Fixed-Duration Acalabrutinib/Venetoclax Combo Improves PFS in Frontline CLL

Treatment with acalabrutinib (Calquence) plus venetoclax (Venclexta), with or without obinutuzumab (Gazyva), significantly improved progression-free survival (PFS), regardless of IGHV mutational status, compared with standard-of-care (SOC) chemoimmunotherapy in patients with treatment-naive chronic lymphocytic leukemia (CLL), according to data from an interim analysis of the phase 3 AMPLIFY trial (NCT03836261) presented at the 2024 ASH Annual Meeting.1,2

At a median follow-up of 40.8 months, the median progression-free survival (PFS) was not reached by blinded independent central review (BICR) with acalabrutinib plus venetoclax (AV) and acalabrutinib plus venetoclax and obinutuzumab (AVO) arms and was 47.6 months with investigator’s choice of fludarabine plus cyclophosphamide and rituximab (Rituxan; FCR) or bendamustine plus rituximab (BR). Treatment with the doublet regimen reduced the risk of disease progression or death by 35% (HR, 0.65; 95% CI, 0.49-0.87; P = .0038), and the triplet reduced this risk by 58% (HR, 0.42; 95% CI, 0.30-0.59; P < .0001). The estimated 36-month PFS rates with acalabrutinib plus venetoclax, with or without obinutuzumab, respectively, were 83.1% and 76.5%, compared with 66.5% with SOC chemoimmunotherapy.

“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,” Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School in Boston, said during a press briefing at the meeting.

The randomized, multicenter, open-label, phase 3 AMPLIFY study enrolled patients with treatment-naive CLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia 2018 criteria who are at least 18 years of age and whose tumors are without del(17p) or TP53 mutations. Patients were required to have an ECOG performance status of 2 or lower. Patients were excluded from the trial if they had a Cumulative Illness Rating Scale-Geriatric of over 6 or if they had significant cardiovascular disease.

A total of 867 patients were randomized 1:1:1 to receive one of the following regimens:

• Oral acalabrutinib at 100 mg twice daily for cycles 1 to 14 plus oral venetoclax daily with a 5-week dose ramp-up of 20 mg, 50 mg, 100 mg, 200 mg, and 400 mg for cycles 3 to 14
• The same acalabrutinib and venetoclax dosing plus intravenous obinutuzumab at 1000 mg for days 1, 8, and 15 of cycle 2 and day 1 of cycles 3 to 7
• Investigator’s choice of FCR or BR per standard dosing protocol for cycles 1 to 6

Crossover between arms was not allowed. Patients were stratified by age (older than 65 years vs 65 years or younger), IGHV mutational status, Rai stage (3 or higher vs less than 3), and geographic region.

BICR-assessed PFS of the acalabrutinib/venetoclax regimen vs SOC chemoimmunotherapy, served as the primary end point. Brown noted that if the primary end point was met, secondary end points would be tested in the following fixed, sequential hierarchy: BICR-assessed PFS of the triplet regimen vs FCR/BR; undetectable minimal residual disease (uMRD) with the doublet vs FCR/BR, uMRD with the triplet vs FCR/BR, and overall survival (OS) of the doublet followed by the triplet regimen, both compared with FCR/BR. There were no plans to compare outcomes between the doublet and triplet regimens, according to Brown.

Additional efficacy findings showed that 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 hazard ratios (HRs) for PFS with AV vs FCR/BR in patients with mutated and unmutated IGHV status were 0.67 (95% CI, 0.39-1.14) and 0.69 (95% CI, 0.48-0.97), respectively. The HRs for PFS with AVO vs FCR/BR in patients with mutated and unmutated IGHV status were 0.58 (95% CI, 0.32-1.02) and 0.35 (95% CI, 0.23-0.53), respectively.

Further, investigators found the highest rate of uMRD among those who received the regimen with obinutuzumab. Of the patients who were evaluated at end of therapy, uMRD rates at a sensitivity level 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.

The 36-month 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). “Of note, the study was conducted at the height of the pandemic, and COVID-19 deaths were seen in 10 patients on the [doublet] arm, 25 on the [triplet] arm, and 21 on the chemoimmunotherapy arm,” Brown explained. Therefore, after pre-planned censoring, the adjusted rates were 97.5%, 96.2%, and 93.7%, respectively. The HRs for OS with AV or AVO vs FCR/BR were 0.27 (95% CI, 0.11-0.60) and 0.47 (95% CI, 0.22-0.95), respectively.

The most common grade 3 or higher adverse effect (AE) was neutropenia, occurring in 26.8% of those who received the AV regimen (n = 291), 35.2% of those given AVO (n = 284), and 32.4% of those given FCR/BR (n = 259). Serious AEs were seen in 24.7%, 38.4%, and 27.4% of patients, respectively.

Patients with treatment-naive CLL have a variety of options, such as a fixed-duration regimen of venetoclax and ibrutinib (Imbruvica); however, Brown noted that despite deep and durable responses, cardiac toxicity remains. When evaluating AEs of interest, 9.3% and 12.0% of patients in the doublet and triplet arms experienced a cardiac event, compared with 3.5% of those in the FCR/BR arm; grade 3 or higher cardiac events occurred in 1.7%, 2.5%, and 1.2% of patients, respectively. However, rates of grade 3 or higher atrial fibrillation (0.3% vs 0.7% vs 0.8%, respectively) and hypertension (2.7% vs 2.1% vs 0.7%) remained low.

Of note, Brown acknowledged that the study was limited by the control group treatment regimen no longer being considered the SOC, which occurred after the trial began in 2019. “I think when physicians are considering whether to use the 2 or the 3-drug regimen, they have to take account of the patient in front of them,” she concluded.

“Based on these impressive data from the AMPLIFY trial, Calquence is only the second-generation BTK inhibitor to demonstrate efficacy in the front-line treatment of patients with chronic lymphocytic leukemia as both a treat-to-progression and a fixed-duration approach,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in a news release on the data.2 “This advance is an important development for patients and their physicians who seek new options and more flexibility in managing this disease in the long term.”

References

1. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab Versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. Blood. 2024;144(suppl 1):1009. doi:10.1182/blood-2024-200701
2. Fixed-duration Calquence plus venetoclax demonstrated superior PFS vs. standard of care in previously untreated CLL, with 77% of patients progression free at three years in AMPLIFY Phase III trial. AstraZeneca. December 8, 2024. Accessed: December 8, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/fixed-duration-calquence-plus-venetoclax-demonstrated-superior-pfs-vs-standard-care-previously-untreated-cll-with-77-of-patients-progression-free-3-years-amplify-phase-iii-trial.html