The combination of ibrutinib, obinutuzumab, and venetoclax was well tolerated and offered a promising response rate in a phase I/II trial of relapsed and untreated mantle cell lymphoma (MCL) patients.
The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib is already used to treat relapsed or refractory MCL in Australia and elsewhere. Resistance often develops, however, as is also the case with single-agent venetoclax. There is preclinical evidence that the combination of the three agents may counter some of the resistance.
The new OAsis study first enrolled patients with relapsed MCL treated with ibrutinib and obinutuzumab, and then included extension cohorts with both relapsed and untreated patients who also received venetoclax. In total it included 48 patients, and the results were published in Blood.
No dose-limiting toxicities were observed in the study, and a venetoclax dose of 400 mg per day was chosen for the extension portion of the trial. The therapy was generally well tolerated, with thrombocytopenia and neutropenia seen as the most common grade 3 or 4 adverse events; this was only reported in relapsed patients.
After six cycles of treatment, the complete response rate was 67% in patients with relapsed MCL, and 86.6% in untreated patients.
Clearance of minimal residual disease (MRD) was seen in 71.5% of the relapsed group, and in 100% of untreated patients, after three cycles of therapy.
At two years the progression-free survival rate in patients with relapsed MCL was 69.5%, and the overall survival rate was 68.6%. In the patients with untreated disease, the two-year PFS rate was 93.3%.
Though cross-trial comparison is difficult and the numbers remain small, the authors, which included senior author Prof Simon Rule of the University of Plymouth, UK, noted that the combination of ibrutinib and venetoclax alone has shown an MRD clearance rate of only 15%, compared to 71.5% with the triple combination.
The triple combination, they wrote, “provides an early and high percentage of MRD negativity with CR and sustained clinical and molecular responses in both relapsed and untreated patients.” The results “strongly support” further development of the combination.
In an accompanying editorial, Dr Kami Maddocks, of the Ohio State University, noted that other research has positioned ibrutinib as a strong second-line treatment option in MCL, but development of resistance has remained a problem.
She highlighted that the new results show the triple combination was effective even in subsets of high-risk patients such as those with TP53-mutated disease.
“Nonchemotherapeutic frontline regimens are likely the future in MCL with the potential to be highly active and reasonably well tolerated,” she wrote. “The rate of clinical and molecular remissions in… treatment-naive patients, along with the improved toxicity profile compared with the relapsed cohort, warrant this triplet to be prioritized for further study, particularly in those with high-risk disease features.”
Dr Maddocks has received research funding from several pharmaceutical companies including Pharmacyclics, which markets ibrutinib along with Janssen. Prof Rule and other study authors have received research funding, grants, and other fees from various companies including Janssen; AbbVie, which markets venetoclax; and Roche, which markets obinutuzumab.