-related reactions (24%).

Grade 3 or higher AEs were seen in 12 patients (48%), while serious AEs occurred in 12 patients (48%), including 5 patients (20%) with grade 5 COVID-19 infection.

The investigators focused their attention on those at risk for tumor lysis syndrome (TLS), which included just 3 patients at cycle 3, requiring initial ramp-up with venetoclax to be done in the inpatient setting. Kumar highlighted that there were no significant TLS events during venetoclax ramp-up, and just 1 grade 4 TLS event occurred after the initial dose of obinutuzumab in a patient who had evidence of spontaneous tumor lysis pretreatment, renal dysfunction, and a high tumor burden.

Unmet Need in MCL

Kumar noted that TP53-mutant MCL tends to be associated with poor survival outcomes.

“In a pooled analysis from the NORDIC MCL-2 and MCL-3 series, despite receipt of optimal intensive…induction [therapy], followed by consolidative autologous stem cell transplant, patients with a P53 mutation suffered dismal outcomes, with a median progression-free survival of 0.9 years and a median overall survival of 1.9 years,” she said, adding that there are currently no standard frontline treatment high-risk patient population, representing an area of unmet need.

With previous demonstration of synergy and activity from dual BTK and BCL2 inhibition, the investigators aimed to determine if the BOVen regimen would be well tolerated and efficacious in treatment-naive TP53-positive patients. In the multicenter, investigator-initiated trial, 25 patients received 160 mg zanubrutinib orally twice daily plus 1000 mg obinutuzumab on dayss 1, 8, and 15 in cycle 1 and then on day 1 of cycles 2 through 8, followed by 400 mg venetoclax orally daily initiated on cycle 3, day 1. Patients were treated for a minimum of 24 cycles. After 24 cycles, the investigators utilized an MRD-driven approach to limit treatments in selected patients: patients who achieved a CR and undetectable MRD status (10-6) could stop therapy, while patients who experienced less than a CR and or had detectable MRD status continued on zanubrutinib and venetoclax.

Key eligibility criteria included those with previously untreated MCL who had a TP53 mutation, an ECOG performance status score of 2 or less, and adequate organ and hematologic function. Two-year PFS served as the primary end point.

“Based on historical data, we found a 2-year PFS rate of greater than or equal to 55% to be promising, and an unacceptable rate to be less than or equal to 30%,” Kumar explained. “Therefore, if 11 or more patients were progression free at 2 years, the treatment regimen would be declared effective.”

Patients were a median age of 68 years (range, 60-73), and the majority were male (76%). Baseline characteristics highlighting high-risk patient features, Kumar said, included 20% with blastic/blastoid pleomorphic histology, 33% with a Ki67 proliferation rate of 50% or more, and 68% with high MIPI classification.

In total, 86% were positive for TP53 and 44% of patients had 17p deletion.

Kumar concluded by noting that the investigators have expanded the study to include an additional 25 patients.

References:

1. Kumar A, Soumerai J, Abramson JS, et al. A Multicenter Phase 2 Trial of Zanubrutinib, Obinutuzumab, and Venetoclax (BOVen) in Patients with Treatment-Naïve, TP53-Mutant Mantle Cell Lymphoma. Blood. 2023;142(Supplement 1):738. doi:10.1182/blood-2023-180069.
2. Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130(17):1903–1910. doi:10.1182/blood-2017-04-779736.
3. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022;386:2482-2494. doi:10.1056/NEJMoa2201817.