Combining Calquence (acalabrutinib) with Venclexta (venetoclax), with or without Gazyva (obinutuzumab), significantly increased progression-free survival for patients with untreated chronic lymphocytic leukemia (CLL), regardless of their IGHV mutational status, compared to standard chemotherapy and immunotherapy, according to data from a phase 3 trial presented at the 2024 ASH Annual Meeting.
At a median follow-up of 40.8 months, the median progression-free survival (PFS) was not reached with Calquence plus Venclexta (AV) and Calquence plus Venclexta and Gazyva (AVO) groups, and was 47.6 months with investigator’s choice of fludarabine plus cyclophosphamide and Rituxan (rituximab; FCR) or bendamustine plus Rituxan (BR). Treatment with the doublet regimen reduced the risk of disease progression or death by 35% and the triplet reduced this risk by 58%. The estimated 36-month PFS rates with Calquence plus Venclexta, with or without Gazyva, respectively, were 83.1% and 76.5%, compared with 66.5% with standard-of-care (SOC) chemoimmunotherapy.
“AMPLIFY provides the first phase 3 evidence of fixed duration therapy with a combination of [Venclexta] and a second generation BTK inhibitor in patients with treatment-naive CLL,” Dr. Jennifer R. Brown, 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 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 evenly to receive one of the following regimens:
- Oral Calquence at 100 milligrams (mg) twice daily for cycles 1 to 14 plus oral Venclexta daily with a five-week dose ramp-up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg for cycles 3 to 14
- The same Calquence and Venclexta dosing plus intravenous Gazyva 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
Additional efficacy findings showed that PFS was improved with Calquence plus Venclexta, with or without Gazyva, regardless of IGHV status.
“Particularly noticeable is the fact that in the [triplet] group, 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 [Gazyva] may overcome the adverse impact of unmutated IGHV,” Brown explained.
Further, investigators found the highest rate of undetectable minimal residual disease (uMRD) among those who received the regimen with Gazyva. Of the patients who were evaluable at end of therapy, uMRD rates at a sensitivity level 10-4 in the peripheral blood were 45% in the doublet group, 95% in the triplet group and 72.9% in the investigators’ choice group.
The 36-month OS rates with the doublet, triplet, and FCR/BR regimens were 94.1%, 87.7% and 85.9%, respectively. “Of note, the study was conducted at the height of the pandemic, and COVID-19 deaths were seen in 10 patients on the [doublet] group, 25 on the [triplet] group and 21 on the chemoimmunotherapy group,” Brown explained. Therefore, after pre-planned censoring, the adjusted rates were 97.5%, 96.2% and 93.7%, respectively.
The most common grade 3 (severe) or worse side effect (AE) was neutropenia, low white blood cell count, occurring in 26.8% of those who received the AV regimen (291 patients), 35.2% of those given AVO (284 patients) and 32.4% of those given FCR/BR (259 patients). 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 Venclexta and Imbruvica (ibrutinib); however, Brown noted that despite deep and durable responses, cardiac toxicity remains. When evaluating AEs of interest, 9.3% and 12% of patients in the doublet and triplet groups experienced a cardiac event, compared with 3.5% of those in the FCR/BR group; grade 3 or worse cardiac events occurred in 1.7%, 2.5% and 1.2% of patients, respectively. However, rates of grade 3 or worse atrial fibrillation (0.3% versus 0.7% versus 0.8%, respectively) and hypertension (2.7% versus 2.1% versus 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 two or the three-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, Oncology R&D, AstraZeneca, stated in a press release on the data. “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.”
Reference:
“Fixed-duration Calquence plus Venclexta with or without Gazyva Versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial.” By Dr. Jennifer R. Brown, et al., Blood.
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