Phase 3 trial of Venclexta for hard-to-treat myeloma misses main goal

But more patients seen to respond to treatment than Pomalyst combo

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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People with hard-to-treat multiple myeloma given a regimen of Venclexta (venetoclax) plus dexamethasone lived longer than those treated with Pomalyst (pomalidomide) plus the corticosteroid, according to data from a Phase 3 clinical trial.

Results from the trial, dubbed CANOVA (NCT03539744), also showed that the Venclexta combo was associated with a significantly higher proportion of patients responding to treatment.

However, the study failed to hit its main goal, as rates of progression-free survival — the time patients lived without signs of cancer progression — were not significantly different between the two treatment regimen groups.

“While the CANOVA trial did not meet its primary [goal], given the potential favorable trends seen in the study, we will discuss these data with health authorities in the near future,” Mariana Cota Stirner, MD, PhD, therapeutic area head oncology hematology at AbbVie, said in a company press release. AbbVie is the therapy’s developer in partnership with Roche’s subsidiary Genentech.

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Testing Venclexta vs. Pomalyst combos for multiple myeloma

Venclexta, sold as Venclyxto in Europe, is an oral treatment that works by blocking the activity of BCL-2, a protein that certain cancer cells use to survive when they otherwise might die.

The therapy is approved in the U.S. for some types of blood cancers, like chronic lymphocytic leukemia and acute myeloid leukemia, but it has not been authorized for use in multiple myeloma. It is jointly commercialized by AbbVie and Genentech in the U.S. and by AbbVie outside the U.S.

The Phase 3 CANOVA trial, launched in 2018, enrolled 263 adults with relapsing or refractory multiple myeloma carrying a common myeloma-causing genetic abnormality. That abnormality, called t(11;14), can indicate an overproduction of BCL-2.

All of the patients had received at least two prior lines of treatment, to which their cancer either did not respond or responded initially, but then relapsed.

In the trial, each was randomly assigned to receive either Venclexta plus the steroid dexamethasone — the VenDex combo — or the approved multiple myeloma treatment Pomalyst plus dexamethasone, dubbed the PomDex combo.

The U.S. Food and Drug Administration put CANOVA and all other Venclexta trials on a partial hold in March 2019. That was done over concerns that the medication could increase the risk of death for some patients, but not those with t(11;14).

The clinical hold on CANOVA was lifted a few months later, after an agreement was reached to revise the trial’s protocol. The revised protocol included new risk mitigation strategies.

The main goal of the study was to compare the effect of the two treatment regimens on progression-free survival, as assessed by an independent review committee.

The results showed that the median progression-free survival time for VenDex-treated patients was longer than that seen for those given the PomDex combo — 9.9 versus 5.8 months.

That difference failed to reach statistical significance, however. That means it is mathematically plausible that it may be due to random chance, and not the effect of the medications. That outcome meant that the trial failed to meet its primary goal.

However, when assessed by the trial’s investigator, median progression-free survival was 9.1 months in the VenDex group and 4.9 months in the PomDex, and this difference nearly reached statistical significance.

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Gains seen in survival time, but not enough to reach goal

Still, the VenDex combo did outperform the PomDex combo on some secondary trial measures.

Nearly two-thirds (62%) of patients treated with VenDex experienced a treatment response — specifically, a reduction in cancer burden — compared with about one-third (35%) of those given PomDex. That difference was statistically significant, researchers noted.

Also, the proportion of patients with a “very good” or better response also was significantly higher in the VenDex group (39% vs. 14%).

The overall median survival time also was longer, by more than half a year, in VenDex-treated patients relative to those on PomDex. However that result, of 32.4 months versus 24.5 months, failed to reach statistical significance.

Exploratory measures showed that the VenDex combo significantly delayed the need for a new treatment, with the median time to starting a next therapy of nearly two years (21.2 months). That compared with less than one year (8.3 months) in the PomDex group.

The safety profile of the VenDex combo was similar to what’s been reported with each individual therapy in previous studies, without reports of new safety concerns. Common side effects in the VenDex group included infection (61%), diarrhea (41%), low counts of certain immune cells (24%), and nausea (22%).

AbbVie will review the overall trial findings with regulators.

“We remain committed to elevating the standard of care for blood cancer patients around the world including patients with multiple myeloma,” Stirner said.