AbbVie’s Venclexta Fails In Combo AML Trial
Pfizer’s Daurismo May Benefit From Venclexta’s VIALE-C Setback
Executive Summary
AbbVie’s Venclexta failed to show a significant improvement in the primary endpoint of overall survival in the Phase III VIALE-C for AML, but there was numerical improvement. Its setback is good news for Pfizer’s rival Daurismo, analysts said.
Prospects for AbbVie Inc.’s Venclexta (venetoclax) becoming a fully approved treatment for acute myeloid leukemia (AML) were thrown into doubt when the B-cell lymphoma-2 inhibitor failed to show a significant improvement in the primary endpoint of overall survival (OS) in the ongoing VIALE-C Phase III study, although it did demonstrate numerical improvement.
AbbVie on 28 February said that the VIALE-C trial evaluating Venclexta in combination with low-dose cytarabine (LDAC) versus LDAC in combination with placebo missed the OS primary endpoint of in patients with AML who were ineligible for intensive chemotherapy at the time of the planned analysis.
Treatment with the venetoclax combination showed a 25% reduction in the risk of death compared to LDAC with placebo (Hazard Ratio [HR]=0.75). The venetoclax with LDAC arm at primary analysis also showed a median OS of 7.2 months versus 4.1 months in the LDAC arm alone. Analysis after an additional six months of follow up showed an increase in median OS of 8.4 months in the venetoclax plus LDAC arm and 4.1 months in the placebo plus LDAC arm (HR=0.70), the company said.
Full results will be published in a peer-reviewed journal and presented at an upcoming medical meeting.
Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech Inc. in the US and by AbbVie outside of the US.
The product was first approved for use in chronic lymphocytic leukemia (CLL ) patients who have 17p deletion and who have been treated with at least one prior therapy in 2016 and later won expanded approvals including in May 2019, as a chemotherapy-free combination regimen for previously untreated CLL patients; it is set to do likewise in Europe. (Also see "New CLL Treatment Paradigm Nears In EU For AbbVie " - Pink Sheet, 5 Feb, 2020.)
In November 2018, it was granted accelerated approval by the US Food and Drug Administration in combination with azacitidine, decitabine, or LDAC for the treatment of newly diagnosed AML in adults who are age 75 years or older, or who have co-morbidities that preclude use of intensive induction chemotherapy based on Phase I/II studies.
The hypomethylating agents decitabine (DAC) and azacitidine (AZA) have long been a mainstay of myeloid therapies, but with minimal success.
Recently, the B-cell lymphoma 2 (BCL-2) protein was shown to play an important role in the survival of leukemia blasts as a key regulator of cell death in AML. Venetoclax, a potent selective oral inhibitor of BCL-2, has previously demonstrated single-agent clinical activity in refractory AML, one of the most aggressive and difficult-to-treat blood cancers, with a very low survival rate and few treatment options.
The VIALE-C combination setback is therefore a disappointment for AML patients and the drug’s promoters. “With the overall survival primary endpoint missed, these are disappointing results for a confirmatory Phase III trial of Venclexta combined with low-dose cytarabine (LDAC),” said Datamonitor Healthcare analyst David Dahan.
“But while disappointing, this blow is softened by the fact that there is still one other ongoing confirmatory Phase III trial, Viale-A, evaluating Venclexta combined with the hypomethylating agent azacytidine,” Dahan noted.
Roche has indicated that a read-out from the Viale-A trial is expected in 2020. While LDAC is used in the EU, it is rarely used in the US and so this latter trial will be more important for the US market. Venclexta is not yet approved in the EU and any submissions will have to await results from Viale-A.
Dahan noted that the Viale-C data showed signs of clinical activity for the Venclexta/cytarabine combination.
“While the primary endpoint of median overall survival failed to reach statistical significance, there was numerical improvement. Interestingly, a post hoc analysis after an additional six months of follow-up showed an increase in overall survival that just managed to cross the threshold for statistical significance as determined by the 95% confidence interval which ranged from 0.50-0.99. This suggests that with an improved trial design, Viale-C may have been successful,” Dahan said.
This failure of Viale-C should improve the outlook for Pfizer Inc.’s hedgehog pathway inhibitor Daurismo (glasdegib) which is approved in the US in the same setting and for which regulatory filings were submitted to the European Medicines Agency in May 2019. (Also see "More Good News For AML As Pfizer And AbbVie/Roche Drugs Get FDA Okay" - Scrip, 22 Nov, 2018.)
In its pivotal trial, BRIGHT 1003, Daurismo plus LDAC succeeded where Venclexta failed. BRIGHT 1003 reported significantly improved overall survival for the Daursimo combination compared with LDAC alone (8.3 months versus 4.3 months; HR 0.46).
“Daurismo may now be favored for the small fraction of patients in the US set to receive LDAC. This advantage may be bigger if Daurismo is also approved in the EU,” Dahan said.
“As we await results from Viale-A, results from Viale-C serve as a reminder that improvements in response rate don't always lead to improvements in overall survival. While there has been a lot of excitement over the approval of Venclexta for AML, results from randomized trials are needed to establish efficacy,” Dahan added.
AbbVie in a statement said Venclexta’s “continued approval for this indication may be contingent upon verification and description of clinical benefit in an ongoing trial.”
“AbbVie has provided the results from VIALE-C to the FDA and other global health authorities and will continue to work with them to ensure that venetoclax remains an appropriately managed option for patients with AML,” the company said.