BTKi-Containing Triplet Active in Relapsed/Untreated Mantle Cell Lymphoma

Results from the study were published in Blood and showed that obinutuzumab plus ibrutinib and venetoclax as treatment of patients with relapsed and untreated mantle cell lymphoma achieved high response rates with favorable tolerability.

Disease relapse is an imminent occurrence among patients with treatment-naïve mantle cell lymphoma (MCL) for whom the standard treatment option is chemoimmunotherapy combined with rituximab (Rituxan) maintenance. This population of patients also experiences a decreasing duration of response (DOR) as they continue on to salvage therapy.

The FDA-approved first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (Imbruvica), has historically demonstrated an overall response rate (ORR) of 68% in patients with relapsed MCL. The efficacy of a Bcl-2 inhibitor venetoclax (Venclexta) has also shown promise for this patient population. Finally, the type 2 glycoengineered humanized anti-CD20 antibody, obinutuzumab (Gazyva) demonstrated promise for addressing relapse on venetoclax. Based on the prior research around these 3 drugs, it was hypothesized that ibrutinib could induce higher response rates while venetoclax and obinutuzumab work together to prevent further relapse in patients. The hypothesis was analyzed in the phase 1/2 OAsIs clinical trial (NCT02558816).

Results from the study were published in Blood and showed that obinutuzumab plus ibrutinib and venetoclax as treatment of patients with relapsed and untreated MCL achieved high response rates with favorable tolerability.

The prospective, open-label, multi-center study was carried out in 5 centers in the France and the United Kingdom. A total of 48 patients with relapsed or refractory MCL were enrolled and divided into cohorts in order to evaluate the efficacy and safety of obinutuzumab combined ibrutinib, a combination never before explored in MCL, as well as the addition of venetoclax to obinutuzumab/ibrutinib. Cohort A was compiled of 9 patients with relapsed disease who were treated with ibrutinib plus obinutuzumab, and in cohort B, the same subgroup received the triplet combination. Cohort C included untreated patients with MCL who were given the triplet combination.

Treatment with ibrutinib was administered at a dose level of 560 mg/d for a minimum of 2 year of until disease progression. Obinutuzumab was given intravenously at 1g every 2 months until cycle 23. Venetoclax was administered to patients at pre-determined doses of 400mg/d, 600mg/d, and 800mg/d. The primary end point was safety defined by unacceptable toxicity at various dose levels. The key secondary end points were response, time to progression, overall survival (OS), and safety defined by the incidence of adverse events (AEs) and serious AEs.

The patients enrolled in cohort A has a median age of 64 years (58 -82) and were predominantly male (67%). Median ages were similar in cohort B and C at 66 years (range, 45-76) and 65 years (range, 51-77), respectively. In cohort B, the majority of patients were male (79%), but in cohort C, the population was predominantly female (60%). Patients in the relapsed cohorts had a median of 1 prior line of therapy which ranged from 1 to 4 in the cohort A and 1 to 3 in cohort B. The median time from the previous line of treatment was 31 months (range, 1-65) for cohort A compared with 24 months (range, 1-172) for cohort B.

The stage of MCL at the time of inclusion in the study was stage II for 11% of cohort A, 12% of cohort B, and none of cohort C. Disease was stage III-IV for 89% of cohort A, 88% of cohort B, and all of cohort C. Bone marrow involvement was observed at baseline in 56% of the patients in cohort A, 415 of cohort B, and 53% of cohort C. The majority of patients included in the study had an intermediate risk MIPI score, including 44% of cohort A, 33% of cohort B, and 73% of cohort C. Most of the patients also had a high-risk MIPIb score including 62% of cohort A, 61% of cohort B, and 55% of cohort C. Fewer patients had a tumor size > 5 cm compared with < 5 cm. ECOG performance status was 0 or 1 for the majority of the study population, although 11% of cohort A and 8% of cohort B had an ECOG performance status of 2 at baseline. A significant proportion of patients in cohorts A and B had blastic disease, and a small proportion of patients in cohort B and C had pleomorphic disease.

