AMPLIFY Data Reveals Advantages of All-Oral BTKi Therapy is Treatment-Naïve CLL

In the phase 3 AMPLIFY study, the survival advantage and deep and durable responses of fixed-duration acalabrutinib plus venetoclax (AV) in fit patients with treatment-naive chronic lymphocytic leukemia (CLL) provide evidence that an all-oral regimen is effective for treatment of this patient population, according to Jennifer R. Brown, MD, of Dana-Farber Cancer Institute. Boston, Massachusetts.¹

Results presented at the 66^th American Society of Hematology Annual Meeting & Exposition by Dr. Brown and colleagues showed that significant improvement in progression-free survival (PFS) was achieved with AV with or without obinutuzumab compared to physician’s choice of either acalabrutinib with venetoclax and obinutuzumab (AVO) or chemoimmunotherapy consisting of fludarabine-cyclophosphamide-rituximab (FCR) or bendamustine plus rituximab (BR).

The basis of this research, according to Dr. Brown et al,¹ is providing a safer option for fit patients with treatment-naive CLL. Although multiple Bruton tyrosine kinase inhibitors (BTKi) are approved for treatment-naive CLL, cardiotoxicity is a major concern with venetoclax and ibrutinib. In a prior noninferiority study, acalabrutinib, a highly selective BTKi, was proven to be safer and more tolerable than ibrutinib.²

In AMPLIFY, 877 patients aged 18 years and older with treatment-naive CLL, without del(17p) or a TP53 mutation were enrolled. Patients were required to have a performance score of 2 or lower. Stratified by age, IGHV mutational status, Rai stage, and geographic location, patients were assessed for the primary endpoints of progression-free survival (PFS), PFS by independent review committee (IRC), undetectable minimal residual disease (uMRD), and overall survival (OS).¹

PFS of AV was compared with FCR or BR, and for IRC-PFS, investigators looked at AVO versus FCR and BR. In terms of uMRD, both AV and AVO were assessed in comparison with FCR and BR. Finally, for OS, investigators evaluated AV versus FCR and BR and AVO versus FCR and BR. Acalabrutinib was administered orally at 100 mg once daily (QD) and twice per day (BID) during cycles 1 to 14. Oral venetoclax was administered at 400 mg QD and BID during cycles 1 to 14, and obinutuzumab 100 mg was sometimes administered via intravenous infusion to patients during cycles 2 to 7.

According to IRC assessment, the median PFS was not reached in the AV treatment arm versus 47.6 months in the FCR or BR arm (HR, 0.65; 95% CI, 0.49-0.87; P=.0038). When AVO was compared with FCR or BR, the median PFS was also not reached with AVO (HR, 0.42; 0.30-0.59; P<.001).

In the subgroup without mutations in IGHV, the median PFS was 51.5 months with AV and not reached with AVO versus 43.4 months with FCR or BR, with HRs of 0.69 (95% CI, 0.48-0.97) and 0.35 (95% CI, 0.23-0.53), respectively. In the uMRD subgroup, median PFS at end of treatment was not reached in the AV and AVO arms; PFS was 49.2 months in the FCR and BR arm, showing HRs of 0.43 (95% CI, 0.24-0.76) and 0.27 (95% CI, 0.16-0.46), respectively.

Compared to treatment with FCR or BR, treatment with AV prolonged OS for fit patients with treatment-naive CLL (HR, 0.33; 95% CI, 0.18-0.56). An OS advantage was also demonstrated with AVO versus FCR or BR (HR, 0.76; 95% CI, 0.49-1.16).

Dr. Brown noted during her presentation that death was a major cause of treatment discontinuation. Fifty-six deaths in the study were related to COVID-19. Other safety data showed that adverse events (AEs) of any grade occurred in 92.8% of the AV arm, 94.7% of the AVO arm, and 91.1% of the FCR or BR arm; grade 3 and higher AEs occurred in 53.6%, 69.4%, and 60.6%, respectively. Serious AEs were observed in 24.7% of the AV arm, 38.4% of the AVO arm, and 27.4% of the FCR or BR arm. Overall, 12.9% of patients in the study had serious AEs leading to death, and 38.8% experienced an AE leading to treatment discontinuation.

The AEs of clinical interest in the study were cardiac events including atrial fibrillation and ventricular tachyarrhythmias. Hypertension, major hemorrhage, neutropenia, and infection were also seen in a significant number of patients and deemed AEs of clinical interest. Notably, cardiac event remained low in both the AV and AVO arms, according to Dr. Brown et al.

References

 

1. Brown J, Seymour J, 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. Abstract #1009. Presented at the 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, California.
2. Byrd J, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31). doi: 10.1200/JCO.21.01210