Oral CLL Combination Seeks FDA Approval for Untreated Patients

Venetoclax and Acalabrutinib Show Promising Progression-Free Survival in Pivotal Trial

A significant advancement in the treatment of chronic lymphocytic leukemia (CLL) is on the horizon as developers submit a new drug application to the FDA for a fixed-duration, oral combination of venetoclax (Venclexta) and acalabrutinib (Calquence) for those newly diagnosed with the blood cancer.

AMPLIFY Trial Data Drives Submission

The submission is underpinned by robust data from the phase 3 AMPLIFY trial. The combination therapy demonstrated a notable advantage in progression-free survival (PFS) compared to traditional chemoimmunotherapy regimens. Findings published in the New England Journal of Medicine revealed that at 36 months, the PFS rate for the venetoclax/acalabrutinib combination reached 76.5%, outperforming the 66.5% achieved with chemoimmunotherapy.

Further analysis of the AMPLIFY trial data indicated a substantial improvement in overall survival rates. The estimated 36-month overall survival rates were 94.1% for the venetoclax and acalabrutinib group, versus 85.9% for the chemoimmunotherapy arm. The trial also reported a 36-month event-free survival (EFS) of 75.9% for the novel combination compared to 64.5% for the standard treatment.

Response rates also favored the venetoclax-based regimen, with an overall response rate (ORR) of 92.8% observed compared to 75.2% with chemoimmunotherapy. Intriguingly, 28.1% of patients on the venetoclax arm experienced disease progression after an initial response, a slightly lower rate than the 33.9% seen in the chemoimmunotherapy group.

“This FDA submission marks a milestone for CLL treatment with the potential approval for the first oral combination regimen of [venetoclax] and acalabrutinib for [patients with] previously untreated chronic blood cancer. This new fixed-treatment duration approach could allow patients the opportunity for time off treatment, if approved, and be potentially practice-changing in frontline CLL care.”

—Svetlana Kobina, MD, Vice President of Global Medical Affairs, Oncology at AbbVie

Trial Design and Patient Demographics

Patients participating in the AMPLIFY trial were randomly assigned to one of three groups: venetoclax/acalabrutinib, acalabrutinib/venetoclax/obinutuzumab (Gazyva), or investigator’s choice of chemoimmunotherapy. Participants were stratified based on age, IGHV mutational status, Rai stage, and geographic region.

The study involved 291 patients in the venetoclax/acalabrutinib arm, 286 in the acalabrutinib/venetoclax/obinutuzumab arm, and 290 in the chemoimmunotherapy arm. The median age across the venetoclax/acalabrutinib and chemoimmunotherapy groups was 61 years. The patient populations were generally similar, with most being male, treated in Europe, having an ECOG performance score of 0 or 1, and unmutated IGHV status.

The primary endpoint of the AMPLIFY trial was PFS, assessed by blinded independent central review. Key secondary endpoints included undetectable minimal residual disease, EFS, ORR, complete response rate with incomplete marrow recovery, duration of response, and safety.

Safety Profile Supports New Application

The safety profiles of the treatment arms were also detailed, with 92.8% of patients in the venetoclax/acalabrutinib group experiencing any grade of adverse effects (AEs), compared to 91.1% in the chemoimmunotherapy group. Grade 3 AEs were reported in 53.6% of the combination arm versus 60.6% in the chemoimmunotherapy arm. Serious AEs occurred in 24.7% versus 27.4%, respectively.

The most frequent AEs in the venetoclax/acalabrutinib arm included neutropenia, hemorrhage, and COVID-19 infection. Tumor lysis syndrome was notably observed in a significantly lower percentage of patients in this arm (0.3%) compared to the chemoimmunotherapy group (3.1%). Importantly, no new safety concerns were identified during the trial.

This potential new treatment option could offer a convenient, oral, fixed-duration therapy for newly diagnosed CLL patients, providing a different approach to managing this chronic leukemia. The FDA’s decision on the supplemental new drug application is anticipated to have a significant impact on frontline CLL treatment protocols.

For context, in 2023, approximately 21,320 new cases of CLL were diagnosed in the United States, according to the American Cancer Society (American Cancer Society, 2024).