AstraZeneca's Calquence (acalabrutinib) in combination with venetoclax has demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care chemoimmunotherapy in previously untreated adult patients with chronic lymphocytic leukemia (CLL). The positive results from the AMPLIFY Phase III trial, which will be presented at the American Society of Hematology (ASH) 2024 Annual Meeting, highlight the potential of this all-oral, fixed-duration regimen to transform the treatment landscape for CLL.
At a median follow-up of 41 months, the Calquence plus venetoclax combination reduced the risk of disease progression or death by 35% compared to chemoimmunotherapy (HR 0.65; 95% CI 0.49-0.87; p=0.0038). The addition of obinutuzumab to Calquence and venetoclax resulted in an even greater reduction in risk, with a 58% decrease compared to standard chemoimmunotherapy (HR 0.42; 95% CI 0.30-0.59; p<0.0001). Median PFS was not reached for either experimental arm, while the chemoimmunotherapy arm had a median PFS of 47.6 months.
Durable Responses and Overall Survival
The investigational arms demonstrated durable responses, with estimated 36-month PFS rates of 76.5% for Calquence plus venetoclax and 83.1% for Calquence plus venetoclax with obinutuzumab, compared to 66.5% for chemoimmunotherapy. Patients in both investigational arms also showed robust overall response rates (ORR) of 92.8% and 92.7%, respectively, versus 75.2% for chemoimmunotherapy.
Interim overall survival (OS) data showed a favorable trend for Calquence plus venetoclax (HR 0.33; 95% CI 0.18-0.56; p<0.0001), though the data were immature at the time of analysis. The trial will continue to assess OS as a key secondary endpoint.
Expert Commentary
Jennifer R. Brown, MD, PhD, Director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, and principal investigator of the trial, noted, “Chronic lymphocytic leukaemia is considered an incurable cancer, and patients live with the disease and the long-term effects of their treatments for many years. The AMPLIFY results show the promise of a new all-oral fixed-duration therapy approach which would allow patients to take breaks from treatment, reducing the risk of long-term adverse events and drug resistance.”
Safety and Tolerability
The safety and tolerability of Calquence were consistent with its known safety profile, and no new safety signals were identified. Grade 3 or higher adverse events (AEs) occurred in 53.6% of patients treated with Calquence plus venetoclax, 69.4% of patients treated with Calquence plus venetoclax with obinutuzumab, and 60.6% for patients treated with standard-of-care chemoimmunotherapy. The most common Grade 3 or higher AE was neutropenia across all arms.
Notably, low rates of tumor lysis syndrome (TLS) were observed in both Calquence arms, with events of any grade seen in 0.3% of patients treated with Calquence plus venetoclax and 0.4% with the addition of obinutuzumab, compared to 3.1% for patients treated with chemoimmunotherapy. No cases of clinical TLS were observed across Calquence treatment arms.
About the AMPLIFY Trial
The AMPLIFY trial is a randomized, global, multi-center, open-label Phase III trial evaluating the efficacy and safety of Calquence in combination with venetoclax with and without obinutuzumab compared to investigator's choice of chemoimmunotherapy in adult patients with previously untreated CLL without del(17p) or TP53 mutation. Patients were randomized 1:1:1 to receive either Calquence plus venetoclax, Calquence plus venetoclax with obinutuzumab for a fixed duration, or standard-of-care chemoimmunotherapy. Both Calquence-containing arms were administered for a fixed duration of 14 cycles (each 28 days), and the standard-of-care chemoimmunotherapy was for 6 cycles. The primary endpoint is PFS in the Calquence and venetoclax arm, as assessed by an Independent Review Committee, and PFS in the Calquence plus venetoclax with obinutuzumab is a key secondary endpoint. Other key secondary endpoints include OS and undetectable measurable residual disease.
