Ibrutinib plus venetoclax yields survival gains in relapsed/refractory mantle cell lymphoma

In the treatment of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), taking ibrutinib and venetoclax together prolongs survival without disease progression, according to the phase III Sympatico study.

Interim analysis showed that over median follow-up of 51.2 months, investigator-assessed median progression-free survival (PFS) was 31.9 months among patients who received ibrutinib plus venetoclax versus 22.1 months among those who received ibrutinib plus placebo. PFS rates at 24 months were 57 percent and 45 percent, respectively. [ASH 2023, abstract LBA-2]

Ibrutinib plus venetoclax reduced the risk of progression or death by 35 percent (hazard ratio [HR], 0.65, 95 percent confidence interval [CI], 0.47–0.88; p=0.0052).

The PFS benefit with the combination remained consistent across prespecified patient subgroups, including those with the more aggressive blastoid MCL variant or TP53-mutated MCL, reported lead study investigator Dr Michael Wang of the University of Texas MD Anderson Cancer Center in Houston, Texas, US.

Wang also shared that the effect of ibrutinib plus venetoclax on PFS held strong even when tested under different conditions in sensitivity analyses.

Aside from PFS, complete response rates were better in the combination group than in the placebo group (54 percent vs 32 percent), as was time to next treatment (TTNT; not reached vs 35.4 months).

Results for overall survival (OS) also favoured ibrutinib plus venetoclax (median, 44.9 vs 38.6 months), although the between-group difference was not statistically significant (HR, 0.85, 95 percent CI, 0.62–1.19).

No unexpected safety findings

“The safety profile of ibrutinib plus venetoclax was consistent with known adverse events (AEs) for each agent, with no new safety signals observed,” Wang noted.

The most common AEs documented with the combination vs ibrutinib plus placebo were neutropenia (31 percent vs 11 percent), pneumonia (13 percent vs 11 percent), thrombocytopenia (13 percent vs 8 percent), anaemia (10 percent vs 3 percent), diarrhoea (8 percent vs 2 percent), leukopenia (7 percent vs 0 percent), MCL (7 percent vs 12 percent), atrial fibrillation (5 percent vs 5 percent), COVID-19 (5 percent vs 1 percent), and hypertension (4 percent vs 9 percent).

Grade ≥3 AEs occurred in 84 percent of patients treated with the combination and in 76 percent of those who received ibrutinib plus placebo, whereas serious AEs occurred in around 60 percent of patients in each treatment group.

There were no cases of clinical tumour lysis syndrome, according to Wang, although 5 percent of patients on ibrutinib plus venetoclax and 2 percent of those on ibrutinib plus placebo had laboratory tumour lysis syndrome. Finally, 10 patients in each treatment group died due to COVID-19, which Wang stated had no meaningful impact on PFS or OS estimates.

Favourable risk-to-benefit ratio

Overall, the findings demonstrate a favourable benefit-risk profile for ibrutinib plus venetoclax in patients with R/R MCL, according to Wang.

“Ibrutinib is a once-daily Bruton tyrosine kinase inhibitor approved in multiple regions for patients with MCL who have received ≥1 prior therapy. Venetoclax [on the other hand] is a BCL-2 inhibitor approved in the US for patients with chronic lymphocytic leukaemia and previously untreated acute myeloid leukaemia,” Wang said.

He noted that the drugs have distinct and complementary modes of action, and evidence of the promising clinical activity of the ibrutinib–venetoclax combination in MCL was already seen in early phase studies. [N Engl J Med 2018;378:1211-1223; J Hematol Oncol 2021;14:195]

Study details

The interim analysis included 267 adult R/R MCL patients (median age 68 years) who had undergone 1-5 lines of therapies. Most of these patients (96 percent) had an ECOG performance score of 0–1, 17 percent had received at least 3 prior lines of therapy, and 22 percent were at high risk of tumour lysis syndrome.

Of the patients, 134 received ibrutinib plus venetoclax and 133 received ibrutinib plus placebo. Ibrutinib was given at 560 mg and had to be taken orally once daily. This drug was administered concurrently with venetoclax (standard 5-week ramp-up to a target dose of 400 mg once daily) or placebo for 2 years, followed by single-agent ibrutinib until progressive disease (PD) or unacceptable toxicity. Patient characteristics at baseline were generally similar between the two treatment groups.

Median duration of treatment was 22.2 months in the combination group and 17.7 months in the placebo group. At the time of analysis, 30 percent of patients in the combination group and 20 percent of patients in the ibrutinib plus placebo group remained on single-agent ibrutinib.