Jennifer R. Brown, MD, PhD, on Fixed-Duration Acalabrutinib/Venetoclax in Fit Patients With CLL: AMPLIFY Trial

I am presenting the results of the phase III AMPLIFY trial. AMPLIFY is a multicenter, randomized trial for treatment naive fit patients with CLL without 17p deletion or TP53 aberration, and it enrolled over 800 patients, randomizing them between 14 cycles of acalabrutinib venetoclax, 14 cycles of acalabrutinib, venetoclax, obinutuzumab, or six cycles of investigator choice of chemoimmunotherapy with roughly equal numbers given FCR and BR. There was no planned crossover in the study. The dosing regimen starts with acalabrutinib for the first month. Those getting obinutuzumab started in the second month and then venetoclax ramp up happens in the third month and acalabrutinib and venetoclax continued together to the end of 14th cycles. The primary endpoint was progression-free survival for acalabrutinib venetoclax compared to chemoimmunotherapy by IRC. And then the first key secondary endpoint was progression-free survival by IRC for the AVO triple drug regimen compared to chemoimmunotherapy. The patients had a median age of 61 were male predominant, and about 60% had unmutated IGHV. So this is a pretty typical population for a first line fit trial in CLL. The primary endpoint was met with an estimated three year landmark PFS of 76% for AV compared to 66.5% for chemoimmunotherapy. The key secondary endpoint for AVO compared to chemoimmunotherapy was also met with a three-year landmark PFS of 83% compared to 66% for chemoimmunotherapy. Rates of undetectable MRD were highest in the triple drug regimen with about 66% in an ITT analysis and 95% in a valuable patient analysis. Overall survival was also prolonged with AV compared to chemoimmunotherapy in the overall analysis and in a pre-planned analysis censoring for Covid death, overall survival was prolonged with both AV and AVO. Of note, the study was conducted at the height of the pandemic, and so there were 10 covid deaths on the AV arm, 25 on the AVO arm and 21 on the chemoimmunotherapy arm. The regimens were generally well tolerated. The most common adverse event was neutropenia, but febrile neutropenia on the investigation arms was rare. Overall SAE rate was only 25% with AV, 38% with AVO. Cardiac events were seen in about 10% of patients on the acalabrutinib containing arms. But atrial fibrillation was rare, only 1% to 2%. Hypertension was seen in about 4% of the acalabrutinib containing arms, but 3% with the chemoimmunotherapy. So in summary, AMPLIFY is a phase three registration trial for the combination of the second generation BTK inhibitor, acalabrutinib with venetoclax, with or without obinutuzumab, and it met its primary endpoint and also showed progression-free survival benefit for the triple drug regimen compared to chemoimmunotherapy. And so we look forward to this regimen potentially becoming available in the United States in the coming year.