The phase 3 AMPLIFY trial, presented at the 2024 American Society of Hematology (ASH) Annual Meeting, reveals that a fixed-duration regimen of acalabrutinib (Calquence) plus venetoclax (Venclexta), with or without obinutuzumab (Gazyva), significantly improves progression-free survival (PFS) compared to standard chemoimmunotherapy in patients with treatment-naive chronic lymphocytic leukemia (CLL). This all-tablet approach offers a promising alternative to traditional chemotherapy, potentially reducing toxicity and improving patient quality of life.
Superior Progression-Free Survival
At a median follow-up of 40.8 months, the median PFS was not reached in the acalabrutinib plus venetoclax (AV) and acalabrutinib plus venetoclax and obinutuzumab (AVO) arms, while it was 47.6 months in the chemoimmunotherapy arm. The doublet regimen (AV) reduced the risk of disease progression or death by 35% (HR, 0.65; 95% CI, 0.49-0.87; P = .0038), and the triplet (AVO) reduced this risk by 58% (HR, 0.42; 95% CI, 0.30-0.59; P < .0001). The estimated 36-month PFS rates for AV and AVO were 83.1% and 76.5%, respectively, compared to 66.5% for chemoimmunotherapy.
Jennifer R. Brown, MD, PhD, from Dana-Farber Cancer Institute, highlighted that "AMPLIFY provides the first phase 3 evidence of fixed duration therapy with a combination of venetoclax and a second generation BTK inhibitor in patients with treatment-naive CLL."
Trial Design and Patient Population
The AMPLIFY trial enrolled 867 patients with treatment-naive CLL, excluding those with del(17p) or TP53 mutations. Patients were randomized 1:1:1 to receive:
- Acalabrutinib 100 mg orally twice daily for cycles 1-14 plus venetoclax daily with a 5-week dose ramp-up from 20 mg to 400 mg for cycles 3-14.
- The same acalabrutinib and venetoclax dosing plus obinutuzumab 1000 mg intravenously on days 1, 8, and 15 of cycle 2 and day 1 of cycles 3-7.
- Investigator's choice of fludarabine plus cyclophosphamide and rituximab (FCR) or bendamustine plus rituximab (BR) for cycles 1-6.
The primary endpoint was BICR-assessed PFS of the acalabrutinib/venetoclax regimen vs. chemoimmunotherapy.
Impact of IGHV Status and MRD
PFS was improved with acalabrutinib plus venetoclax, with or without obinutuzumab, regardless of IGHV status. "Particularly noticeable is the fact that in the [triplet] arm, those patients with unmutated IGHV [36-month PFS rate, 82.8%] are doing as well as those with mutated IGHV [36-month PFS rate, 83.6%], suggesting that the addition of obinutuzumab may overcome the adverse impact of unmutated IGHV," Brown explained.
The highest rate of undetectable minimal residual disease (uMRD) was observed in the triplet arm. At the end of therapy, uMRD rates at a sensitivity level of 10^-4 in the peripheral blood were 45.0% in the doublet arm, 95.0% in the triplet arm, and 72.9% in the FCR/BR arm.
Overall Survival and Safety
The 36-month overall survival (OS) rates with the doublet, triplet, and FCR/BR regimens were 94.1%, 87.7%, and 85.9%, respectively. The HR for OS with AV vs FCR/BR was 0.33 (95% CI, 0.18-0.56); with AVO vs FCR/BR, the HR for OS was 0.76 (95% CI, 0.48-1.18). After censoring for COVID-19 deaths, the adjusted rates were 97.5%, 96.2%, and 93.7%, respectively.
The most common grade 3 or higher adverse event was neutropenia, occurring in 26.8% of those who received AV, 35.2% of those given AVO, and 32.4% of those given FCR/BR. Cardiac events were infrequent, with low rates of atrial fibrillation and hypertension.
Implications for CLL Treatment
The AMPLIFY trial demonstrates that fixed-duration acalabrutinib and venetoclax, with or without obinutuzumab, can achieve deep, durable responses while avoiding the cumulative toxicities of chemoimmunotherapy. This advance offers a new, all-oral option for managing CLL, providing patients with more flexibility and a better quality of life. Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, noted that Calquence is the second-generation BTK inhibitor to demonstrate efficacy in the front-line treatment of CLL as both a treat-to-progression and a fixed-duration approach.
