Fixed-Duration Acalabrutinib Plus Venetoclax Beats Chemoimmunotherapy in First-Line CLL; Adding Obinutuzumab Boosts PFS

A fixed-duration schedule of acalabrutinib (Calquence, AstraZenca) plus venetoclax (Venclexta, AbbVie) offered better outcomes than chemoimmunotherapy for patients with newly diagnosed chronic lymphocytic leukemia (CLL).

Adding obinutuzumab (Gazyva) to acalabrutinib and venetoclax offered even better results, according to results from the phase 3 AMPLIFY trial (NCT03836261) presented Monday at the 66th American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.¹

Led by Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, the study is the first to evaluate a fixed-duration regimen of venetoclax, the first-generation BCL2 inhibitor, with a second-generation Bruton tyrosine kinase (BTK) inhibitor, acalabrutinib. Although combinations involving BTK inhibitors and venetoclax—with and without obinutuzumab—have been studied, the concept of a fixed-duration schedule in newly diagnosed CLL has appeal, given how long many patients may live with the disease.

Jennifer R. Brown, MD, PhD | Image credit: DFCI

“Chronic lymphocytic leukemia is considered an incurable cancer, and patients live with the disease and the long-term effects of their treatments for many years,” Brown said in a statement. “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.”²

Besides the appeal for patients, there may be interest among payers on limiting CLL treatment costs with fixed-duration regimens. A study in the Journal of Managed Care Specialty Pharmacy that appeared this fall found that although costs for a venetoclax-obinutuzumab combination were comparable to a BTK inhibitor for months 1 to12, the venetoclax combo achieved 67% savings in total costs over the next 6 months.³

With combinations involving both BTK inhibitors and venetoclax in front-line treatment becoming standard of care, total costs may matter more.

Patients in AMPLIFY were newly diagnosed adults at least 18 years of age with ECOG status of 2 or less and no deletion (17p) or TP53 mutations, which Brown said was a “typical” CLL population.³ Patients were randomized 1:1:1 to receive either acalabrutinib and venetoclax, acalabrutinib, venetoclax and obituzumumab, or investigator’s choice of chemoimmunotherapy (either fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab).

For those in the investigational arm taking all 3 drugs, acalabrutinib was given in the first month, followed by obinutuzumab the second month, with venetoclax added the third month.

The primary end point was progression-free survival (PFS), as determined by blinded independent central review of the acalabrutinib-venetoclax arm in the intent-to-treat population compared with chemoimmunotherapy; comparisons with the addition of obinutuzumab were secondary end points. Results showed the following:

• 867 were randomized, with 291 taking acalabrutinib and venetoclax; 286 taking acalabrutinib, venetoclax, and obinutuzumab; and 290 taking chemoimmunotherapy.
• Median age was 61 years; the population was 64.5% male, and 58.6% had unmutated IGHV.
• At a median follow-up of 41 months, both investigational arms showed a statistically significant improvement in PFS over chemoimmunotherapy, with an estimated 36-month PFS rate of 76.5% for acalabrutinib plus venetoclax and 83.1% for acalabrutinib, venetoclax, and obinutuzumab; compared with 66.5% for chemoimmunotherapy.
• The arm with acalabrutinib and venetoclax showed a 35% improvement in PFS over the control arm (HR, 0.65; P = .0038), while the arm that added in obinutuzumab had a 58% improvement in PFS (HR, 0.42; P < .0001).
• Overall response rate as assessed by central review was 92.8% for acalabrutinib and venetoclax (95% CI, 89.4-95.4) and 92.7% when adding obinutuzumab (95% CI, 89.2-95.3) compared with 75.2% for chemoimmunotherapy (95% CI, 70.0–79.9).
• Overall survival (OS) data were significantly affected by COVID-19, but data were trending in favor of the investigational arms compared with the chemoimmunotherapy arms; for acalabrutinib and venetoclax, the HR was 0.33 (95% CI, 0.18-0.56; P < .0001); for the acalabrutinib, venetoclax, and obinutuzumab arm, the OS HR was 0.76 (95% CI, 0.49-1.18; P = .2224). Before the cutoff of April 30, 2024, deaths in each arm were 18, 37, and 42 patients, respectively. Included in that number are 10, 25, and 21 deaths related to COVID-19.

Adverse events (AEs) of grade 3 or higher included neutropenia across all arms: 26.8%, 35.2%, and 32.4%, respectively. Other AEs included tumor lysis syndrome, a known side effect of venetoclax, atrial fibrillation, and hypertension. Serious AEs were seen in 24.7%, 38.4%, and 27.4% of each arm, respectively.

Rates of undetectable minimal residual disease (MRD) were highest among the patients who received obinutuzumab in their regimen. Patients evaluated at the end of therapy had MRD rates of 45.0%, 95.0% in the triplet arm, and 72.9%, respectively, all to 10^–4.

“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. Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA. Abstract 1009.
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. News release. AstraZeneca. December 8, 2024. Accessed December 10, 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
3. Huntington SF, Manzoor BS, Dureshahwar J, et al. Real-world comparison of health care costs of venetoclax-obinutuzumab vs Bruton's tyrosine kinase inhibitor use among US Medicare beneficiaries with chronic lymphocytic leukemia in the frontline setting. J Manag Care Spec Pharm. 2024;30(10):1106-1116. doi:10.18553/jmcp.2024.24049