Addition of Obinutuzumab and Venetoclax to Ibrutinib Overcomes Resistance in R/R MCL, Shows Activity in Newly Diagnosed MCL

Steven Le Gouill, MD, PhD

In relapsed and untreated patients with mantle cell lymphoma (MCL), the combination of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta) achieved molecular response rates and was found to be well tolerated, results from the phase 1/2 OAsIs trial (NCT02558816) demonstrate.

Traditionally, the newly diagnosed MCL population is treated with immuno-chemotherapy combined with rituximab (Rituxan) maintenance, but eventually, the duration of response in these patients declines, and patients relapse. In the relapsed setting of MCL, the FDA-approved Bruton’s tyrosine kinase (BTK) inhibitor for this population is ibrutinib, which alone has been shown to achieve an objective response rate (ORR) of 68%, a 2-year progression-free survival (PFS) rate of 31%, and 2-year overall survival (OS) rate of 47%. The issue is that patients can develop resistance to ibrutinib, and the mechanisms of resistance can include BTK mutations, activation of the alterative NF-κB, and others.

Based on earlier research, Steven Le Gouill, MD, PhD, of Nantes University Hospital and INSERM, and fellow investigators believed that by adding a BCL-2 inhibitor like venetoclax to ibrutinib, as well as a glycoengineered humanized anti-CD20 antibody like obinutuzumab, the mechanisms of resistance to ibrutinib would be addressed.

In the OAsIs study, 48 patients were enrolled and evaluated for the primary end point of safety, as defined by unacceptable toxicity observed with the triplet regimen. The secondary end points included ORR, time to progression, OS, and safety determined by the incidence of adverse events (AEs) and incidence and severity of tumor lysis syndrome.

Patients in the study were divided into 3 cohorts. In cohort A, 9 patients were treated with fixed doses of ibrutinib 560 mg/day and obinutuzumab 1 g given intravenously to determine the safety of the combination. In cohort B, Le Gouill et al assessed the maximum tolerated dose of ibrutinib when used in the triplet combination. Thus, the cohort B dose of ibrutinib escalated from 400 mg/day to 800 mg/day. Finally, in cohort C, patients received the same dosing as cohort B, but with a fixed dose of venetoclax determined by the data and safety monitoring committee (DSMC). In cohort A and B, patients were respectively relapsed and relapsed/refractory. Cohort C was comprised of newly diagnosed patients.

Of the 48 patients in the study, the notable baseline characteristics showed that 12 patients had a high Mantle Cell Lymphoma International Prognostic Index (MIPI) score. Of the 37 patients test for TP53 alterations, 4 patients were found to have bi-allelic alterations. Also, of the 35 patients assessed for IGHV mutation status, the mutation was found in 25 patients.

Dose-limiting toxicities (DLTs) in the study were evaluated during cycle 1 for cohort A and during cycle 2 for cohorts B and C. In the 9 patients treated with obinutuzumab plus ibrutinib plus venetoclax, no DLTs were observed in the first 6 patients with venetoclax given at up to 600 mg/day. However, once the dose of venetoclax was escalated to 800 mg/day and combined with obinutuzumab plus ibrutinib, grade 3 neutropenia was observed. Three additional patients were assessed for DLTs following a recommendation from the DSMC, and there were no additional DLTs observed.

Overall, grade 1/2 AEs occurred in more than 20% of each patient cohort. For cohorts A and B, the most common AEs of any grade were thrombocytopenia (89% and 46%, respectively) and musculoskeletal pain (67% and 42%). In cohort C, the most common any-grade AEs were diarrhea and musculoskeletal pain. Regarding tumor lysis syndrome, there was 1 grade 3 and 1 grade 2 event observed.

Treatment was stopped for 3 patients during the analysis due to AEs of thrombocytopenia and neutropenia experienced during cycle 6. A patient from cohort C also discontinued treatment during cycle 9 due to acute peripheral neuropathy. Notably, the patient who stopped therapy due to acute peripheral neuropathy did achieve a complete response (CR) to the triplet during cycle 6, which continued for at least 6 months after treatment ended.

Further, based on Cheson or Lugano criteria, 7 out of 9 patients achieved a CR on treatment with obinutuzumab combined with ibrutinib and venetoclax. A total of 6 patients completed all 24 cycles of the triplet therapy. CRs were seen in subgroups including in 1 patient each with TP53 wild-type disease and who underwent allograft. In addition, 2 patients with blastoid variant achieved a CR at the end of cycle 6.

Patients with MCL were followed for survival for a median of 45 months (range, 39-49). The 1- and 2-year PFS and OS rates observed were 89% (95% CI, 70.6%-100.0%) in cohort A. The PFS rate at 1 year in cohort B was PFS was 74.5% (95% CI, 58.8%-94.5%) with a median follow-up of 17 months (range, 10-35). The 1-year OS rate was 87.5% (95% CI, 75.2%-100%). Finally, in the untreated cohort C, patients were followed for a median of 14 months (range, 5-19), and the 1-year OS and PFS rates were 100% and 93.3% (95% CI, 81.5%-100%), respectively. The median duration of response was not yet reached.

Assessments of minimal residual disease (MRD) and presence of TP53 alteration were carried out during the study. With the triplet regiment, Gouill et al stated that “it provides an early and high percentage of MRD negativity with complete remission and sustained clinical and molecular responses in both relapsed and untreated patients. Known high-risk features such as TP53 alteration appear not to impact on the efficacy but numbers are small. OAsIs strongly supports further clinical investigations of the combination of obinutuzumab, venetoclax and ibrutinib, for untreated MCL patients.”

Reference:

Gouill SL, Morschhauser F, Chiron D, et al. Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Blood. 2021;137(7):877-887. doi:10.1182/blood.20200087