Promising results of combination therapy with ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma

The phase III SYMPATICO study is evaluating the efficacy and tolerability of ibrutinib plus venetoclax, compared with ibrutinib plus placebo, in patients with relapsed or refractory mantle cell lymphoma (R/R MCL). Ibrutinib plus venetoclax resulted in a statistically significant improvement in progression-free survival, complete response rates and time to next treatment, with no new safety signals observed.

Ibrutinib and venetoclax have distinct and complementary modes of action, and the combination has shown promising clinical activity in early phase studies in mantle cell lymphoma (MCL). At ASH 2023, the primary analysis results from the multinational, randomised, double-blind, phase III SYMPATICO study, comparing ibrutinib plus venetoclax vs. ibrutinib plus placebo in patients with relapsed/refractory (R/R) MCL were presented.

Study design

Patients ≥18 years with relapsed or refractory mantle cell lymphoma who received 1-5 previous therapies were randomised 1:1 to ibrutinib (560 mg once daily) and venetoclax (5-week ramp-up to the target dose of 400 mg once daily) or ibrutinib and placebo for 2 years. Patients subsequently received ibrutinib monotherapy (560 mg once daily) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) by investigator assessment using the Lugano criteria. Additional sensitivity analyses included PFS assessment by independent review committee (IRC) and censoring per US FDA rules. Key secondary endpoints were tested hierarchically in the following order: the percentage of patients who achieved a complete response (CR) based on investigator assessment, time to next therapy, overall survival (OS) and the percentage of patients who responded (ORR) based on assessment by the investigators.

Results

A total of 267 patients were included in the study, 134 in the ibrutinib plus venetoclax arm and 133 in the ibrutinib and placebo arm. Median age of the patients was 68 years, 96% had an ECOG performance status of 0 or 1, 17% received ≥3 prior therapies and 22% were at an increased risk for tumour lysis syndrome [TLS]). At baseline, patients in the ibrutinib plus venetoclax vs. ibrutinib plus placebo arms had median ages 69 vs. 67 years, high-risk simplified MCL International Prognostic Index score 38% vs. 31%, bulky disease ≥5 cm 46% vs. 40%, bone marrow involvement 46% vs. 41%, splenomegaly 31% vs. 25%, and TP53 mutated 30% vs. 28%. Other baseline characteristics were generally similar between arms. After a median follow-up of 51.2 months, treatment with ibrutinib and venetoclax resulted in longer investigator-assessed PFS compared with ibrutinib and placebo (median 31.9 vs. 22.1 months; HR[95%CI]: 0.65[0.47-0.88], p= 0.0052). PFS rates at 24 months were 57% and 45% with ibrutinib plus venetoclax and ibrutinib plus placebo, respectively. PFS benefit with ibrutinib plus venetoclax versus ibrutinib plus placebo was generally consistent across prespecified subgroups, including those with blastoid variant or TP53-mutated MCL. Sensitivity analyses of PFS data showed similar results. A statistically significant difference was found in CR rate (54% vs. 32%; p= 0.0004) and time to next therapy (median not reached vs. 35.4 months; p= 0.0096). Furthermore, ORR (82% vs. 74%; p= 0.1279) and the median duration of response (42.1 months vs. 27.6 months) were also in favour of treatment with ibrutinib and venetoclax. OS was numerically improved at this interim analysis (median 44.9 vs. 38.6 months; HR[95% CI]: 0.85[0.62-1.19]).

Adverse events (AEs) of grade 3 or higher occurred in 84% of patients in the venetoclax group and 76% of patients in the placebo group. The most common AEs of grade 3 or higher were neutropenia (31% vs. 11%), pneumonia (13% vs. 11%), thrombocytopenia (13% vs. 8%), anaemia (10% vs. 3%), and diarrhoea (8% vs. 2%). Serious AEs occurred in 60% of patients in each group. TLS-specific laboratory abnormalities occurred in 5% and 2% of patients in the venetoclax and placebo groups, respectively, but none of the patients developed clinical TLS.

Conclusion

Primary data from the phase III SYMPATICO study show that combination therapy with ibrutinib and venetoclax compared to ibrutinib and placebo leads to better PFS, higher CR rate and longer time to next therapy in patients with relapsed or refractory mantle cell lymphoma who have previously received 1-5 therapies. The interim analysis of OS data showed a numerical, but not statistically significant difference between both groups. The safety profile of ibrutinib plus venetoclax was consistent with known AEs for each agent and no new safety signals were observed.

Reference

Wang M, et al. Ibrutinib combined with venetoclax in patients with relapsed/refractory mantle cell lymphoma: primary analysis results from the randomized phase 3 SYMPATICO Study. Presented at ASH 2023; Abstract LBA-2.