Of the cytogenetic and molecular features observed at baseline, IGHV mutated disease identified by next-generation sequencing was the most prominent. Eleven percent of cohort A had IGHV mutations as well as 29% of cohort B and 135 of cohort C. The second-most prominent mutation was TP53 mutations, which were seen in 11% of cohort A, 21% of cohort B, and 13% of cohort C.

Triplet Safe for Use in Relapsed and Untreated MCL

Cohort B was opened after no dose limiting toxicities (DLTs) were observed in cohort A, per the study’s protocol. Of the first 6 patients to receive obinutuzumab plus ibrutinib and venetoclax in cohort B, no DLTs were observed, which set the dose level for the remainder of the trial at 400mg/d. Even after setting the recommended dose of venetoclax, no patients in the study experienced DLTs.

Grade 1/2 AEs were reported in >20 of patients in the study. The most common any-grade AEs for all cohorts were neutropenia, and lymphopenia. Neutropenia of any grade occurred in 56% of cohort A, 38% of cohort B, and 13% of cohort C. Lymphopenia was observed in 22% of cohort A, 12% of cohort B, and 7% of cohort C. Overall grade 3/4 AEs were observed in 89% of the patients in cohort A, 75% of cohort B and 53% ofcohort C. Notably, venetoclax was temporarily discontinued or had a dose reduction in cohort B due to neutropenia.

Responses to Ibrutinib Triplet

Following treatment discontinuation in 3 patients from cohort A, a complete response (CR) was achieved in 1 of out 2 patients who had blastic disease at end of cycle 6. At a median follow-up of 45 months (range, 39 to 49), the progression-free survival (PFS) and OS rate at 1 and 2 years were both 89% (95% CI, 70,6% - 100,0%). The median DOR was not reached in this cohort.

In cohort B, an 84% ORR was observed after patients completed 2 cycles of therapy. Responses included CRs and unconfirmed CRs (Cru) in 9 patients. Then, by the end of cycle 6, 16 patients had a CR/CRu while 4 patients had progressive disease. Patients in cohort B were followed for a median of 17 months (range, 10-35). The results showed a 1-year PFS of 74.5% (95% CI, 58.8- 94.5%) and a 1-year OS of 87.5% (95% CI, 75.2- 100%). The median DOR was not reached in this population.

One patient in cohort C had disease progression at cycle 4 and was not included in the response assessment. The remaining patients were shown to have responded to the triplet regimen and remain disease free while on treatment. Median follow-up in this cohort was 14 months (range 5-19). At 1 year, the OS rate was 100% and the PFS rate was 93.3% (95% CI, 81.5- 100%). The median DOR was not reached.

A notable efficacy finding with the combination of obinutuzumab plus ibrutinib and venetoclax in OAsIs was that response were observed on a molecular level. There were 43 minimal residual disease (MRD)-evaluable patients include 4 from cohort a, 10 from cohort B, and 12 from cohort C. At baseline 81% of patients were MRD-negative while 6 were positive, including 1 patients with a TP53 mutation. After treatment, molecular response rates 66% MRD-negativity in cohort A, 71.4%-MRD negativity in cohort B, and 100% of patient were MRD negative in cohort C. It was noted that IGHV mutations had no association with molecular responses.

Based on the OAsIs findings, investigators led by Steven Le Gouill, MD, PhD, of Centre Hospitalier Universitaire de Nantes concluded that obinutuzumab plus ibrutinib and venetoclax is a highly active regimen in relapsed or untreated MCL. They highlighted that presence of TP53 mutation did not impact response in this study and support the clinical use of the regimen.

Reference:

Le Gouill S, Morschhauser F, Chiron D, et al. Ibrutinib, obinutuzumab and venetoclax in relapsed and untreated patients with mantle-cell lymphoma, a phase I/II trial. Blood. Published online November 12, 2020. doi: 10.1182/blood.2020008727