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SAN DIEGO -- Patients with relapsed/refractory mantle cell lymphoma (MCL) lived significantly longer without disease progression with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta), according to a randomized trial reported here.

Median progression-free survival (PFS) increased from 22.1 months with ibrutinib alone to 31.9 months with the combination. The results favored combination therapy across all prespecified patient subgroups. Time to next therapy, complete response rate, and duration of response all increased significantly with the addition of venetoclax to ibrutinib. A preliminary analysis of overall survival (OS) showed a trend favoring the combination (44.9 vs 38.6 months) but not a statistically significant advantage.

The combination's safety was consistent with the known adverse-event profiles of the two drugs, said Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, during the American Society of Hematology (ASH) meeting.

"Overall, the addition of venetoclax to ibrutinib had a favorable benefit-risk ratio in patients with relapsed/refractory mantle cell lymphoma," said Wang. "In my personal opinion, in the countries where ibrutinib is indicated to treat mantle cell lymphoma, this combination is a new standard of care for relapsed/refractory mantle cell lymphoma."

His wording of the conclusion likely alluded to ibrutinib distributor AbbVie's decision earlier this year to of the Bruton's tyrosine kinase inhibitor for MCL. AbbVie did not respond to a 番茄社区app request for comment on the study and its possible impact on the withdrawal decision.

During a discussion after Wang's presentation, a member of the audience asked how the results compare with those of .

After cautioning the questioner about cross-trial comparisons, Wang said: "They were similar in efficacy and safety. Certainly, it's a good tolerability profile [with ibrutinib-venetoclax], and it should be the new standard."

Another unidentified questioner asked about the regimen's tolerability across different age groups, noting differences by age in chronic lymphocytic leukemia (CLL) patients treated with ibrutinib.

"We plan to do some analyses when we are ready to publish the manuscript, and if you wait for the manuscript to come out, I think you will be satisfied," said Wang.

During an ASH press briefing prior to his presentation, Wang was asked whether the lack of a significant OS benefit at this point tempered his enthusiasm for the combination.

"This is an ongoing study," said Wang. "For the current OS analysis we had 144 events. We need 170 events in order to increase the [statistical] power. That should probably occur sometime in 2025."

Several lines of evidence supported evaluating the combination of ibrutinib and venetoclax in MCL. Single-agent ibrutinib has shown activity in MCL and has approved indications in multiple countries outside the U.S., Wang noted in the introduction to the results. The BCL-2 inhibitor venetoclax has approval in multiple countries as single-agent therapy for CLL and untreated acute myelogenous leukemia.

Ibrutinib plus chemoimmunotherapy significantly improved PFS in the randomized phase III trial involving patients with newly diagnosed MCL, but the combination was associated with more adverse events. However, the similarly designed phase III trial in relapsed/refractory marginal zone lymphoma failed to meet the primary endpoint of PFS. Both studies were cited in the AbbVie announcement of its decision to withdraw FDA accelerated approval for the two indications.

The ibrutinib-venetoclax combination leverages complementary modes of action, and synergistic antitumor activity has been demonstrated in preclinical models of MCL, said Wang. Preliminary clinical studies in patients with relapsed/refractory MCL produced promising clinical activity, leading to the randomized phase III study.

The trial involved 267 adults who had received at least one, and as many as five, prior lines of therapy for MCL. Prior treatment had to include at least one rituximab (Rituxan)/anti-CD20-containing regimen. Patients were randomized to ibrutinib plus either venetoclax or placebo and treated for up to 24 months, followed by single-agent ibrutinib until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS.

The study population had a median age of about 68, and 60% of the patients had received one prior line of therapy. Most patients had typical histology, and about 85% of the patients were intermediate or high risk. Wang said 45-50% of patients had wild-type TP53, and 40-45% had bulky disease.

The primary analysis showed that the addition of venetoclax to ibrutinib reduced the hazard for disease progression or death by 35% (HR 0.65, 95% CI 0.47-0.88, P=0.0052). PFS assessment by independent review showed a 33% reduction in the hazard ratio.

The median time to next treatment was 35.4 months in the placebo arm versus not yet reached in the venetoclax group (P=0.0096). The overall response rate favored venetoclax (82% vs 74%) but did not achieve statistical significance. The complete response rate was significantly higher with venetoclax (54% vs 32%, P=0.0004). Median duration of response was 42.1 months with ibrutinib-venetoclax and 27.6 months with ibrutinib-placebo.

Grade ≥3 adverse events (AEs), serious AEs, and AEs leading to discontinuation were similar between the two groups. Any-grade AEs that occurred more often with the addition of venetoclax included diarrhea (65% vs 34%), neutropenia (34% vs 14%), nausea (31% vs 17%), and anemia (22% vs 12%). The only grade ≥3 AE that occurred more often with venetoclax was neutropenia (31% vs 11%).

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